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Sample records for fluoxetine potentiates methylphenidate-induced

  1. Therapeutic potential of fluoxetine in neurological disorders

    NARCIS (Netherlands)

    Mostert, Jop P.; Koch, Marcus W.; Heerings, Marco; Heersema, Dorothea J.; De Keyser, Jacques

    2008-01-01

    The selective serotonin reuptake inhibitor (SSRI) fluoxetine, which is registered for a variety of psychiatric disorders, has been found to stimulate the cAMP-responsive element binding protein (CREB), increase the production of brain-derived neurotrophic factor (BNDF) and the neurotrophic peptide

  2. Fluoxetine potentiation of omega-3 fatty acid antidepressant effect: evaluating pharmacokinetic and brain fatty acid-related aspects in rodents.

    Science.gov (United States)

    Laino, Carlos Horacio; Garcia, Pilar; Podestá, María Fernanda; Höcht, Christian; Slobodianik, Nora; Reinés, Analía

    2014-10-01

    We previously reported that combined fluoxetine administration at antidepressant doses renders additive antidepressant effects, whereas non-antidepressant doses potentiate the omega-3 fatty acid antidepressant effect. In the present study, we aimed to evaluate putative pharmacokinetic and brain omega-3 fatty acid-related aspects for fluoxetine potentiation of omega-3 fatty acid antidepressant effect in rats. Coadministration of omega-3 fatty acids with a non-antidepressant dose of fluoxetine (1 mg/kg day) failed to affect both brain fluoxetine concentration and norfluoxetine plasma concentration profile. Fluoxetine plasma concentrations remained below the sensitivity limit of the detection method. Either antidepressant (10 mg/kg day) or non-antidepressant (1 mg/kg day) doses of fluoxetine in combination with omega-3 fatty acids increased hippocampal docosapentaenoic acid (DPA, 22:5 omega-3) levels. Although individual treatments had no effects on DPA concentration, DPA increase was higher when omega-3 were combined with the non-antidepressant dose of fluoxetine. Chronic DPA administration exerted antidepressant-like effects in the forced swimming test while increasing hippocampal docosahexaenoic (22:6 omega-3) and DPA levels. Our results suggest no pharmacokinetic interaction and reveal specific hippocampal DPA changes after fluoxetine and omega-3 combined treatments in our experimental conditions. The DPA role in the synergistic effect of fluoxetine and omega-3 combined treatments will be for sure the focus of future studies. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3316-3325, 2014. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

  3. Fluoxetine, a selective inhibitor of serotonin uptake, potentiates morphine analgesia without altering its discriminative stimulus properties or affinity for opioid receptors

    International Nuclear Information System (INIS)

    Hynes, M.D.; Lochner, M.A.; Bemis, K.G.; Hymson, D.L.

    1985-01-01

    The analgesic effect of morphine in the rat tail jerk assay was enhanced by the serotonin uptake inhibitor, fluoxetine. Tail jerk latency was not affected by fluoxetine alone. Morphine's affinity for opioid receptors labeled in vitro with 3 H-naloxone or 3 H-D-Ala 2 -D-Leu 5 -enkephalin was not altered by fluoxetine, which has no affinity for these sites at concentrations as high as 1000 nM. In rats trained to discriminate morphine from saline, fluoxetine at doses of 5 or 10 mg/kg were recognized as saline. Increasing the fluoxetine dose to 20 mg/kg did not result in generalization to either saline or morphine. The dose response curve for morphine generalization was not significantly altered by fluoxetine doses of 5 or 10 mg/kg. Those rats treated with the combination of morphine and 20 mg/kg of fluoxetine did not exhibit saline or morphine appropriate responding. Fluoxetine potentiates the analgesic properties of morphine without enhancing its affinity for opioid receptors or its discriminative stimulus properties. 30 references, 2 figures, 2 tables

  4. A possible participation of transient receptor potential vanilloid type 1 channels in the antidepressant effect of fluoxetine.

    Science.gov (United States)

    Manna, Shyamshree S S; Umathe, Sudhir N

    2012-06-15

    The present study investigated the influence of transient receptor vanilloid type 1 (TRPV1) channel agonist (capsaicin) and antagonist (capsazepine) either alone or in combination with traditional antidepressant drug, fluoxetine; or a serotonin hydroxylase inhibitor, para-chlorophenylalanine; or a glutamate N-methyl-D-aspartate (NMDA) receptor agonist, NMDA on the forced swim test and tail suspension test using male Swiss mice. Results revealed that intracerebroventricular injections of capsaicin (200 and 300 μg/mouse) and capsazepine (100 and 200 μg/mouse) reduced the immobility time, exhibiting antidepressant-like activity that was comparable to the effects of fluoxetine (2.5-10 μg/mouse) in both the tests. However, in the presence of inactive dose (10 μg/mouse) of capsazepine, capsaicin (300 μg/mouse) had no influence on the indices of both tests, signifying that the effects are TRPV1-mediated. Further, the antidepressant-like effects of both the TRPV1 ligands were neutralized in mice-pretreated with NMDA (0.1 μg/mouse), suggestive of the fact that decreased glutamatergic transmission might contribute to the antidepressant-like activity. In addition, co-administration of sub-threshold dose of capsazepine (10 μg/mouse) and fluoxetine (1.75 μg/mouse) produced a synergistic effect in both the tests. In contrast, inactive doses of capsaicin (10 and 100 μg/mouse) partially abolished the antidepressant effect of fluoxetine (10 μg/mouse), while its effect was potentiated by active dose of capsaicin (200 μg/mouse). Moreover, pretreatment of mice with para-chlorophenylalanine (300 mg/kg/day × 3 days, i.p.) attenuated the effects of capsaicin and capsazepine, demonstrating a probable interplay between serotonin and TRPV1, at least in parts. Thus, our data indicate a possible role of TRPV1 in depressive-like symptoms. Copyright © 2012 Elsevier B.V. All rights reserved.

  5. Potentiation of omega-3 fatty acid antidepressant-like effects with low non-antidepressant doses of fluoxetine and mirtazapine.

    Science.gov (United States)

    Laino, Carlos Horacio; Fonseca, Cristina; Sterin-Speziale, Norma; Slobodianik, Nora; Reinés, Analía

    2010-12-01

    Despite the advances in psychopharmacology, the treatment of depressive disorders is still not satisfactory. Side effects and resistance to antidepressant drugs are the greatest complications during treatment. Based on recent evidence, omega-3 fatty acids may influence vulnerability and outcome in depressive disorders. The aim of this study was to further characterize the omega-3 antidepressant-like effect in rats in terms of its behavioral features in the depression model forced swimming test either alone or in combination with antidepressants fluoxetine or mirtazapine. Ultimately, we prompted to determine the lowest dose at which omega-3 fatty acids and antidepressant drugs may still represent a pharmacological advantage when employed in combined treatments. Chronic diet supplementation with omega-3 fatty acids produced concentration-dependent antidepressant-like effects in the forced swimming test displaying a behavioral profile similar to fluoxetine but different from mirtazapine. Fluoxetine or mirtazapine at antidepressant doses (10 and 20 mg/kg/day, respectively) rendered additive effects in combination with omega-3 fatty acid supplementation (720 mg/kg/day). Beneficial effects of combined treatment were also observed at sub-effective doses (1 mg/kg/day) of fluoxetine or mirtazapine, since in combination with omega-3 fatty acids (720 mg/kg/day), antidepressants potentiated omega-3 antidepressant-like effects. The antidepressant-like effects occurred in the absence of changes in brain phospholipid classes. The therapeutic approach of combining omega-3 fatty acids with low ineffective doses of antidepressants might represent benefits in the treatment of depression, especially in patients with depression resistant to conventional treatments and even may contribute to patient compliance by decreasing the magnitude of some antidepressant dose-dependent side effects. Copyright © 2010 Elsevier B.V. All rights reserved.

  6. SYNTHESIS, CRYSTAL STRUCTURE AND ANTIOXIDANT POTENTIAL OF DI-(TV-CINNAMYL) FLUOXETINE CHLORIDE

    OpenAIRE

    KANWAL, NOSHEEN; SAHIN, ONUR; HUSAAIN, ERUM A; ULLAHKHAN, ISLAM; BUYUKGUNGOR, ORHAN

    2013-01-01

    A new derivative of Fluoxetine, N,N-dicinnamyl-N-methyl-3-phenyl-3- [4-(trifluoromethyl) phenoxy]butan-1-aminium chloride hydrate [Di-(N-Cinnamyl) Fluoxetine Chloride hydrate] was synthesized and characterized by single-crystal X-ray diffraction studies, elemental analyzer, thermogravimetric and FTIR spectroscopy analysis. The titled compound [C35H37ClF3NO2] crystallized in monoclinic, having unit cell parameters a = 19.155(14) A°, b = 9.193(5) A°, c = 18.596(13) A° and belongs to P2(1)/c spa...

  7. Paracetamol potentiates the antidepressant-like and anticompulsive-like effects of fluoxetine.

    Science.gov (United States)

    Manna, Shyamshree S S; Umathe, Sudhir N

    2015-04-01

    Recent studies suggest the possible involvement of serotonergic and endocannabinoid systems in analgesic, anxiolytic, and anticonvulsant-like actions of paracetamol. Considering the fact that these systems play intricate roles in affective disorders, we investigated the effects of paracetamol in depression-like and compulsion-like behavior. Swiss mice (20-22 g) were subjected to forced swim, tail suspension, or marble-burying tests after an injection of paracetamol either alone or in the presence of AM251 (a CB1 antagonist), fenclonine (pCPA: a 5-HT synthesis inhibitor), AM404 (anandamide uptake inhibitor) or fluoxetine. Paracetamol dose dependently (50-400 mg/kg) decreased depressive and compulsive behaviors. These effects were comparable to those of fluoxetine (5, 10, or 20 mg/kg) and AM404 (10 or 20 mg/kg). Interestingly, fenclonine pretreatment completely abolished the effects of a 50 mg/kg dose of paracetamol. However, similar effects were not observed in AM251-pretreated mice at the same dose. In contrast, AM251 completely antagonized the effects of the 400 mg/kg dose, which was otherwise partially blocked in fenclonine-treated mice. Similar sets of results were observed with fluoxetine and AM404. Thus, it appears that paracetamol-induced antidepressant-like and anticompulsive effects may, at least partially, involve both the serotonergic and the endocannabinoid system. In addition, coadministration of paracetamol and fluoxetine/AM404 at subeffective doses produced synergistic effects, indicating that subthreshold doses of fluoxetine and paracetamol may enable better management in depression and obsessive-compulsive disorder comorbid patients.

  8. Radiosynthesis of [F-18]fluoxetine as a potential radiotracer for serotonin reuptake sites

    International Nuclear Information System (INIS)

    Das, M.K.; Mukherjee, Jogeshwar

    1993-01-01

    Synthesis of 4-nitro-α-bromo-α,α-difluorotoluene was accomplished in two steps starting from 4-nitrobenzaldehyde, with a 30% overall yield. Radiolabeling of 4-nitro-α-bromo-α, α-difluorotoluene with no-carrier-added [ 18 F]fluoride provided 4-nitro-α,α-difluoro-α-[ 18 F] fluorotoluene in 2-4% yields with a specific activity of 2590 GBq/mmol (70 Ci/mmol). The effect of the reaction temperature on the radiochemical yield and specific activity of the radiolabeling reaction was studied. Radiochemical yields increased, whereas specific activity decreased, with increasing temperature. Radiosynthesis of [ 18 F] fluoxetine involved coupling of 4-nitro-α,α-difluoro-α-[ 18 F]fluorotoluene with the sodium alkoxide of (S)-3-(methylamino)-1-phenyl-1-propanol. The overall yield of HPLC purified [ 18 F]fluoxetine was 1-2% (decay-corrected; total radiosynthesis time, 150-180 min). The specific activity of the product was 1480 GBq/mmol (40 Ci/mmol). (Author)

  9. Radiosynthesis of [F-18]fluoxetine as a potential radiotracer for serotonin reuptake sites

    Energy Technology Data Exchange (ETDEWEB)

    Das, M.K.; Mukherjee, Jogeshwar (Chicago Univ., IL (United States). Dept. of Radiology)

    1993-05-01

    Synthesis of 4-nitro-[alpha]-bromo-[alpha],[alpha]-difluorotoluene was accomplished in two steps starting from 4-nitrobenzaldehyde, with a 30% overall yield. Radiolabeling of 4-nitro-[alpha]-bromo-[alpha], [alpha]-difluorotoluene with no-carrier-added [[sup 18]F]fluoride provided 4-nitro-[alpha],[alpha]-difluoro-[alpha]-[[sup 18]F] fluorotoluene in 2-4% yields with a specific activity of 2590 GBq/mmol (70 Ci/mmol). The effect of the reaction temperature on the radiochemical yield and specific activity of the radiolabeling reaction was studied. Radiochemical yields increased, whereas specific activity decreased, with increasing temperature. Radiosynthesis of [[sup 18]F] fluoxetine involved coupling of 4-nitro-[alpha],[alpha]-difluoro-[alpha]-[[sup 18]F]fluorotoluene with the sodium alkoxide of (S)-3-(methylamino)-1-phenyl-1-propanol. The overall yield of HPLC purified [[sup 18]F]fluoxetine was 1-2% (decay-corrected; total radiosynthesis time, 150-180 min). The specific activity of the product was 1480 GBq/mmol (40 Ci/mmol). (Author).

  10. An exploratory investigation of various modes of action and potential adverse outcomes of fluoxetine in marine mussels

    International Nuclear Information System (INIS)

    Franzellitti, Silvia; Buratti, Sara; Capolupo, Marco; Du, Bowen; Haddad, Samuel P.; Chambliss, C. Kevin; Brooks, Bryan W.; Fabbri, Elena

    2014-01-01

    Highlights: • Mode of action (MOA) related endpoints and biomarkers of toxicity were assessed in mussels exposed to fluoxetine (FX). • Significant FX bioaccumulation was observed in tissues of mussels exposed to 30 and 300 ng/L FX. • Alterations of cAMP-related cell signaling were observed in exposed mussels as part of the MOA of FX. • FX reduced the health status of mussels inducing lysosomal effects in digestive gland and antioxidant responses in gills. • The importance of considering additional MOAs and adverse outcome pathways for FX impacts on mussels is highlighted. - Abstract: The present study investigated possible adverse outcome pathways (AOPs) of the antidepressant fluoxetine (FX) in the marine mussel Mytilus galloprovincialis. An evaluation of molecular endpoints involved in modes of action (MOAs) of FX and biomarkers for sub-lethal toxicity were explored in mussels after a 7-day administration of nominal FX concentrations encompassing a range of environmentally relevant values (0.03–300 ng/L). FX bioaccumulated in mussel tissues after treatment with 30 and 300 ng/L FX, resulting in bioconcentration factor (BCF) values ranging from 200 to 800, which were higher than expected based solely on hydrophobic partitioning models. Because FX acts as a selective serotonin (5-HT) re-uptake inhibitor increasing serotonergic neurotransmission at mammalian synapses, cell signaling alterations triggered by 5-HT receptor occupations were assessed. cAMP levels and PKA activities were decreased in digestive gland and mantle/gonads of FX-treated mussels, consistent with an increased occupation of 5-HT1 receptors negatively coupled to the cAMP/PKA pathway. mRNA levels of a ABCB gene encoding the P-glycoprotein were also significantly down-regulated. This membrane transporter acts in detoxification towards xenobiotics and in altering pharmacokinetics of antidepressants; moreover, it is under a cAMP/PKA transcriptional regulation in mussels. Potential stress

  11. An exploratory investigation of various modes of action and potential adverse outcomes of fluoxetine in marine mussels

    Energy Technology Data Exchange (ETDEWEB)

    Franzellitti, Silvia, E-mail: silvia.franzellitti@unibo.it [University of Bologna, Interdepartment Centre for Environmental Science Research, via S. Alberto 163, 48123 Ravenna (Italy); University of Bologna, Department of Biological, Geological, and Environmental Sciences, via Selmi 3, 40100 Bologna (Italy); Buratti, Sara; Capolupo, Marco [University of Bologna, Interdepartment Centre for Environmental Science Research, via S. Alberto 163, 48123 Ravenna (Italy); Du, Bowen; Haddad, Samuel P. [Department of Environmental Science, Baylor University, Waco, TX 76798 (United States); Chambliss, C. Kevin [Department of Chemistry and Biochemistry, Baylor University, Waco, TX 76798 (United States); Brooks, Bryan W. [Department of Environmental Science, Baylor University, Waco, TX 76798 (United States); Fabbri, Elena [University of Bologna, Interdepartment Centre for Environmental Science Research, via S. Alberto 163, 48123 Ravenna (Italy); University of Bologna, Department of Biological, Geological, and Environmental Sciences, via Selmi 3, 40100 Bologna (Italy)

    2014-06-01

    Highlights: • Mode of action (MOA) related endpoints and biomarkers of toxicity were assessed in mussels exposed to fluoxetine (FX). • Significant FX bioaccumulation was observed in tissues of mussels exposed to 30 and 300 ng/L FX. • Alterations of cAMP-related cell signaling were observed in exposed mussels as part of the MOA of FX. • FX reduced the health status of mussels inducing lysosomal effects in digestive gland and antioxidant responses in gills. • The importance of considering additional MOAs and adverse outcome pathways for FX impacts on mussels is highlighted. - Abstract: The present study investigated possible adverse outcome pathways (AOPs) of the antidepressant fluoxetine (FX) in the marine mussel Mytilus galloprovincialis. An evaluation of molecular endpoints involved in modes of action (MOAs) of FX and biomarkers for sub-lethal toxicity were explored in mussels after a 7-day administration of nominal FX concentrations encompassing a range of environmentally relevant values (0.03–300 ng/L). FX bioaccumulated in mussel tissues after treatment with 30 and 300 ng/L FX, resulting in bioconcentration factor (BCF) values ranging from 200 to 800, which were higher than expected based solely on hydrophobic partitioning models. Because FX acts as a selective serotonin (5-HT) re-uptake inhibitor increasing serotonergic neurotransmission at mammalian synapses, cell signaling alterations triggered by 5-HT receptor occupations were assessed. cAMP levels and PKA activities were decreased in digestive gland and mantle/gonads of FX-treated mussels, consistent with an increased occupation of 5-HT1 receptors negatively coupled to the cAMP/PKA pathway. mRNA levels of a ABCB gene encoding the P-glycoprotein were also significantly down-regulated. This membrane transporter acts in detoxification towards xenobiotics and in altering pharmacokinetics of antidepressants; moreover, it is under a cAMP/PKA transcriptional regulation in mussels. Potential stress

  12. Fluoxetine Facilitates Fear Extinction Through Amygdala Endocannabinoids

    Science.gov (United States)

    Gunduz-Cinar, Ozge; Flynn, Shaun; Brockway, Emma; Kaugars, Katherine; Baldi, Rita; Ramikie, Teniel S; Cinar, Resat; Kunos, George; Patel, Sachin; Holmes, Andrew

    2016-01-01

    Pharmacologically elevating brain endocannabinoids (eCBs) share anxiolytic and fear extinction-facilitating properties with classical therapeutics, including the selective serotonin reuptake inhibitor, fluoxetine. There are also known functional interactions between the eCB and serotonin systems and preliminary evidence that antidepressants cause alterations in brain eCBs. However, the potential role of eCBs in mediating the facilitatory effects of fluoxetine on fear extinction has not been established. Here, to test for a possible mechanistic contribution of eCBs to fluoxetine's proextinction effects, we integrated biochemical, electrophysiological, pharmacological, and behavioral techniques, using the extinction-impaired 129S1/Sv1mJ mouse strain. Chronic fluoxetine treatment produced a significant and selective increase in levels of anandamide in the BLA, and an associated decrease in activity of the anandamide-catabolizing enzyme, fatty acid amide hydrolase. Slice electrophysiological recordings showed that fluoxetine-induced increases in anandamide were associated with the amplification of eCB-mediated tonic constraint of inhibitory, but not excitatory, transmission in the BLA. Behaviorally, chronic fluoxetine facilitated extinction retrieval in a manner that was prevented by systemic or BLA-specific blockade of CB1 receptors. In contrast to fluoxetine, citalopram treatment did not increase BLA eCBs or facilitate extinction. Taken together, these findings reveal a novel, obligatory role for amygdala eCBs in the proextinction effects of a major pharmacotherapy for trauma- and stressor-related disorders and anxiety disorders. PMID:26514583

  13. Fluoxetine Is a Potent Inhibitor of Coxsackievirus Replication

    OpenAIRE

    Zuo, Jun; Quinn, Kevin K.; Kye, Steve; Cooper, Paige; Damoiseaux, Robert; Krogstad, Paul

    2012-01-01

    No antiviral drugs currently exist for the treatment of enterovirus infections, which are often severe and potentially life threatening. Molecular screening of small molecule libraries identified fluoxetine, a selective serotonin reuptake inhibitor, as a potent inhibitor of coxsackievirus replication. Fluoxetine did not interfere with either viral entry or translation of the viral genome. Instead, fluoxetine and its metabolite norfluoxetine markedly reduced the synthesis of viral RNA and prot...

  14. Acute fluoxetine modulates emotional processing in young adult volunteers.

    Science.gov (United States)

    Capitão, L P; Murphy, S E; Browning, M; Cowen, P J; Harmer, C J

    2015-08-01

    Fluoxetine is generally regarded as the first-line pharmacological treatment for young people, as it is believed to show a more favourable benefit:risk ratio than other antidepressants. However, the mechanisms through which fluoxetine influences symptoms in youth have been little investigated. This study examined whether acute administration of fluoxetine in a sample of young healthy adults altered the processing of affective information, including positive, sad and anger cues. A total of 35 male and female volunteers aged between 18 and 21 years old were randomized to receive a single 20 mg dose of fluoxetine or placebo. At 6 h after administration, participants completed a facial expression recognition task, an emotion-potentiated startle task, an attentional dot-probe task and the Rapid Serial Visual Presentation. Subjective ratings of mood, anxiety and side effects were also taken pre- and post-fluoxetine/placebo administration. Relative to placebo-treated participants, participants receiving fluoxetine were less accurate at identifying anger and sadness and did not show the emotion-potentiated startle effect. There were no overall significant effects of fluoxetine on subjective ratings of mood. Fluoxetine can modulate emotional processing after a single dose in young adults. This pattern of effects suggests a potential cognitive mechanism for the greater benefit:risk ratio of fluoxetine in adolescent patients.

  15. Fluoxetine (Prozac) and Pregnancy

    Science.gov (United States)

    ... this study, women who stopped using fluoxetine by the end of the second trimester did not seem to ... affects the mother by changing chemical levels in the brain. In theory, these changes might also have an effect on ...

  16. Delirium Associated With Fluoxetine Discontinuation: A Case Report.

    Science.gov (United States)

    Fan, Kuang-Yuan; Liu, Hsing-Cheng

    Withdrawal symptoms on selective serotonin reuptake inhibitor (SSRI) discontinuation have raised clinical attention increasingly. However, delirium is rarely reported in the SSRI discontinuation syndrome. We report a case of delirium developing after fluoxetine discontinuation in a 65-year-old female patient with major depressive disorder. She experienced psychotic depression with limited response to treatment of fluoxetine 40 mg/d and quetiapine 100 mg/d for 3 months. After admission, we tapered fluoxetine gradually in 5 days because of its limited effect. However, delirious pictures developed 2 days after we stopped fluoxetine. Three days later, we added back fluoxetine 10 mg/d. Her delirious features gradually improved, and the clinical presentation turned into previous psychotic depression state. We gradually increased the medication to fluoxetine 60 mg/d and olanzapine 20 mg/d in the following 3 weeks. Her psychotic symptoms decreased, and there has been no delirious picture noted thereafter. Delirium associated with fluoxetine discontinuation is a much rarer complication in SSRI discontinuation syndrome. The symptoms of SSRI discontinuation syndrome may be attributable to a rapid decrease in serotonin availability. In general, the shorter the half-life of any medication, the greater the likelihood patients will experience discontinuation symptoms. Genetic vulnerability might be a potential factor to explain that SSRI discontinuation syndrome also occurred rapidly in people taking long-half-life fluoxetine. The genetic polymorphisms of both pharmacokinetic and pharmacodynamic pathways might be potentially associated with SSRI discontinuation syndrome.

  17. Possible effect of norepinephrine transporter polymorphisms on methylphenidate-induced changes in neuropsychological function in attention-deficit hyperactivity disorder

    Directory of Open Access Journals (Sweden)

    Park Subin

    2012-05-01

    Full Text Available Abstract Background Dysregulation of noradrenergic system may play important roles in pathophysiology of attention-deficit/hyperactivity disorder (ADHD. We examined the relationship between polymorphisms in the norepinephrine transporter SLC6A2 gene and attentional performance before and after medication in children with ADHD. Methods Fifty-three medication-naïve children with ADHD were genotyped and evaluated using the continuous performance test (CPT. After 8-weeks of methylphenidate treatment, these children were evaluated by CPT again. We compared the baseline CPT measures and the post-treatment changes in the CPT measures based on the G1287A and the A-3081T polymorphisms of SLC6A2. Results There was no significant difference in the baseline CPT measures associated with the G1287A or A-3081T polymorphisms. After medication, however, ADHD subjects with the G/G genotype at the G1287A polymorphism showed a greater decrease in the mean omission error scores (p = 0.006 than subjects with the G/A or A/A genotypes, and subjects with the T allele at the A-3081T polymorphism (T/T or A/T showed a greater decrease in the mean commission error scores (p = 0.003 than those with the A/A genotypes. Conclusions Our results provide evidence for the possible role of the G1287A and A-3081T genotypes of SLC6A2 in methylphenidate-induced improvement in attentional performance and support the noradrenergic hypothesis for the pathophysiology of ADHD.

  18. Possible effect of norepinephrine transporter polymorphisms on methylphenidate-induced changes in neuropsychological function in attention-deficit hyperactivity disorder.

    Science.gov (United States)

    Park, Subin; Kim, Jae-Won; Yang, Young-Hui; Hong, Soon-Beom; Park, Min-Hyeon; Kim, Boong-Nyun; Shin, Min-Sup; Yoo, Hee-Jeong; Cho, Soo-Churl

    2012-05-16

    Dysregulation of noradrenergic system may play important roles in pathophysiology of attention-deficit/hyperactivity disorder (ADHD). We examined the relationship between polymorphisms in the norepinephrine transporter SLC6A2 gene and attentional performance before and after medication in children with ADHD. Fifty-three medication-naïve children with ADHD were genotyped and evaluated using the continuous performance test (CPT). After 8-weeks of methylphenidate treatment, these children were evaluated by CPT again. We compared the baseline CPT measures and the post-treatment changes in the CPT measures based on the G1287A and the A-3081T polymorphisms of SLC6A2. There was no significant difference in the baseline CPT measures associated with the G1287A or A-3081T polymorphisms. After medication, however, ADHD subjects with the G/G genotype at the G1287A polymorphism showed a greater decrease in the mean omission error scores (p = 0.006) than subjects with the G/A or A/A genotypes, and subjects with the T allele at the A-3081T polymorphism (T/T or A/T) showed a greater decrease in the mean commission error scores (p = 0.003) than those with the A/A genotypes. Our results provide evidence for the possible role of the G1287A and A-3081T genotypes of SLC6A2 in methylphenidate-induced improvement in attentional performance and support the noradrenergic hypothesis for the pathophysiology of ADHD.

  19. Global gene expression in larval zebrafish (Danio rerio) exposed to selective serotonin reuptake inhibitors (fluoxetine and sertraline) reveals unique expression profiles and potential biomarkers of exposure

    International Nuclear Information System (INIS)

    Park, June-Woo; Heah, Tze Ping; Gouffon, Julia S.; Henry, Theodore B.; Sayler, Gary S.

    2012-01-01

    Larval zebrafish (Danio rerio) were exposed (96 h) to selective serotonin reuptake inhibitors (SSRIs) fluoxetine and sertraline and changes in transcriptomes analyzed by Affymetrix GeneChip ® Zebrafish Array were evaluated to enhance understanding of biochemical pathways and differences between these SSRIs. The number of genes differentially expressed after fluoxetine exposure was 288 at 25 μg/L and 131 at 250 μg/L; and after sertraline exposure was 33 at 25 μg/L and 52 at 250 μg/L. Same five genes were differentially regulated in both SSRIs indicating shared molecular pathways. Among these, the gene coding for FK506 binding protein 5, annotated to stress response regulation, was highly down-regulated in all treatments (results confirmed by qRT-PCR). Gene ontology analysis indicated at the gene expression level that regulation of stress response and cholinesterase activities were influenced by these SSRIs, and suggested that changes in transcription of these genes could be used as biomarkers of SSRI exposure. - Highlights: ► Exposure of zebrafish to selective serotonin reuptake inhibitors (SSRIs). ► Fluoxetine and sertraline generate different global gene expression profiles. ► Genes linked to stress response and acetylcholine esterase affected by both SSRIs. - Global gene expression profiles in zebrafish exposed to selective serotonin reuptake inhibitors.

  20. Cognitive performance of juvenile monkeys after chronic fluoxetine treatment.

    Science.gov (United States)

    Golub, Mari S; Hackett, Edward P; Hogrefe, Casey E; Leranth, Csaba; Elsworth, John D; Roth, Robert H

    2017-08-01

    Potential long term effects on brain development are a concern when drugs are used to treat depression and anxiety in childhood. In this study, male juvenile rhesus monkeys (three-four years of age) were dosed with fluoxetine or vehicle (N=16/group) for two years. Histomorphometric examination of cortical dendritic spines conducted after euthanasia at one year postdosing (N=8/group) suggested a trend toward greater dendritic spine synapse density in prefrontal cortex of the fluoxetine-treated monkeys. During dosing, subjects were trained for automated cognitive testing, and evaluated with a test of sustained attention. After dosing was discontinued, sustained attention, recognition memory and cognitive flexibility were evaluated. Sustained attention was affected by fluoxetine, both during and after dosing, as indexed by omission errors. Response accuracy was not affected by fluoxetine in post-dosing recognition memory and cognitive flexibility tests, but formerly fluoxetine-treated monkeys compared to vehicle controls had more missed trial initiations and choices during testing. Drug treatment also interacted with genetic and environmental variables: MAOA genotype (high- and low transcription rate polymorphisms) and testing location (upper or lower tier of cages). Altered development of top-down cortical regulation of effortful attention may be relevant to this pattern of cognitive test performance after juvenile fluoxetine treatment. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  1. Fluoxetine Decreases the Proliferation and Adipogenic Differentiation of Human Adipose-Derived Stem Cells

    Directory of Open Access Journals (Sweden)

    Bo Kyung Sun

    2015-07-01

    Full Text Available Fluoxetine was originally developed as an antidepressant, but it has also been used to treat obesity. Although the anti-appetite effect of fluoxetine is well-documented, its potential effects on human adipose-derived stem cells (ASCs or mature adipocytes have not been investigated. Therefore, we investigated the mechanisms underlying the inhibitory effects of fluoxetine on the proliferation of ASCs. We also investigated its inhibitory effect on adipogenic differentiation. Fluoxetine significantly decreased ASC proliferation, and signal transduction PCR array analysis showed that it increased expression of autophagy-related genes. In addition, fluoxetine up-regulated SQSTM1 and LC3B protein expression as detected by western blotting and immunofluorescence. The autophagy inhibitor, 3-methyladenine (3-MA, significantly attenuated fluoxetine-mediated effects on ASC proliferation and SQSTM1/LC3B expression. In addition, 3-MA decreased the mRNA expression of two autophagy-related genes, beclin-1 and Atg7, in ASCs. Fluoxetine also significantly inhibited lipid accumulation and down-regulated the levels of PPAR-γ and C/EBP-α in ASCs. Collectively, these results indicate that fluoxetine decreases ASC proliferation and adipogenic differentiation. This is the first in vitro evidence that fluoxetine can reduce fat accumulation by inhibiting ASC proliferation and differentiation.

  2. Fluoxetine Decreases the Proliferation and Adipogenic Differentiation of Human Adipose-Derived Stem Cells

    Science.gov (United States)

    Sun, Bo Kyung; Kim, Ji Hye; Choi, Joon-Seok; Hwang, Sung-Joo; Sung, Jong-Hyuk

    2015-01-01

    Fluoxetine was originally developed as an antidepressant, but it has also been used to treat obesity. Although the anti-appetite effect of fluoxetine is well-documented, its potential effects on human adipose-derived stem cells (ASCs) or mature adipocytes have not been investigated. Therefore, we investigated the mechanisms underlying the inhibitory effects of fluoxetine on the proliferation of ASCs. We also investigated its inhibitory effect on adipogenic differentiation. Fluoxetine significantly decreased ASC proliferation, and signal transduction PCR array analysis showed that it increased expression of autophagy-related genes. In addition, fluoxetine up-regulated SQSTM1 and LC3B protein expression as detected by western blotting and immunofluorescence. The autophagy inhibitor, 3-methyladenine (3-MA), significantly attenuated fluoxetine-mediated effects on ASC proliferation and SQSTM1/LC3B expression. In addition, 3-MA decreased the mRNA expression of two autophagy-related genes, beclin-1 and Atg7, in ASCs. Fluoxetine also significantly inhibited lipid accumulation and down-regulated the levels of PPAR-γ and C/EBP-α in ASCs. Collectively, these results indicate that fluoxetine decreases ASC proliferation and adipogenic differentiation. This is the first in vitro evidence that fluoxetine can reduce fat accumulation by inhibiting ASC proliferation and differentiation. PMID:26204837

  3. Neonatal programming with testosterone propionate reduces dopamine transporter expression in nucleus accumbens and methylphenidate-induced locomotor activity in adult female rats.

    Science.gov (United States)

    Dib, Tatiana; Martínez-Pinto, Jonathan; Reyes-Parada, Miguel; Torres, Gonzalo E; Sotomayor-Zárate, Ramón

    2018-07-02

    Research in programming is focused on the study of stimuli that alters sensitive periods in development, such as prenatal and neonatal stages, that can produce long-term deleterious effects. These effects can occur in various organs or tissues such as the brain, affecting brain circuits and related behaviors. Our laboratory has demonstrated that neonatal programming with sex hormones affects the mesocorticolimbic circuitry, increasing the synthesis and release of dopamine (DA) in striatum and nucleus accumbens (NAcc). However, the behavioral response to psychostimulant drugs such as methylphenidate and the possible mechanism(s) involved have not been studied in adult rats exposed to sex hormones during the first hours of life. Thus, the aim of this study was to examine the locomotor activity induced by methylphenidate (5mg/kg i.p.) and the expression of the DA transporter (DAT) in NAcc of adult rats exposed to a single dose of testosterone propionate (TP: 1mg/50μLs.c.) or estradiol valerate (EV: 0.1mg/50μLs.c.) at postnatal day 1. Our results demonstrated that adult female rats treated with TP have a lower methylphenidate-induced locomotor activity compared to control and EV-treated adult female rats. This reduction in locomotor activity is related with a lower NAcc DAT expression. However, neither methylphenidate-induced locomotor activity nor NAcc DAT expression was affected in EV or TP-treated adult male rats. Our results suggest that early exposure to sex hormones affects long-term dopaminergic brain areas involved in the response to psychostimulants, which could be a vulnerability factor to favor the escalating doses of drugs of abuse. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Fluoxetine disrupts motivation and GABAergic signaling in adolescent female hamsters.

    Science.gov (United States)

    Shannonhouse, John L; DuBois, Dustin W; Fincher, Annette S; Vela, Alejandra M; Henry, Morgan M; Wellman, Paul J; Frye, Gerald D; Morgan, Caurnel

    2016-08-01

    Initial antidepressant treatment can paradoxically worsen symptoms in depressed adolescents by undetermined mechanisms. Interestingly, antidepressants modulate GABAA receptors, which mediate paradoxical effects of other therapeutic drugs, particularly in females. Although the neuroanatomic site of action for this paradox is unknown, elevated GABAA receptor signaling in the nucleus accumbens can disrupt motivation. We assessed fluoxetine's effects on motivated behaviors in pubescent female hamsters - anhedonia in the reward investigational preference (RIP) test as well as anxiety in the anxiety-related feeding/exploration conflict (AFEC) test. We also assessed accumbal signaling by RT-PCR and electrophysiology. Fluoxetine initially worsened motivated behaviors at puberty, relative to adulthood. It also failed to improve these behaviors as pubescent hamsters transitioned into adulthood. Low accumbal mRNA levels of multiple GABAA receptor subunits and GABA-synthesizing enzyme, GAD67, assessed by RT-PCR, suggested low GABAergic tone at puberty. Nonetheless, rapid fluoxetine-induced reductions of α5GABAA receptor and BDNF mRNA levels at puberty were consistent with age-related differences in GABAergic responses to fluoxetine and disruption of the motivational state. Whole-cell patch clamping of accumbal slices also suggested low GABAergic tone by the low amplitude of miniature inhibitory postsynaptic currents (mIPSCs) at puberty. It also confirmed age-related differences in GABAergic responses to fluoxetine. Specifically, fluoxetine potentiated mIPSC amplitude and frequency at puberty, but attenuated the amplitude during adulthood. These results implicate GABAergic tone and GABAA receptor plasticity in adverse motivational responses and resistance to fluoxetine during adolescence. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Up-regulation of melanin synthesis by the antidepressant fluoxetine.

    Science.gov (United States)

    Liao, Sha; Shang, Jing; Tian, Xiaoli; Fan, Xueqi; Shi, Xiupu; Pei, Siran; Wang, Qian; Yu, Boyang

    2012-08-01

    Fluoxetine, a member of the class of selective serotonin reuptake inhibitors, is a potent antidepressant commonly used in clinical practice. Here, we report that fluoxetine increases cellular tyrosinase (TYR) activity, enhances the protein levels of microphthalmia-associated transcription factor (MITF), TYR and tyrosinase-related protein-1 (TRP-1) and eventually leads to a dramatic increase in melanin production in both murine B16F10 melanoma cells and normal human melanocytes (NHMCs). In well-characterized C57BL/6 mouse models, systemic application of fluoxetine increased hair pigmentation by up-regulating hair follicular MITF, TYR, TRP-1 and tyrosinase-related protein-2 (TRP-2) protein levels. Using a serotonin 1A receptor (SR1A) antagonist and RNA interference (RNAi) technique, we revealed that SR1A appears to be one of the involved pathways in the fluoxetine-induced melanogenesis in B16F10 cells. These results suggest that fluoxetine may hold a significant therapeutic potential for treating skin hypopigmentation disorders, and SR1A may serve as a novel target in modulating melanogenesis. © 2012 John Wiley & Sons A/S.

  6. Fluoxetine, an antidepressant, suppresses glioblastoma by evoking AMPAR-mediated calcium-dependent apoptosis

    Science.gov (United States)

    Liu, Kao-Hui; Yang, Shun-Tai; Lin, Yen-Kuang; Lin, Jia-Wei; Lee, Yi-Hsuan; Wang, Jia-Yi; Hu, Chaur-Jong; Lin, En-Yuan; Chen, Shu-Mei; Then, Chee-Kin; Shen, Shing-Chuan

    2015-01-01

    The efficacy of glioblastoma chemotherapy is not satisfactory; therefore, a new medication is expected to improve outcomes. As much evidence shows that antidepressants decrease cancer incidence and improve patients' quality of life, we therefore attempted to explore the potential for fluoxetine to be used to treat GBM and its possible underlying mechanism. The expression level of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) was determined using immunohistochemical staining and PCR analysis. The mechanism of fluoxetine-induced apoptosis of gliomas was elucidated. Computer modeling and a binding assay were conducted to investigate the interaction of fluoxetine with the AMPAR. The therapeutic effect of fluoxetine was evaluated using an animal model. We found that fluoxetine directly bound to AMPAR, thus inducing transmembrane Ca2+ influx. The rise in the intracellular calcium concentration ([Ca2+]i) causes mitochondrial Ca2+ overload, thereby triggering apoptosis. AMPARs are excessively expressed in glioma tissues, suggesting that fluoxetine specifically executes glioma cells. Our in vivo study revealed that fluoxetine suppressed the growth of glioblastomas in brains of Nu/Nu mice, an effect similar to that produced by temozolomide. Our preclinical studies suggest fluoxetine, a commonly used antidepressant, might be selectively toxic to gliomas and could provide a new approach for managing this disease. PMID:25671301

  7. FLUOXETINE INHIBITS OSTEOBLAST DIFFERENTIATION & MINERALIZATION IN FRACTURE HEALING

    Science.gov (United States)

    Bradaschia-Correa, Vivian; Josephson, Anne M; Mehta, Devan; Mizrahi, Matthew; Neibart, Shane S; Liu, Chao; Kennedy, Oran; Castillo, Alesha B; Egol, Kenneth A; Leucht, Philipp

    2016-01-01

    Chronic use of selective serotonin reuptake inhibitors (SSRIs) for the treatment of depression has been linked to osteoporosis. In this study, we investigated the effect of chronic SSRI use on fracture healing in two murine models of bone regeneration. First, we performed a comprehensive analysis of endochondral bone healing in a femur fracture model. C57/BL6 mice treated with fluoxetine, the most commonly prescribed SSRI, developed a normal cartilaginous soft-callus at 14 days after fracture and demonstrated a significantly smaller and biomechanically weaker bony hard-callus at 28 days. In order to further dissect the mechanism that resulted in a smaller bony regenerate, we used an intramembranous model of bone healing and revealed that fluoxetine treatment resulted in a significantly smaller bony callus at 7 and 14 days postinjury. In order to test whether the smaller bony regenerate following fluoxetine treatment was caused by an inhibition of osteogenic differentiation and/or mineralization, we employed in vitro experiments, which established that fluoxetine treatment decreases osteogenic differentiation and mineralization and that this effect is serotonin-independent. Finally, in a translational approach, we tested whether cessation of the medication would result in restoration of the regenerative potential. However, histologic and µCT analysis revealed non-union formation in these animals with fibrous tissue interposition within the callus. In conclusion, fluoxetine exerts a direct, inhibitory effect on osteoblast differentiation and mineralization, shown in two disparate murine models of bone repair. Discontinuation of the drug did not result in restoration of the healing potential, but rather led to complete arrest of the repair process. Besides the well-established effect of SSRIs on bone homeostasis, our study provides strong evidence that fluoxetine use negatively impacts fracture healing. PMID:27869327

  8. Pharmacokinetics of Fluoxetine in Pregnant Baboons (Papio spp.)

    Science.gov (United States)

    Shoulson, Rivka L; Stark, Raymond L; Garland, Marianne

    2014-01-01

    Fluoxetine is used to treat a number of psychiatric conditions in humans and behavioral problems in animals. Its use in pregnancy must balance maternal benefit with potential risk to the fetus. Knowledge of adult and fetal drug disposition can assist clinicians in selecting therapy that minimizes adverse effects to the fetus. Nonhuman primate models are used frequently in drug dose-translation studies, and pregnancy in baboons has many similarities to human pregnancy. Accordingly, pharmacokinetic analysis of a series of fluoxetine and norfluoxetine administrations to pregnant baboons was performed. The mean maternal baboon steady-state clearance of fluoxetine (42 mL/min/kg) was considerably higher than that in humans. Norfluoxetine, the major active metabolite, had a higher metabolite-to-drug ratio (8.7) than that found in humans, particularly with oral dosing. These results are consistent with more extensive metabolism in baboons than in humans and leads to a higher clearance than would be expected from allometric scaling. Fetal-to-maternal fluoxetine and norfluoxetine ratios under steady-state conditions were similar to those in humans, with fetal concentrations of fluoxetine 42% and norfluoxetine 47% of maternal concentrations. The fetal clearance of fluoxetine (303 ± 176 mL/min) and norfluoxetine (450 mL/min) exceeded reported placental blood flow. Understanding these species-associated differences in metabolism is a prerequisite to extrapolating data between species. Nonetheless, nonhuman primates are likely to remain valuable models for pharmacokinetic studies during pregnancy, particularly those directed toward fetal neurodevelopmental effects. Our results also are applicable to determining appropriate dosing of nonhuman primates in clinical settings. PMID:25650979

  9. Fluoxetine Inhibits Natural Decay of Long-Term Memory via Akt/GSK-3β Signaling.

    Science.gov (United States)

    Yi, Jee Hyun; Zhang, JiaBao; Ko, Sang Yoon; Kwon, Huiyoung; Jeon, Se Jin; Park, Se Jin; Jung, Jiwook; Kim, Byung C; Lee, Young Choon; Kim, Dong Hyun; Ryu, Jong Hoon

    2018-02-09

    Understanding the mechanisms underlying the natural decay of long-term memory can help us find means of extending the duration of long-term memory. However, the neurobiological processes involved in the decay of long-term memory are poorly understood. In the present study, we examined the effect of acute and chronic treatment of fluoxetine on natural decay of long-term memory and the possible mechanism. Late administration of fluoxetine prolonged the persistence of long-term memory in mice, as demonstrated by object location recognition and Barnes maze tests. Fluoxetine altered Akt/glycogen synthase kinase-3β (GSK-3β)/β-catenin signaling in the hippocampus. Late short- and long-term pharmacological inhibition of GSK-3β mimicked the effect of fluoxetine on memory persistence. Pharmacological inhibition of Akt blocked the effect of fluoxetine on memory persistence. Finally, late infusion of fluoxetine increased hippocampal long-term potentiation (LTP) and pharmacological inhibition of GSK-3β blocked the natural decline in LTP. These results demonstrate that GSK-3β might be a key molecule in memory decay process, and fluoxetine extends the period of long-term memory maintenance via Akt/GSK-3β signaling.

  10. Fluoxetine Blocks Nav1.5 Channels via a Mechanism Similar to That of Class 1 Antiarrhythmics

    Science.gov (United States)

    Poulin, Hugo; Bruhova, Iva; Timour, Quadiri; Theriault, Olivier; Beaulieu, Jean-Martin; Frassati, Dominique

    2014-01-01

    The voltage-gated Nav1.5 channel is essential for the propagation of action potentials in the heart. Malfunctions of this channel are known to cause hereditary diseases. It is a prime target for class 1 antiarrhythmic drugs and a number of antidepressants. Our study investigated the Nav1.5 blocking properties of fluoxetine, a selective serotonin reuptake inhibitor. Nav1.5 channels were expressed in HEK-293 cells, and Na+ currents were recorded using the patch-clamp technique. Dose-response curves of racemic fluoxetine (IC50 = 39 μM) and its optical isomers had a similar IC50 [40 and 47 μM for the (+) and (−) isomers, respectively]. Norfluoxetine, a fluoxetine metabolite, had a higher affinity than fluoxetine, with an IC50 of 29 μM. Fluoxetine inhibited currents in a frequency-dependent manner, shifted steady-state inactivation to more hyperpolarized potentials, and slowed the recovery of Nav1.5 from inactivation. Mutating a phenylalanine (F1760) and a tyrosine (Y1767) in the S6 segment of domain (D) IV (DIVS6) significantly reduced the affinity of fluoxetine and its frequency-dependent inhibition. We used a noninactivating Nav1.5 mutant to show that fluoxetine displays open-channel block behavior. The molecular model of fluoxetine in Nav1.5 was in agreement with mutational experiments in which F1760 and Y1767 were found to be the key residues in binding fluoxetine. We concluded that fluoxetine blocks Nav1.5 by binding to the class 1 antiarrhythmic site. The blocking of cardiac Na+ channels should be taken into consideration when prescribing fluoxetine alone or in association with other drugs that may be cardiotoxic or for patients with conduction disorders. PMID:25028482

  11. Fluoxetine protects against IL-1β-induced neuronal apoptosis via downregulation of p53.

    Science.gov (United States)

    Shan, Han; Bian, Yaqi; Shu, Zhaoma; Zhang, Linxia; Zhu, Jialei; Ding, Jianhua; Lu, Ming; Xiao, Ming; Hu, Gang

    2016-08-01

    Fluoxetine, a selective serotonin reuptake inhibitor, exerts neuroprotective effects in a variety of neurological diseases including stroke, but the underlying mechanism remains obscure. In the present study, we addressed the molecular events in fluoxetine against ischemia/reperfusion-induced acute neuronal injury and inflammation-induced neuronal apoptosis. We showed that treatment of fluoxetine (40 mg/kg, i.p.) with twice injections at 1 h and 12 h after transient middle cerebral artery occlusion (tMCAO) respectively alleviated neurological deficits and neuronal apoptosis in a mouse ischemic stroke model, accompanied by inhibiting interleukin-1β (IL-1β), Bax and p53 expression and upregulating anti-apoptotic protein Bcl-2 level. We next mimicked neuroinflammation in ischemic stroke with IL-1β in primary cultured cortical neurons and found that pretreatment with fluoxetine (1 μM) prevented IL-1β-induced neuronal apoptosis and upregulation of p53 expression. Furthermore, we demonstrated that p53 overexpression in N2a cell line abolished the anti-apoptotic effect of fluoxetine, indicating that p53 downregulation is required for the protective role of fluoxetine in IL-1β-induced neuronal apoptosis. Fluoxetine downregulating p53 expression could be mimicked by SB203580, a specific inhibitor of p38, but blocked by anisomycin, a p38 activator. Collectively, our findings have revealed that fluoxetine protects against IL-1β-induced neuronal apoptosis via p38-p53 dependent pathway, which give us an insight into the potential of fluoxetine in terms of opening up novel therapeutic avenues for neurological diseases including stroke. Copyright © 2016 Elsevier Ltd. All rights reserved.

  12. Reduced efficacy of fluoxetine following MDMA ("Ecstasy")-induced serotonin loss in rats.

    Science.gov (United States)

    Durkin, Sarah; Prendergast, Alison; Harkin, Andrew

    2008-12-12

    Long-term serotonin (5-HT) neuronal loss is currently a major cause of concern associated with recreational use of the substituted amphetamine 3,4 methylenedioxymethamphetamine (MDMA; "Ecstasy"). Such loss may be problematic considering that psychiatric disorders such as depression and anxiety and responses to first line treatments for these disorders are associated with 5-HT. In this study the effects of prior exposure to MDMA on behavioural and central neurochemical changes induced by the serotonin (5-HT) re-uptake inhibitor and antidepressant fluoxetine were examined in rats. Animals were administered MDMA (10 mg/kg. i.p.) four times daily for two consecutive days. One week later the animals were subjected to treatment with fluoxetine (10 mg/kg, i.p.). Fluoxetine treatment groups received either acute (saline injections for 20 days followed by 3 fluoxetine treatments over 24 h) or chronic (once daily fluoxetine for 21 days) drug administration. Prior exposure to MDMA resulted in an attenuation of fluoxetine-induced swimming behaviour in the modified forced swimming test (FST); a behavioural test of antidepressant action. In parallel MDMA treatment resulted in significant regional depletions of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) accompanied by a reduction in cortical [3H] paroxetine binding to nerve terminal 5-HT transporters. MDMA-induced 5-HT loss was enhanced in animals following chronic fluoxetine administration. Elimination of fluoxetine and its metabolite norfluoxetine from the brain abolished this interaction between MDMA and fluoxetine treatment. Fluoxetine administration reduced both 5-HIAA and the 5-HIAA:5-HT metabolism ratio, which was attenuated in animals pre-treated with MDMA. Overall the results show that MDMA induces long-term 5-HT loss in the rodent brain and consequently diminishes behaviour and reductions in 5-HT metabolism induced by the antidepressant fluoxetine. These results have potential clinical relevance

  13. Long-term Ameliorative Effects of the Antidepressant Fluoxetine Exposure on Cognitive Deficits in 3 × TgAD Mice.

    Science.gov (United States)

    Jin, Li; Gao, Li-Feng; Sun, Dong-Sheng; Wu, Hao; Wang, Qun; Ke, Dan; Lei, Hao; Wang, Jian-Zhi; Liu, Gong-Ping

    2017-08-01

    Fluoxetine, a selective serotonin reuptake inhibitor, is neuroprotective; therefore, it has been applied to treat some neurodegenerative disorders. For instance, chronic fluoxetine exposure has short-term effects on Alzheimer's disease (AD). However, the long-term ameliorative effects of fluoxetine exposure on AD have not been reported. In the present study, 6-month-old 3 × TgAD mice were treated with fluoxetine for 15 days, and then the influence of fluoxetine was detected at 20 days after the drug withdrawal. We found that chronic fluoxetine treatment ameliorated cognitive deficits of 3 × TgAD mice and increased the volume of the hippocampal CA1 and dentate gyrus (DG) with increased neuron number and dendritic spine density. Meanwhile, fluoxetine exposure also stimulated the long-term potentiation (LTP) in hippocampal DG. The synaptic-related protein expression increased via activation of the cyclic AMP response element binding (CREB) protein/brain-derived neurotrophic factor (BDNF) signaling pathway induced by fluoxetine exposure. Lastly, we found that fluoxetine treatment decreased beta-amyloid (Aβ) levels. These results further certified that fluoxetine may be a potent effective drug for AD.

  14. Fluoxetine: clinical pharmacology and physiologic disposition

    International Nuclear Information System (INIS)

    Lemberger, L.; Bergstrom, R.F.; Wolen, R.L.; Farid, N.A.; Enas, G.G.; Aronoff, G.R.

    1985-01-01

    Fluoxetine (30 mg), administered for 7 days to normal volunteers, produced a 66% inhibition of tritiated serotonin uptake into platelets. Plasma concentrations of fluoxetine correlated positively with inhibition of serotonin uptake. Fluoxetine is well absorbed after oral administration in both the fed and fasted states and demonstrates dose proportionality. Fluoxetine disappears from plasma with a half-life of 1-3 days; its metabolite norfluoxetine has a plasma half-life of 7-15 days. After administration of 14 C-fluoxetine, approximately 65% of the administered dose of radioactivity is recovered in urine and about 15% in feces. Fluoxetine, given as a single dose or in multiple doses over 8 days, did not produce significant effects on the plasma disappearance of warfarin, diazepam, tolbutamide, or chlorothiazide. Coadministration of fluoxetine and ethanol did not result in an increase from control values in the blood ethanol levels, nor did it produce significant changes in physiologic, psychometric, or psychomotor activity. Pharmacokinetics of fluoxetine in the elderly and normal volunteers appear to be similar. In addition, pharmacokinetic analyses in patients with varying degrees of renal impairment did not show significant differences from healthy subjects

  15. Fluoxetine Alleviates Behavioral Depression while Decreasing Acetylcholine Release in the Nucleus Accumbens Shell

    Science.gov (United States)

    Chau, David T; Rada, Pedro V; Kim, Kay; Kosloff, Rebecca A; Hoebel, Bartley G

    2011-01-01

    Selective serotonin reuptake inhibitors, such as fluoxetine, have demonstrated the ability to alleviate behavioral depression in the forced swim test; however, the sites and mechanisms of their actions remain to be further elucidated. Previous studies have suggested that behavioral depression in the swim test is mediated in part by acetylcholine (ACh) stimulating the cholinergic M1 receptors in the nucleus accumbens (NAc) shell. The current study tested whether acute, local, and chronic, subcutaneous fluoxetine treatments increase escape motivation during the swim test while simultaneously lowering extracellular ACh in the NAc shell. Experiment 1: Fluoxetine (1.0 mM) infused unilaterally in the NAc shell for 40 min reduced extracellular ACh while simultaneously increasing swimming time. Experiment 2: Fluoxetine (0.2, 0.5, and 0.75 mM) infused bilaterally in the NAc shell on day 3 dose-dependently decreased immobility and increased the total escape attempts (swimming and climbing) compared with Ringer given on day 2. Experiment 3: Fluoxetine (0.5 mM) infused bilaterally in the NAc for 40 min did not affect activities in an open field. Experiment 4: Chronic systemic fluoxetine treatment decreased immobility scores and increased total escape attempt scores compared with control saline treatment. In all, 14 days after the initial swim test, basal extracellular ACh in the shell was still elevated in the saline-treated group, but not in the fluoxetine-treated group. In summary, these data suggest that one of the potential mechanisms by which fluoxetine alleviates behavioral depression in the forced swim test may be to suppress cholinergic activities in the NAc shell. PMID:21525864

  16. Fluoxetine Prevents Oligodendrocyte Cell Death by Inhibiting Microglia Activation after Spinal Cord Injury

    Science.gov (United States)

    Lee, Jee Y.; Kang, So R.

    2015-01-01

    Abstract Oligodendrocyte cell death and axon demyelination after spinal cord injury (SCI) are known to be important secondary injuries contributing to permanent neurological disability. Thus, blocking oligodendrocyte cell death should be considered for therapeutic intervention after SCI. Here, we demonstrated that fluoxetine, an antidepressant drug, alleviates oligodendrocyte cell death by inhibiting microglia activation after SCI. After injury at the T9 level with a Precision Systems and Instrumentation (Lexington, KY) device, fluoxetine (10 mg/kg, intraperitoneal) was administered once a day for the indicated time points. Immunostaining with CD11b (OX-42) antibody and quantification analysis showed that microglia activation was significantly inhibited by fluoxetine at 5 days after injury. Fluoxetine also significantly inhibited activation of p38 mitogen-activated protein kinase (p38-MAPK) and expression of pro-nerve growth factor (pro-NGF), which is known to mediate oligodendrocyte cell death through the p75 neurotrophin receptor after SCI. In addition, fluoxetine attenuated activation of Ras homolog gene family member A and decreased the level of phosphorylated c-Jun and, ultimately, alleviated caspase-3 activation and significantly reduced cell death of oligodendrocytes at 5 days after SCI. Further, the decrease of myelin basic protein, myelin loss, and axon loss in white matter was also significantly blocked by fluoxetine, as compared to vehicle control. These results suggest that fluoxetine inhibits oligodendrocyte cell death by inhibiting microglia activation and p38-MAPK activation, followed by pro-NGF production after SCI, and provide a potential usage of fluoxetine for a therapeutic agent after acute SCI in humans. PMID:25366938

  17. Atorvastatin and Fluoxetine Prevent Oxidative Stress and Mitochondrial Dysfunction Evoked by Glutamate Toxicity in Hippocampal Slices.

    Science.gov (United States)

    Ludka, Fabiana K; Dal-Cim, Tharine; Binder, Luisa Bandeira; Constantino, Leandra Celso; Massari, Caio; Tasca, Carla I

    2017-07-01

    Atorvastatin has been shown to exert a neuroprotective action by counteracting glutamatergic toxicity. Recently, we have shown atorvastatin also exerts an antidepressant-like effect that depends on both glutamatergic and serotonergic systems modulation. Excitotoxicity is involved in several brain disorders including depression; thus, it is suggested that antidepressants may target glutamatergic system as a final common pathway. In this study, a comparison of the mechanisms involved in the putative neuroprotective effect of a repetitive atorvastatin or fluoxetine treatment against glutamate toxicity in hippocampal slices was performed. Adult Swiss mice were treated with atorvastatin (10 mg/kg, p.o.) or fluoxetine (10 mg/kg, p.o.), once a day during seven consecutive days. On the eighth day, animals were killed and hippocampal slices were obtained and subjected to an in vitro protocol of glutamate toxicity. An acute treatment of atorvastatin or fluoxetine was not neuroprotective; however, the repeated atorvastatin or fluoxetine treatment prevented the decrease in cellular viability induced by glutamate in hippocampal slices. The loss of cellular viability induced by glutamate was accompanied by increased D-aspartate release, increased reactive oxygen species (ROS) and nitric oxide (NO) production, and impaired mitochondrial membrane potential. Atorvastatin or fluoxetine repeated treatment also presented an antidepressant-like effect in the tail suspension test. Atorvastatin or fluoxetine treatment was effective in protecting mice hippocampal slices from glutamate toxicity by preventing the oxidative stress and mitochondrial dysfunction.

  18. Fluoxetin Upregulates Connexin 43 Expression in Astrocyte

    Directory of Open Access Journals (Sweden)

    Hossein Mostafavi

    2014-02-01

    Full Text Available Introduction: Recent studies have shown that astrocytes play major roles in normal and disease condition of the central nervous system including multiple sclerosis (MS. Molecular target therapy studies in MS have revealed that connexin-43 (Cx43 and Aquaporin-4 (AQP4 contents of astrocytes undergo expression alteration. Fluoxetine had some effects in MS patients unrelated to its known antidepressant effects. Some of fluoxetine effects were attributed to its capability of cAMP signaling pathway stimulation. This study aimed to investigate possible acute effects of fluoxetine on Cx43 and AQP4 expression in astrocyte.  Methods: Astrocytoma cells were treated for 24 hours with fluoxetine (10 and 20 &mug/ml with or without adenyl cyclase (AC and protein kinase A (PKA inhibition. Cx43 expression at both mRNA and protein levels and AQP4 expression at mRNA level were evaluated.  Results: Acquired results showed that fluoxetine with and without AC and PKA inhibition resulted in Cx43 up-regulation both in mRNA and protein levels, whereas AQP4 expression have not changed.  Discussion: In conclusion, data showed that fluoxetine alone and in the absence of serotonin acutely up-regulated Cx43 expression in astrocytes that can be assumed in molecular target therapy of MS patients. It seems that cAMP involvement in fluoxetine effects need more researches.

  19. Fluoxetine impairs GABAergic signaling in hippocampal slices from neonatal rats

    Directory of Open Access Journals (Sweden)

    Enrico eCherubini

    2013-05-01

    Full Text Available Fluoxetine (Prozac, an antidepressant known to selectively inhibit serotonin reuptake, is widely used to treat mood disorders in women suffering from depression during pregnancy and postpartum period. Several lines of evidence suggest that this drug, which crosses the human placenta and is secreted into milk during lactation, exerts its action not only by interfering with serotoninergic but also with GABAergic transmission. GABA is known to play a crucial role in the construction of neuronal circuits early in postnatal development. The immature hippocampus is characterized by an early type of network activity, the so-called Giant Depolarizing Potentials (GDPs, generated by the synergistic action of glutamate and GABA, both depolarizing and excitatory. Here we tested the hypothesis that fluoxetine may interfere with GABAergic signaling during the first postnatal week, thus producing harmful effects on brain development. At micromolar concentrations fluoxetine severely depressed GDPs frequency (IC50 22 M in a reversible manner and independently of its action on serotonin reuptake. This effect was dependent on a reduced GABAergic (but not glutamatergic drive to principal cells most probably from parvalbumin-positive fast spiking neurons. Cholecystokinin-positive GABAergic interneurons were not involved since the effects of the drug persisted when cannabinoid receptors were occluded with WIN55,212-2, a CB1/CB2 receptor agonist. Fluoxetine effects on GABAergic transmission were associated with a reduced firing rate of both principal cells and interneurons further suggesting that changes in network excitability account for GDPs disruption. This may have critical consequences on the functional organization and stabilization of neuronal circuits early in postnatal development.

  20. Novel radioiodinated sibutramine and fluoxetine as models for brain imaging

    International Nuclear Information System (INIS)

    Motaleb, M.A.; El-Kolaly, M.T.; Rashed, H.M.; Abd El-Bary, A.

    2011-01-01

    Brain imaging is a process which allows scientists and physicians to view and monitor the areas of the brain which allow diagnosis and following up different abnormalities in the brain. The aim of this study was to develop potential radiopharmaceuticals for the non-invasive brain imaging. Sibutramine and fluoxetine (two drugs that have the ability to cross blood-brain barrier) were successfully labeled with 125 I via direct electrophilic substitution reaction at ambient temperature. The reaction parameters studied were substrate concentration, oxidizing agent concentration, pH of the reaction mixture, reaction temperature, reaction time and in vitro stability of the iodocompounds. The iodocompounds gave maximum labeling yield of 92 ± 2.77 and 93 ± 2.1%, respectively, and maintained stability throughout working period (24 h). Biodistribution studies showed that maximum in vivo uptake of the iodocompounds in the brain was 5.7 ± 0.19 and 6.14 ± 0.26% injected activity/g tissue organ, respectively, at 15 and 5 min post-injection, whereas the clearance from the mice appeared to proceed via the hepatobiliary pathway. Brain uptake of 125 I-sibutramine and 125 I-fluoxetine is higher than that of 99m Tc-ECD and 99m Tc-HMPAO (currently used radiopharmaceuticals for brain imaging) and so radioiodinated sibutramine and fluoxetine could be used instead of 99m Tc-ECD and 99m Tc-HMPAO for brain SPECT. (author)

  1. Behavioral interactions of simvastatin and fluoxetine in tests of anxiety and depression

    Directory of Open Access Journals (Sweden)

    Santos T

    2012-10-01

    Full Text Available Tainaê Santos,1 Monaliza Marizete Baungratz,1 Suellen Priscila Haskel,2 Daniela Delwing de Lima,3 Júlia Niehues da Cruz,4 Débora Delwing Dal Magro,5 José Geraldo Pereira da Cruz51Department of Medicine, 2Department of Physiotherapy, Regional University of Blumenau, Santa Catarina, Brazil; 3Department of Pharmacy, University of Joinville Region, Santa Catarina, Brazil; 4Department of Medicine, University of the Extreme South of Santa Catarina, Santa Catarina, Brazil; 5Department of Natural Sciences, Regional University of Blumenau, Santa Catarina, BrazilAbstract: Simvastatin inhibits 3-hydroxy-3-methylglutaryl CoA reductase, the rate-limiting enzyme in the cholesterol biosynthetic pathway, and is widely used to control plasma cholesterol levels and prevent cardiovascular disease. However, emerging evidence indicates that the beneficial effects of simvastatin extend to the central nervous system. The effects of simvastatin combined with fluoxetine provide an exciting and potential paradigm to decreased anxiety and depression. Thus, the present paper investigates the possibility of synergistic interactions between simvastatin and fluoxetine in models of anxiety and depression. We investigated the effects of subchronically administered simvastatin (1 or 10 mg/kg/day combined with fluoxetine (2 or 10 mg/kg at 24, 5, and 1 hour on adult rats before conducting behavioral tests. The results indicate that simvastatin and/or fluoxetine treatment reduces anxiety-like behaviors in the elevated plus-maze and open-field tests. Our results showed that simvastatin and/or fluoxetine induced a significant increase in the swimming activity during the forced swimming test (antidepressant effect, with a concomitant increase in climbing time in simvastatin-treated animals only (noradrenergic activation. We hypothesize that anxiolytic and antidepressant effects of simvastatin and/or fluoxetine produce their behavioral effects through similar mechanisms and provide

  2. In vitro adsorption study of fluoxetine in activated carbons and activated carbon fibres

    Energy Technology Data Exchange (ETDEWEB)

    Nabais, J.M. Valente; Mouquinho, A.; Galacho, C.; Carrott, P.J.M.; Ribeiro Carrott, M.M.L. [Centro de Quimica de Evora e Departamento de Quimica da Universidade de Evora, Rua Romao Ramalho no. 59, 7000-671 Evora (Portugal)

    2008-05-15

    We study the in vitro adsorption of fluoxetine hydrochloride by different adsorbents in simulated gastric and intestinal fluid, pH 1.2 and 7.5, respectively. The tested materials were two commercial activated carbons, carbomix and maxsorb MSC30, one activated carbon fibre produced in our laboratory and also three MCM-41 samples, also produced by us. Selected samples were modified by liquid phase oxidation and thermal treatment in order to change the surface chemistry without significant modifications to the porous characteristics. The fluoxetine adsorption follows the Langmuir model. The calculated Q{sub 0} values range from 54 to 1112 mg/g. A different adsorption mechanism was found for the adsorption of fluoxetine in activated carbon fibres and activated carbons. In the first case the most relevant factors are the molecular sieving effect and the dispersive interactions whereas in the activated carbons the mechanism seams to be based on the electrostatic interactions between the fluoxetine molecules and the charged carbon surface. Despite the different behaviours most of the materials tested have potential for treating potential fluoxetine intoxications. (author)

  3. Fluoxetine

    Science.gov (United States)

    ... treated with electroshock therapy (procedure in which small electric shocks are administered to the brain to treat ... may make you drowsy. Do not drive a car or operate machinery until you know how this ...

  4. Fluoxetine treatment ameliorates depression induced by perinatal arsenic exposure via a neurogenic mechanism

    Science.gov (United States)

    Tyler, Christina R.; Solomon, Benjamin R.; Ulibarri, Adam L.; Allan, Andrea M.

    2014-01-01

    Several epidemiological studies have reported an association between arsenic exposure and increased rates of psychiatric disorders, including depression, in exposed populations. We have previously demonstrated that developmental exposure to low amounts of arsenic induces depression in adulthood along with several morphological and molecular aberrations, particularly associated with the hippocampus and the hypothalamic–pituitary–adrenal (HPA) axis. The extent and potential reversibility of this toxin-induced damage has not been characterized to date. In this study, we assessed the effects of fluoxetine, a selective serotonin reuptake inhibitor antidepressant, on adult animals exposed to arsenic during development. Perinatal arsenic exposure (PAE) induced depressive-like symptoms in a mild learned helplessness task and in the forced swim task after acute exposure to a predator odor (2,4,5-trimethylthiazoline, TMT). Chronic fluoxetine treatment prevented these behaviors in both tasks in arsenic-exposed animals and ameliorated arsenic-induced blunted stress responses, as measured by corticosterone (CORT) levels before and after TMT exposure. Morphologically, chronic fluoxetine treatment reversed deficits in adult hippocampal neurogenesis (AHN) after PAE, specifically differentiation and survival of neural progenitor cells. Protein expression of BDNF, CREB, the glucocorticoid receptor (GR), and HDAC2 was significantly increased in the dentate gyrus of arsenic animals after fluoxetine treatment. This study demonstrates that damage induced by perinatal arsenic exposure is reversible with chronic fluoxetine treatment resulting in restored resiliency to depression via a neurogenic mechanism. PMID:24952232

  5. Evaluation of interleukin-6 and serotonin as biomarkers to predict response to fluoxetine.

    Science.gov (United States)

    Manoharan, Aarthi; Rajkumar, Ravi Philip; Shewade, Deepak Gopal; Sundaram, Rajan; Muthuramalingam, Avin; Paul, Abialbon

    2016-05-01

    Only 30% of major depressive disorder (MDD) patients achieve complete remission with a serotonergic antidepressant (selective serotonin reuptake inhibitor). We investigated the potential of serotonin (5-HT) and interleukin-6 (IL-6) to serve as functional biomarkers of fluoxetine response. Serum IL-6 and 5-HT were measured in 73 MDD patients (39 responders and 34 non-responders) pre- and 6 weeks post-treatment and in 44 normal controls with ELISA. Fluoxetine and norfluoxetine were measured using LC MS/MS. IL-6 levels were significantly higher in MDD patients when compared with controls (p Fluoxetine and norfluoxetine concentrations were not significantly different in responders and non-responders, and there was no correlation between fluoxetine concentrations and percentage reduction in 5-HT from week 0 to 6. 5-HT and IL-6 may not serve as useful markers of response to fluoxetine because of inconsistent results across different studies. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  6. Chronic administration of fluoxetine and pro-inflammatory cytokine change in a rat model of depression.

    Directory of Open Access Journals (Sweden)

    Yanxia Lu

    Full Text Available This study evaluated the chronic effects of fluoxetine, a commonly prescribed SSRI antidepressant, on the peripheral and central levels of inflammatory cytokines including IL-1β, IL-6, TNF-α and IL-17 over a 4-interval in a rat model of chronic mild stress (CMS which resembles the human experience of depression. Twenty-four Sprague-Dawley rats were randomly assigned to CMS+vehicle (n = 9, CMS+fluoxetine (n = 9 and the control (n = 6 groups. Sucrose preference and forced swim tests were performed to assess behavioral change. Blood samples were collected on day 0, 60, 90 and 120 for measurement of cytokine levels in plasma. On day 120, the brain was harvested and central level of cytokines was tested using Luminex. Four months of fluoxetine treatment resulted in changes in the sucrose preference and immobility time measurements, commensurate with antidepressant effects. The CMS+vehicle group exhibited elevated plasma levels of IL-1β, IL-17, and TNF-α on day 60 or 120. Rats treated with fluoxetine demonstrated lower IL-1β in plasma and brain after 90 and 120-day treatment respectively (p<0.05. There was a trend of reduction of IL-6 and TNF-α concentration. This study revealed the potential therapeutic effects of fluoxetine by reducing central and peripheral levels of IL-1β in the alleviation of depressive symptoms.

  7. Sex-dependent effects of fluoxetine and triiodothyronine in the forced swim test in rats.

    Science.gov (United States)

    Lifschytz, Tzuri; Shalom, Galit; Lerer, Bernard; Newman, Michael E

    2006-02-01

    The effects of triiodothyronine (T3) and fluoxetine, administered separately and combined, on behavior of male and female rats in the forced swim test, a procedure for screening antidepressant-like activity, were determined. There were no consistent effects of low doses of fluoxetine (5 mg/kg) or T3 (20 microg/kg), administered daily for 2 weeks. Fluoxetine administered daily at 10 mg/kg for 7 days reduced immobility and increased active behaviors in male rats, but had no effects in female rats. The effects of fluoxetine in male rats were not potentiated by T3. In female rats, T3 at 100 microg/kg given daily for 7 days decreased immobility and increased swimming when these were measured 72 h after the last injection, but not when measurements were performed at an earlier time point. These results provide some support from an animal model for the efficacy of T3 as antidepressant therapy in female patients, but do not provide support for the augmentation and acceleration effects seen clinically when T3 is used in conjunction with established antidepressants such as fluoxetine.

  8. Fluoxetine reverses the behavioral despair induced by neurogenic stress in mice: role of N-methyl-d-aspartate and opioid receptors.

    Science.gov (United States)

    Haj-Mirzaian, Arya; Kordjazy, Nastaran; Ostadhadi, Sattar; Amiri, Shayan; Haj-Mirzaian, Arvin; Dehpour, AhmadReza

    2016-06-01

    Opioid and N-methyl-d-aspartate (NMDA) receptors mediate different effects of fluoxetine. We investigated whether opioid and NMDA receptors are involved in the protective effect of fluoxetine against the behavioral despair induced by acute physical stress in male mice. We used the forced swimming test (FST), tail suspension test (TST), and open-field test (OFT) for behavioral evaluation. We used fluoxetine, naltrexone (opioid receptor antagonist), MK-801 (NMDA receptor antagonist), morphine (opioid receptor agonist), and NMDA (NMDA receptor agonist). Acute foot-shock stress (FSS) significantly induced behavioral despair (depressive-like) and anxiety-like behaviors in tests. Fluoxetine (5 mg/kg) reversed the depressant-like effect of FSS, but it did not alter the locomotion and anxiety-like behavior in animals. Acute administration of subeffective doses of naltrexone (0.3 mg/kg) or MK-801 (0.01 mg/kg) potentiated the antidepressant-like effect of fluoxetine, while subeffective doses of morphine (1 mg/kg) and NMDA (75 mg/kg) abolished this effect of fluoxetine. Also, co-administration of subeffective doses of naltrexone (0.05 mg/kg) and MK-801 (0.003 mg/kg) with fluoxetine (1 mg/kg) induced a significant decrease in the immobility time in FST and TST. Our results showed that opioid and NMDA receptors (alone or in combination) are involved in the antidepressant-like effect of fluoxetine against physical stress.

  9. Compound list: fluoxetine hydrochloride [Open TG-GATEs

    Lifescience Database Archive (English)

    Full Text Available fluoxetine hydrochloride FLX 00158 ftp://ftp.biosciencedbc.jp/archive/open-tggates/...LATEST/Human/in_vitro/fluoxetine_hydrochloride.Human.in_vitro.Liver.zip ftp://ftp.biosciencedbc.jp/archive/o...pen-tggates/LATEST/Rat/in_vivo/Liver/Single/fluoxetine_hydrochloride.Rat.in_vivo.Liver.Single.zip ftp://ftp....biosciencedbc.jp/archive/open-tggates/LATEST/Rat/in_vivo/Liver/Repeat/fluoxetine_hydrochloride.Rat.in_vivo.Liver.Repeat.zip ...

  10. Rapsyn congenital myasthenic syndrome worsened by fluoxetine.

    Science.gov (United States)

    Visser, Amy C; Laughlin, Ruple S; Litchy, William J; Benarroch, Eduardo E; Milone, Margherita

    2017-01-01

    Fluoxetine is a selective serotonin reuptake inhibitor and long-lived open channel blocker of the acetylcholine receptor, often used in the treatment of slow-channel congenital myasthenic syndromes (CMS). We report a 42-year-old woman who had a history of episodic limb weakness that worsened after initiation of fluoxetine for treatment of depression. Genetic testing for CMS revealed a homozygous pathogenic mutation in the rapsyn (RAPSN) gene (p.Asn88Lys). Electrodiagnostic testing was performed before and 1 month after discontinuation of fluoxetine. The 2 Hz repetitive nerve stimulation of the fibular and spinal accessory nerves showed a baseline decrement of 36% and 14%, respectively. One month after discontinuing fluoxetine, the spinal accessory nerve decrement was no longer present, and the decrement in the fibular nerve was improved at 17%. This case demonstrates worsening of both clinical and electrophysiologic findings in a patient with CMS secondary to a RAPSN mutation treated with fluoxetine. Muscle Nerve 55: 131-135, 2017. © 2016 Wiley Periodicals, Inc.

  11. Fluoxetine ameliorates atopic dermatitis-like skin lesions in BALB/c mice through reducing psychological stress and inflammatory response

    Directory of Open Access Journals (Sweden)

    Yanxi Li

    2016-09-01

    Full Text Available Atopic dermatitis (AD is a common chronic inflammatory skin disorder, and patients with AD suffer from severe psychological stress, which markedly increases the prevalence rate of depression and anxiety disorders in later life. Fluoxetine, a selective serotonin reuptake inhibitor, has recently been reported to exert anti-inflammatory and immunosuppressive effects. However, it is unclear whether fluoxetine is effective in the treatment of AD through reducing psychological stress and inflammatory reaction. Here, we reported that a BALB/c mouse model of AD was induced by application of 2,4‑dinitrochlorobenzene (DNCB onto hairless dorsal skin. Chronic fluoxetine treatment (10 mg/kg per day, i.p. significantly attenuated AD-like symptoms, as reflected by a dramatic decrease in scratching bouts, as well as a decrease in anxiety- and depressive-like behaviors. Furthermore, these behavioral changes were accompanied by a significant decrease in epidermal thickness, the number of mast cells in skin tissue, mRNA levels of interleukin-4 (IL-4 and IL-13 in the spleen, as well as serum immunoglobulin E (IgE in the DNCB-treated mice by treatment with fluoxetine. Taken together, these results indicate that fluoxetine may suppress psychological stress and inflammatory response during AD development, and subsequently ameliorate AD symptoms, suggesting that fluoxetine may be a potential therapeutic agent against AD in clinic.

  12. Bioconcentration of the antidepressant fluoxetine and its effects on the physiological and biochemical status in Daphnia magna.

    Science.gov (United States)

    Ding, Jiannan; Zou, Hua; Liu, Qingqing; Zhang, Shanshan; Mamitiana Razanajatovo, Roger

    2017-08-01

    The aim of this study was to evaluate the bioconcentration potential of fluoxetine and its biological effects in Daphnia magna. After 48h of waterborne exposure, the bioconcentration of fluoxetine in D. magna was determined to be 460.61 and 174.41Lkg -1 for nominal exposure concentrations of 0.5 and 5µgL -1 , respectively. Moreover, various biological endpoints, including physiological responses (filtration and ingestion rates), enzymatic biomarkers related to neurotoxicity [acetylcholinesterase (AChE)] and antioxidant defense [superoxide dismutase (SOD)], and an oxidative stress damage marker [malondialdehyde (MDA)], were assessed. Fluoxetine exposure increased the filtration rate of daphnia, while the ingestion rate was not obviously modified. AChE activity was significantly inhibited, highlighting the neurotoxicity of fluoxetine on D. magna. However, with some alterations in the SOD activity and MDA content, no obvious oxidative damage was observed in D. magna exposed to fluoxetine at the tested concentrations. These results indicate that fluoxetine can be accumulated and consequently induce physiological and biochemical perturbations in D. magna. Copyright © 2017. Published by Elsevier Inc.

  13. 21 CFR 520.980 - Fluoxetine.

    Science.gov (United States)

    2010-04-01

    ... FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.980 Fluoxetine. (a) Specifications. Each... conjunction with a behavior modification plan. (3) Limitations. Federal law restricts this drug to use by or...

  14. Effect of addition of yohimbine (alpha-2-receptor antagonist) to the antidepressant activity of fluoxetine or venlafaxine in the mouse forced swim test.

    Science.gov (United States)

    Dhir, Ashish; Kulkarni, S K

    2007-01-01

    Studies have suggested that alpha(2)-adrenoceptors strongly affect monoaminergic neurotransmission by enhancing not only noradrenergic but also serotonergic firing rates. With this background in mind, the present study was undertaken to monitor the effect of addition of yohimbine (alpha(2)-adrenoceptor antagonist) to the effect of fluoxetine (selective serotonin reuptake inhibitor) or venlafaxine (dual reuptake inhibitors of both serotonin and norepinephrine) in Porsolt's forced swim test (FST) using male Laca strain mice. The immobility period was recorded in mouse FST during a 6-min period. Different doses of fluoxetine or venlafaxine were administered 30 min before exposing the animals to the test procedure. In the combination study, yohimbine (2 mg/kg i.p.) was administered 15 min before the administration of different doses of fluoxetine or venlafaxine. Fluoxetine (5, 10, 20 and 40 mg/kg) [F = 28.352] or venlafaxine (2, 4, 8 and 16 mg/kg) [F = 17.842] dose-dependently inhibited the immobility period in mice. Addition of yohimbine (2 mg/kg i.p.) potentiated the antidepressant action of fluoxetine or venlafaxine in mouse FST as the animals showed a decrease in the immobility period compared to the fluoxetine or venlafaxine per se group, respectively. The present study not only demonstrated the association of alpha(2)-receptors in the antidepressant effect of fluoxetine or venlafaxine, but also supports its adjuvant therapy with other antidepressant drugs. (c) 2007 S. Karger AG, Basel.

  15. Amelioration of ongoing experimental autoimmune encephalomyelitis with fluoxetine.

    Science.gov (United States)

    Bhat, Roopa; Mahapatra, Sidharth; Axtell, Robert C; Steinman, Lawrence

    2017-12-15

    In patients with multiple sclerosis, the selective serotonin reuptake inhibitor, fluoxetine, resulted in less acute disease activity. We tested the immune modulating effects of fluoxetine in a mouse model of multiple sclerosis, i.e. experimental autoimmune encephalomyelitis (EAE). We show that fluoxetine delayed the onset of disease and reduced clinical paralysis in mice with established disease. Fluoxetine had abrogating effects on proliferation of immune cells and inflammatory cytokine production by both antigen-presenting cells and T cells. Specifically, in CD 4 T cells, fluoxetine increased Fas-induced apoptosis. We conclude that fluoxetine possesses immune-modulating effects resulting in the amelioration of symptoms in EAE. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Effects of amitriptyline and fluoxetine on synaptic plasticity in the dentate gyrus of hippocampal formation in rats

    Directory of Open Access Journals (Sweden)

    Ghasem Zarei

    2014-01-01

    Full Text Available Background: Several studies have been shown that antidepressant drugs have contradictory effects on cognitive processes. Therefore, the aim of this study was to investigate the effects of amitriptyline and fluoxetine on synaptic plasticity in the dentate gyrus (DG of the hippocampal formation in rat. Materials and Methods: Experimental groups were the control, the fluoxetine, and amitriptyline. The rats were treated for 21 days and then, paired pulse facilitation/inhibition (PPF/I and long-term potentiation (LTP in perforant path-DG synapses were assessed (by 400 Hz tetanization. Field excitatory post-synaptic potential (fEPSP slope and population spike (PS amplitude were measured. Results: The results of PPF/I showed that PS amplitude ratios were increased in 10-70 ms inter-stimulus intervals in the amitriptyline group compared to the control group. In the fluoxetine group, EPSP slope ratios were decreased in intervals 30, 40, and 50 ms inter-stimulus intervals compared to the control group. The PS-LTP was significantly lower in the fluoxetine and the amitriptyline groups with respect to the control group. Conclusion: The results showed that fluoxetine and amitriptyline affect synaptic plasticity in the hippocampus and these effects is probably due to the impact on the number of active neurons.

  17. Dual effects of fluoxetine on mouse early embryonic development

    International Nuclear Information System (INIS)

    Kim, Chang-Woon; Choe, Changyong; Kim, Eun-Jin; Lee, Jae-Ik; Yoon, Sook-Young; Cho, Young-Woo; Han, Sunkyu; Tak, Hyun-Min; Han, Jaehee; Kang, Dawon

    2012-01-01

    Fluoxetine, a selective serotonin reuptake inhibitor, regulates a variety of physiological processes, such as cell proliferation and apoptosis, in mammalian cells. Little is known about the role of fluoxetine in early embryonic development. This study was undertaken to investigate the effect of fluoxetine during mouse early embryonic development. Late two-cell stage embryos (2-cells) were cultured in the presence of various concentrations of fluoxetine (1 to 50 μM) for different durations. When late 2-cells were incubated with 5 μM fluoxetine for 6 h, the percentage that developed into blastocysts increased compared to the control value. However, late 2-cells exposed to fluoxetine (5 μM) over 24 h showed a reduction in blastocyst formation. The addition of fluoxetine (5 μM) together with KN93 or KN62 (calcium/calmodulin-dependent protein kinase II (CaMKII) inhibitors) failed to increase blastocyst formation. Fluoxetine treatment inhibited TREK-1 and TREK-2, members of the two-pore domain K + channel family expressed in mouse embryos, activities, indicating that fluoxetine-induced membrane depolarization in late 2-cells might have resulted from TREK inhibition. In addition, long-term exposure to fluoxetine altered the TREK mRNA expression levels. Furthermore, injection of siRNA targeting TREKs significantly decreased blastocyst formation by ∼ 30% compared to injection of scrambled siRNA. Long-term exposure of fluoxetine had no effect on blastocyst formation of TREK deficient embryos. These results indicate that low-dose and short-term exposures of late 2-cells to fluoxetine probably increase blastocyst formation through activation of CaMKII-dependent signal transduction pathways, whereas long-term exposure decreases mouse early embryonic development through inhibition of TREK channel gating. Highlights: ► Short-term exposure of 2-cells to fluoxetine enhances mouse blastocyst formation. ► The enhancive effect of fluoxetine is resulted from CaMKII activation

  18. Dual effects of fluoxetine on mouse early embryonic development

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Chang-Woon [Department of Physiology and Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 660-751 (Korea, Republic of); Department of Obstetrics and Gynecology, Samsung Changwon Hospital, Sungkyunkwan University, Changwon 630-723 (Korea, Republic of); Choe, Changyong [National Institute of Animal Science, RDA, Cheonan 330-801 (Korea, Republic of); Kim, Eun-Jin [Department of Physiology and Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 660-751 (Korea, Republic of); Lee, Jae-Ik [Department of Obstetrics and Gynecology, Gyeongsang National University Hospital, Jinju 660-702 (Korea, Republic of); Yoon, Sook-Young [Fertility Center of CHA Gangnam Medical Center, CHA University, Seoul 135-081 (Korea, Republic of); Cho, Young-Woo; Han, Sunkyu; Tak, Hyun-Min; Han, Jaehee [Department of Physiology and Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 660-751 (Korea, Republic of); Kang, Dawon, E-mail: dawon@gnu.ac.kr [Department of Physiology and Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 660-751 (Korea, Republic of)

    2012-11-15

    Fluoxetine, a selective serotonin reuptake inhibitor, regulates a variety of physiological processes, such as cell proliferation and apoptosis, in mammalian cells. Little is known about the role of fluoxetine in early embryonic development. This study was undertaken to investigate the effect of fluoxetine during mouse early embryonic development. Late two-cell stage embryos (2-cells) were cultured in the presence of various concentrations of fluoxetine (1 to 50 μM) for different durations. When late 2-cells were incubated with 5 μM fluoxetine for 6 h, the percentage that developed into blastocysts increased compared to the control value. However, late 2-cells exposed to fluoxetine (5 μM) over 24 h showed a reduction in blastocyst formation. The addition of fluoxetine (5 μM) together with KN93 or KN62 (calcium/calmodulin-dependent protein kinase II (CaMKII) inhibitors) failed to increase blastocyst formation. Fluoxetine treatment inhibited TREK-1 and TREK-2, members of the two-pore domain K{sup +} channel family expressed in mouse embryos, activities, indicating that fluoxetine-induced membrane depolarization in late 2-cells might have resulted from TREK inhibition. In addition, long-term exposure to fluoxetine altered the TREK mRNA expression levels. Furthermore, injection of siRNA targeting TREKs significantly decreased blastocyst formation by ∼ 30% compared to injection of scrambled siRNA. Long-term exposure of fluoxetine had no effect on blastocyst formation of TREK deficient embryos. These results indicate that low-dose and short-term exposures of late 2-cells to fluoxetine probably increase blastocyst formation through activation of CaMKII-dependent signal transduction pathways, whereas long-term exposure decreases mouse early embryonic development through inhibition of TREK channel gating. Highlights: ► Short-term exposure of 2-cells to fluoxetine enhances mouse blastocyst formation. ► The enhancive effect of fluoxetine is resulted from Ca

  19. Fluoxetine effect on gestation and fetal development

    Directory of Open Access Journals (Sweden)

    Ösz Bianca Eugenia

    2014-08-01

    Full Text Available The prenatal exposure to selective serotonin reuptake inhibitors (SSRIs is very controversial. There is no conclusive evidence for increased risk of malformations after SSRI use in pregnancy. The aim of the study was to determine how fluoxetine is affecting gestation and fetal development in rats. Twenty sexually mature female Wistar rats weighting between 250-260 g received 20 mg/kg body weight fluoxetine from the first day of gestation and during the entire gestation period.The drug was administered by oral route. Healthy, primipareus animals were selected along with 20 female Wistar rats, as control group. Mature males were caged with virgin females for an entire week. Rat’s behaviour during gestation, after birth and rats body weight was examined. The number of healthy pups was also noted. The females not giving birth after 21 days to any pup were anesthetized (halothane through gas scavenging apparatus untilled death and the gravid uterus were dissected out and examined. Compared to the controlled group, in which weight gain was more significant, the animals from the experimental group had a slight increase in body weight. The weight gain normally induced by gestation, is less significant in fluoxetine treated rats due to the increase serotonin levels in the brain. The uteri examination of pregnant rats showed an increase in the number of dead and resorbed rat embryos. Preclinical studies suggest that the inclusion of fluoxetine in pregnancy category C is justified and the appropriateness of its administration in pregnancy is still an unresolved issue.

  20. Comparison between herbal medicine and fluoxetine for depression: a systematic review of randomized controlled trials.

    Science.gov (United States)

    Ren, Yi; Zhu, Chenjun; Wu, Jianjun; Zheng, Ruwen; Cao, Huijaun

    2015-10-01

    To evaluate the effectiveness and safety of Chinese herbal medicine (CHM) versus fluoxetine on depression. A systematic review of randomized controlled trials (RCTs). RCT with two parallel groups that compared CHM and fluoxetine on treatment of depression with reported decreased Hamilton Depression Scale (HAMD) and adverse events during treatment were included after searching through six electric-databases. The methodological quality of RCTs was assessed according to the Cochrane risk of bias tool. Meta-analysis was conducted using RevMan 5.3 software with pooled mean difference (MD) or risk ratio (RR) and their 95% confidence interval (CI) if no significant heterogeneity was detected. A SOF table was generated using GRADEPro software to evaluate the overall quality of the evidence. Twenty-six trials with 3294 participants were included in the review. Most of them had high risk of bias during conducting and reporting. The results achieved weak evidence which showed CHM had similar effect to fluoxetine (20mg/day) on relieving depression according to HAMD assessment (for primary depression: MD=-0.08, 95%CI -0.98-0.82; for secondary depression: MD=-0.36, 95%CI -1.55-0.83), but fewer incidences of adverse events than the drug (for primary depression: RR=0.31, 95%CI 0.17-0.59; for post-stroke depression: RR=0.04, 95%CI 0.00-0.25). No serious adverse event was found in neither CHM nor fluoxetine group. Due to the poor quality of included trials and the potential publication bias of this review, no confirmed conclusion could be draw to evaluate the effectiveness and safety of CHM for depression compared with fluoxetine. Copyright © 2015 Elsevier Ltd. All rights reserved.

  1. Inhibitory effect of chronic oral treatment with fluoxetine on capsaicin-induced external carotid vasodilatation in anaesthetised dogs.

    Science.gov (United States)

    Muñoz-Islas, Enriqueta; González-Hernández, Abimael; Lozano-Cuenca, Jair; Ramírez-Rosas, Martha Beatríz; Medina-Santillán, Roberto; Centurión, David; MaassenVanDenBrink, Antoinette; Villalón, Carlos M

    2015-10-01

    During migraine, capsaicin-sensitive trigeminal sensory nerves release calcitonin gene-related peptide (CGRP), resulting in cranial vasodilatation and central nociception. Moreover, 5-HT is involved in the pathophysiology of migraine and depression. Interestingly, some limited lines of evidence suggest that fluoxetine may be effective in migraine prophylaxis, but the underlying mechanisms are uncertain. Hence, this study investigated the canine external carotid vasodilator responses to capsaicin, α-CGRP and acetylcholine before and after acute and chronic oral treatment with fluoxetine. Forty-eight vagosympathectomised male mongrel dogs were prepared to measure blood pressure, heart rate and external carotid blood flow. The thyroid artery was cannulated for infusions of agonists. In 16 of these dogs, a spinal cannula was inserted (C1-C3) for infusions of 5-HT. The external carotid vasodilator responses to capsaicin, α-CGRP and acetylcholine remained unaffected after intracarotid or i.v. fluoxetine. In contrast, the vasodilator responses to capsaicin, but not those to α-CGRP or acetylcholine, were inhibited after chronic oral treatment with fluoxetine (300 µg/kg; for 90 days) or intrathecal 5-HT. Chronic oral fluoxetine inhibited capsaicin-induced external carotid vasodilatation, and this inhibition could partly explain its potential prophylactic antimigraine action. © International Headache Society 2015.

  2. Fluoxetine and the mitochondria: A review of the toxicological aspects.

    Science.gov (United States)

    de Oliveira, Marcos Roberto

    2016-09-06

    Fluoxetine (a selective serotonin reuptake inhibitor (SSRI)) is used as an antidepressant by modulating the levels of serotonin in the synaptic cleft. Nevertheless, fluoxetine also induces undesirable effects, such as anxiety, sexual dysfunction, sleep disturbances, and gastrointestinal impairments. Fluoxetine has been viewed as an agent that may interfere with cell fate by triggering apoptosis. On the other hand, fluoxetine intake has been associated with increased cancer risk. Nonetheless, data remain contradictory and no conclusions were taken. Several studies demonstrated that fluoxetine interacts with mitochondria triggering apoptosis and/or altering mitochondrial function by modulating the activity of respiratory chain components and enzymes of the Krebs cycle. Furthermore, fluoxetine affects mitochondria-related redox parameters in different experimental models. In this review, data demonstrating the effects of fluoxetine upon mammalian mitochondria are described and discussed, as well as several unsolved questions in this field of research are addressed. A separate section deals with future needs regarding the research involving the impact of fluoxetine treatment upon mitochondria and mitochondria-related signaling. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  3. Factors influencing fluoxetine-induced sexual dysfunction in female rats

    Science.gov (United States)

    Adams, Sarah; Heckard, Danyeal; Hassell, James; Uphouse, Lynda

    2012-01-01

    Treatment with selective serotonin reuptake inhibitors, such as fluoxetine, produces sexual side effects with low sexual desire being the most prevalent effect in females. In few studies have preclinical models for such antidepressant-induced sexual dysfunction been fruitful. In the current manuscript, the effects of fluoxetine on multiple measures of female sexual motivation and sexual receptivity were examined. Ovariectomized, Fischer rats were primed with 10 μg estradiol benzoate and 500 μg progesterone. Partner preference, active investigation of the male, and measures of sexual behavior were examined after injection with 15 mg/kg fluoxetine. Factors (pretesting for sexual behavior, size of the test arena, non-contact time with a male) that differ among experiments designed to study antidepressant-induced female rat sexual dysfunction were studied. The male preference ratio was not affected by fluoxetine treatment but active investigation of the male was reduced; lordosis behavior was inhibited and pretesting for sexual receptivity amplified fluoxetine's inhibition; size of the testing arena or non-contact experience with the male had no effect. Regardless of test condition, when given the opportunity to escape from the male, fluoxetine-treated females displayed escape behavior. Measures of male preference and active investigation, but not lordosis behavior, appeared to be affected by fluoxetine's impact on activity. The collective data provided a behavioral profile of fluoxetine-induced sexual dysfunction. These findings reinforce the value of multiple measures when attempting to model antidepressant-induced female sexual dysfunction. PMID:22835821

  4. Chronic fluoxetine dissociates contextual from auditory fear memory.

    Science.gov (United States)

    Sanders, Jeff; Mayford, Mark

    2016-10-06

    Fluoxetine is a medication used to treat Major Depressive Disorder and other psychiatric conditions. These experiments studied the effects of chronic fluoxetine treatment on the contextual versus auditory fear memory of mice. We found that chronic fluoxetine treatment of adult mice impaired their contextual fear memory, but spared auditory fear memory. Hippocampal perineuronal nets, which are involved in contextual fear memory plasticity, were unaltered by fluoxetine treatment. These data point to a selective inability to form contextual fear memory as a result of fluoxetine treatment, and they suggest that a blunting of hippocampal-mediated aversive memory may be a therapeutic action for this medication. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  5. Effect of Fluoxetine on the Hippocampus of Wistar Albino Rats in Cold Restraint Stress Model.

    Science.gov (United States)

    Jayakumar, Saikarthik; Raghunath, Gunapriya; Ilango, Saraswathi; Vijayakumar, J; Vijayaraghavan, R

    2017-06-01

    Stress has been known to be a potential modulator of learning and memory. Long term stress can lead to depression. Fluoxetine is a selective serotonin reuptake inhibitor group of drug used in the treatment of depression. The present study was conducted to evaluate the potential of Fluoxetine on cold restraint induced stress in the hippocampus of Wistar rats. A total of 18 male wistar albino rats were divided randomly into three groups (n=6). Group 1 was the control group which were kept in normal laboratory conditions. Group 2 was the negative control group which were given cold restraint stress for period of four weeks. Group 3 was the experimental group, where the animals were pretreated with fluoxetine 10 mg/kg for a period of one week followed by cold restraint stress for 30 minutes and cotreated with fluoxetine 10 mg/kg for a period of four weeks. The whole study was done for a period of five weeks followed by behavioural studies and subsequently sacrificed with removal of brain for various histological, Immunohistochemical (IHC), neurochemical and antioxidant analysis. The values were expressed as Mean±SEM. One-way analysis of variance followed by Tukey's multiple comparisons test was used for the comparison of means. A probability of 0.05 and less was taken as statistically significant using Prism Graphpad software version 6.01. The results show there was significant improvement in the Morris water maze test after treatment with fluoxetine in Group 2. Similar results were also noted in the levels of neurotransmitters and antioxidant levels in brain and also in the number of cells counted in IHC and histological studies by H&E when Group 3 was compared with Group 2. The treatment reversed the damage in Group 2 which was comparable with the control group. The results revealed that administration of fluoxetine 10 mg/kg given orally has a potential antistressor effect by improving the neurogenic and neuroprotective effect on the cold restraint stress induced

  6. Cellular correlates of enhanced anxiety caused by acute treatment with the selective serotonin reuptake inhibitor fluoxetine in rats

    Directory of Open Access Journals (Sweden)

    Shilpa eRavinder

    2011-12-01

    Full Text Available Selective serotonin reuptake inhibitors (SSRIs are used extensively in the treatment of depression and anxiety disorders. The therapeutic benefits of SSRIs typically require several weeks of continuous treatment. Intriguingly, according to clinical reports, symptoms of anxiety may actually increase during the early stages of treatment although more prolonged treatment alleviates affective symptoms. Consistent with earlier studies that have used animal models to capture this paradoxical effect of SSRIs, we find that rats exhibit enhanced anxiety-like behavior on the elevated plus-maze one hour after a single injection of the SSRI fluoxetine. Next we investigated the potential neural substrates underlying the acute anxiogenic effects by analyzing the morphological and physiological impact of acute fluoxetine treatment on principal neurons of the basolateral amygdala (BLA, a brain area that plays a pivotal role in fear and anxiety. Although earlier studies have shown that behavioral or genetic perturbations that are anxiogenic for rodents also increase dendritic spine-density in the BLA, we find that a single injection of fluoxetine does not cause spinogenesis on proximal apical dendritic segments on BLA principal neurons an hour later. However, at the same time point when a single dose of fluoxetine caused enhanced anxiety, it also enhanced action potential firing in BLA neurons in ex vivo slices. Consistent with this finding, in vitro bath application of fluoxetine caused higher spiking frequency and this increase in excitability was correlated with an increase in the input resistance of these neurons. Our results suggest that enhanced excitability of amygdala neurons may contribute to the increase in anxiety-like behavior observed following acute fluoxetine treatment.

  7. Corticosterone Facilitates Fluoxetine-Induced Neuronal Plasticity in the Hippocampus

    Science.gov (United States)

    Kobayashi, Katsunori; Ikeda, Yumiko; Asada, Minoru; Inagaki, Hirofumi; Kawada, Tomoyuki; Suzuki, Hidenori

    2013-01-01

    The hippocampal dentate gyrus has been implicated in a neuronal basis of antidepressant action. We have recently shown a distinct form of neuronal plasticity induced by the serotonergic antidepressant fluoxetine, that is, a reversal of maturation of the dentate granule cells in adult mice. This “dematuration” is induced in a large population of dentate neurons and maintained for at least one month after withdrawal of fluoxetine, suggesting long-lasting strong influence of dematuration on brain functioning. However, reliable induction of dematuration required doses of fluoxetine higher than suggested optimal doses for mice (10 to 18 mg/kg/day), which casts doubt on the clinical relevance of this effect. Since our previous studies were performed in naive mice, in the present study, we reexamined effects of fluoxetine using mice treated with chronic corticosterone that model neuroendocrine pathophysiology associated with depression. In corticosterone-treated mice, fluoxetine at 10 mg/kg/day downregulated expression of mature granule cell markers and attenuated strong frequency facilitation at the synapse formed by the granule cell axon mossy fiber, suggesting the induction of granule cell dematuration. In addition, fluoxetine caused marked enhancement of dopaminergic modulation at the mossy fiber synapse. In vehicle-treated mice, however, fluoxetine at this dose had no significant effects. The plasma level of fluoxetine was comparable to that in patients taking chronic fluoxetine, and corticosterone did not affect it. These results indicate that corticosterone facilitates fluoxetine-induced plastic changes in the dentate granule cells. Our finding may provide insight into neuronal mechanisms underlying enhanced responsiveness to antidepressant medication in certain pathological conditions. PMID:23675498

  8. Fluoxetine induces autophagic cell death via eEF2K-AMPK-mTOR-ULK complex axis in triple negative breast cancer.

    Science.gov (United States)

    Sun, Dejuan; Zhu, Lingjuan; Zhao, Yuqian; Jiang, Yingnan; Chen, Lixia; Yu, Yang; Ouyang, Liang

    2018-04-01

    Triple negative breast cancer (TNBC) is a complex and intrinsically aggressive tumour with poor prognosis, and the discovery of targeted small-molecule drugs for TNBC treatment still remains in its infancy. In this study, we aimed to discover a small-molecule agent for TNBC treatment and illuminate its potential mechanisms. Cell viability was detected by using methylthiazoltetrazolium (MTT) assay. Electron microscopy, GFP-LC3 transfection, monodansylcadaverine staining and apoptosis assay were performed to determine Fluoxetine-induced autophagy and apoptosis. Western blotting and siRNA transfection were carried out to investigate the mechanisms of Fluoxetine-induced autophagy. iTRAQ-based proteomics analysis was used to explore the underlying mechanisms. We have demonstrated that Fluoxetine had remarkable anti-proliferative activities and induced autophagic cell death in MDA-MB-231 and MDA-MB-436 cells. The mechanism for Fluoxetine-induced autophagic cell death was associated with inhibition of eEF2K and activation of AMPK-mTOR-ULK complex axis. Further iTRAQ-based proteomics and network analyses revealed that Fluoxetine-induced mechanism was involved in BIRC6, BNIP1, SNAP29 and Bif-1. These results demonstrate that Fluoxetine induces apoptosis and autophagic cell death in TNBC, which will hold a promise for the future TNBC therapy. © 2017 John Wiley & Sons Ltd.

  9. The Distribution of Fluoxetine and Norfluoxetine in Postmortem Fluids and Tissues

    Science.gov (United States)

    2007-06-01

    of fluoxetine and nor- fluoxetine in dogs following oral administration of fluoxetine hydrochloride ( Prozac ). J Forensic Sci, 42(5):812-6, 1997. 6...flight crews are submitted to the Federal Aviation Administration’s Civil Aerospace Medical Institute for toxicological analysis. Fluoxetine ( Prozac ...heart muscle, and brain. Specimens were extracted using solid-phase extraction and analyzed by GC/MS. Deuterated fluoxetine and norfluoxetine were

  10. Protective effects of fluoxetine on decompression sickness in mice.

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    Jean-Eric Blatteau

    Full Text Available Massive bubble formation after diving can lead to decompression sickness (DCS that can result in central nervous system disorders or even death. Bubbles alter the vascular endothelium and activate blood cells and inflammatory pathways, leading to a systemic pathophysiological process that promotes ischemic damage. Fluoxetine, a well-known antidepressant, is recognized as having anti-inflammatory properties at the systemic level, as well as in the setting of cerebral ischemia. We report a beneficial clinical effect associated with fluoxetine in experimental DCS. 91 mice were subjected to a simulated dive at 90 msw for 45 min before rapid decompression. The experimental group received 50 mg/kg of fluoxetine 18 hours before hyperbaric exposure (n = 46 while controls were not treated (n = 45. Clinical assessment took place over a period of 30 min after surfacing. At the end, blood samples were collected for blood cells counts and cytokine IL-6 detection. There were significantly fewer manifestations of DCS in the fluoxetine group than in the controls (43.5% versus 75.5%, respectively; p = 0.004. Survivors showed a better and significant neurological recovery with fluoxetine. Platelets and red cells were significantly decreased after decompression in controls but not in the treated mice. Fluoxetine reduced circulating IL-6, a relevant marker of systemic inflammation in DCS. We concluded that fluoxetine decreased the incidence of DCS and improved motor recovery, by limiting inflammation processes.

  11. Modeling of the temporal patterns of fluoxetine prescriptions and suicide rates in the United States.

    Directory of Open Access Journals (Sweden)

    Michael S Milane

    2006-06-01

    Full Text Available To study the potential association of antidepressant use and suicide at a population level, we analyzed the associations between suicide rates and dispensing of the prototypic SSRI antidepressant fluoxetine in the United States during the period 1960-2002.Sources of data included Centers of Disease Control and US Census Bureau age-adjusted suicide rates since 1960 and numbers of fluoxetine sales in the US, since its introduction in 1988. We conducted statistical analysis of age-adjusted population data and prescription numbers. Suicide rates fluctuated between 12.2 and 13.7 per 100,000 for the entire population from the early 1960s until 1988. Since then, suicide rates have gradually declined, with the lowest value of 10.4 per 100,000 in 2000. This steady decline is significantly associated with increased numbers of fluoxetine prescriptions dispensed from 2,469,000 in 1988 to 33,320,000 in 2002 (r(s = -0.92; p < 0.001. Mathematical modeling of what suicide rates would have been during the 1988-2002 period based on pre-1988 data indicates that since the introduction of fluoxetine in 1988 through 2002 there has been a cumulative decrease in expected suicide mortality of 33,600 individuals (posterior median, 95% Bayesian credible interval 22,400-45,000.The introduction of SSRIs in 1988 has been temporally associated with a substantial reduction in the number of suicides. This effect may have been more apparent in the female population, whom we postulate might have particularly benefited from SSRI treatment. While these types of data cannot lead to conclusions on causality, we suggest here that in the context of untreated depression being the major cause of suicide, antidepressant treatment could have had a contributory role in the reduction of suicide rates in the period 1988-2002.

  12. An improved method for preparing tritium labeled fluoxetine

    International Nuclear Information System (INIS)

    Hsi, R.S.P.; Stolle, W.T.

    1996-01-01

    Palladium-on-charcoal catalyzed reduction of N-methyl-3-(3-bromo) phenyl-3-(4-trifluoromethyl)phenoxypropylamine (1) with tritium gas produces a mixture of the debrominated product [ 3 H]fluoxetine (2) and N-methyl-3-[3- 3 H]phenylpropylamine (3), which results from cleavage of the benzylic carbon-oxygen bond. Carrying out this reaction in the presence of pyridine eliminates hydrogenolysis and produces [ 3 H]fluoxetine as the sole product. (author)

  13. Fluoxetine regulates cell growth inhibition of interferon-α.

    Science.gov (United States)

    Lin, Yu-Min; Yu, Bu-Chin; Chiu, Wen-Tai; Sun, Hung-Yu; Chien, Yu-Chieh; Su, Hui-Chen; Yen, Shu-Yang; Lai, Hsin-Wen; Bai, Chyi-Huey; Young, Kung-Chia; Tsao, Chiung-Wen

    2016-10-01

    Fluoxetine, a well-known anti-depression agent, may act as a chemosensitizer to assist and promote cancer therapy. However, how fluoxetine regulates cellular signaling to enhance cellular responses against tumor cell growth remains unclear. In the present study, addition of fluoxetine promoted growth inhibition of interferon-alpha (IFN-α) in human bladder carcinoma cells but not in normal uroepithelial cells through lessening the IFN-α-induced apoptosis but switching to cause G1 arrest, and maintaining the IFN-α-mediated reduction in G2/M phase. Activations and signal transducer and transactivator (STAT)-1 and peroxisome proliferator-activated receptor alpha (PPAR-α) were involved in this process. Chemical inhibitions of STAT-1 or PPAR-α partially rescued bladder carcinoma cells from IFN-α-mediated growth inhibition via blockades of G1 arrest, cyclin D1 reduction, p53 downregulation and p27 upregulation in the presence of fluoxetine. However, the functions of both proteins were not involved in the control of fluoxetine over apoptosis and maintained the declined G2/M phase of IFN-α. These results indicated that activation of PPAR-α and STAT-1 participated, at least in part, in growth inhibition of IFN-α in the presence of fluoxetine.

  14. Gastrointestinal Hemorrhage Related to Fluoxetine in a Patient With Stroke.

    Science.gov (United States)

    Wee, Tze Chao

    2017-11-01

    We report on a patient who developed massive gastrointestinal hemorrhage related to the use of fluoxetine in combination with aspirin and clopidogrel. A 58-year-old man was admitted with a posterior circulation infarct with significant weakness in all four limbs and dysarthria. Aspirin and clopidogrel were started. Fluoxetine was started for pharmacological neurostimulation to promote motor recovery and for low mood. He developed gastrointestinal hemorrhage a week after fluoxetine was started. Fluoxetine was suspended and investigations failed to reveal the source of the bleeding. He was then restarted on fluoxetine along with dual antiplatelets, and gastrointestinal hemorrhage recurred after 1 week. He was extensively investigated for a source of gastrointestinal hemorrhage, and again no source could be identified. Eventually, fluoxetine was switched to mirtazapine with no further gastrointestinal hemorrhage. He remained on dual antiplatelets. A number of case-control and cohort studies had identified the association of gastrointestinal hemorrhage with the use of selective serotonin reuptake inhibitor (SSRI). We hope to raise awareness of this association in physical medicine and rehabilitation physicians as the use of SSRI is expected to rise.

  15. Fluoxetine Administration in Juvenile Monkeys: Implications for Pharmacotherapy in Children

    Directory of Open Access Journals (Sweden)

    Mari S. Golub

    2018-02-01

    Full Text Available Fluoxetine therapy has been approved for children with major depressive disorder and obsessive compulsive disorder for over 14 years and has expanded to other childhood behavior disorders. As use increases, more detail on fluoxetine effects during juvenile brain development can help maintain safe and effective use of this therapy. Here, a narrative review is provided of previously published findings from a large nonhuman primate project. Fluoxetine was administered to juvenile male rhesus monkeys for an extended period (2 years prior to puberty. Compared to controls, treated monkeys showed sleep disruption, facilitated social interaction, greater impulsivity, and impaired sustained attention during treatment. No effects on growth were seen. Metabolomics assays characterized a distinctive response to fluoxetine and demonstrated individual differences that were related to the impulsivity measure. Fluoxetine interactions with monoamine oxidase A polymorphisms that influenced behavior and metabolomics markers were an important, previously unrecognized finding of our studies. After treatment was discontinued, some behavioral effects persisted, but short-term memory and cognitive flexibility testing did not show drug effects. This detailed experimental work can contribute to clinical research and continued safe and effective fluoxetine pharmacotherapy in children.

  16. A novel chiral GC/MS method for the analysis of fluoxetine and norfluoxetine enantiomers in biological fluids

    Directory of Open Access Journals (Sweden)

    Janet Mifsud

    2012-01-01

    Full Text Available Aims: A novel robust chiral gas chromatographic/mass spectrometric (GC/MS method for the separation and measurement of fluoxetine and norfluoxetine enantiomers in urine and plasma was developed. Materials and Methods: The drug was extracted from the samples by a liquid-liquid technique, using chloroform, and the enantiomers were separated and measured on a chiral gas chromatographic column (HYDRODEX β-6TBDM®, 0.25 μm × 0.25 mm × 50 m. GC/MS instrumentation was used for the acquisition of data in the electron impact selective-ion monitoring mode. Results: The ions chosen were of a mass-to-charge ratio (m/z exactly equal to 44 units, in order to measure fluoxetine enantiomers, 134 units in order to measure norfluoxetine enantiomers, and 58 units in order to measure diphenhydramine, the internal standard. The method was found to be linear and reproducible in the 50-500 ng/mL concentration range for both urine samples and plasma samples and for both fluoxetine and norfluoxetine, with correlation coefficients ranging between 0.994 and 0.997. Conclusions: This methodology has an enormous potential for application in pharmacokinetic studies of the enantiomers of fluoxetine

  17. Determination of fluoxetine in pharmaceutical and biological samples based on the silver nanoparticle enhanced fluorescence of fluoxetine-terbium complex.

    Science.gov (United States)

    Lotfi, Ali; Manzoori, Jamshid L

    2016-11-01

    In this study, a simple and sensitive spectrofluorimetric method is presented for the determination of fluoxetine based on the enhancing effect of silver nanoparticles (AgNPs) on the terbium-fluoxetine fluorescence emission. The AgNPs were prepared by a simple reduction method and characterized by UV-Vis spectroscopy and transmission electron microscopy. It was indicated that these AgNPs have a remarkable amplifying effect on the terbium-sensitized fluorescence of fluoxetine. The effects of various parameters such as AgNP and Tb 3+ concentration and the pH of the media were investigated. Under obtained optimal conditions, the fluorescence intensity of the terbium-fluoxetine-AgNP system was enhanced linearly by increasing the concentration of fluoxetine in the range of 0.008 to 19 mg/L. The limit of detection (b + 3s) was 8.3 × 10 -4 mg/L. The interference effects of common species found in real samples were also studied. The method had good linearity, recovery, reproducibility and sensitivity, and was satisfactorily applied for the determination of fluoxetine in tablet formulations, human urine and plasma samples. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  18. Sex-specific antidepressant effects of dietary creatine with and without sub-acute fluoxetine in rats

    Science.gov (United States)

    Allen, Patricia J.; D'Anci, Kristen E.; Kanarek, Robin B.; Renshaw, Perry F.

    2013-01-01

    The potential role of metabolic impairments in the pathophysiology of depression is motivating researchers to evaluate the treatment efficacy of creatine, a naturally occurring energetic and neuroprotective compound found in brain and muscle tissues. Growing evidence is demonstrating the benefit of oral creatine supplements for reducing depressive symptoms in humans and animals. A novel question is whether dietary creatine, when combined with antidepressant drug therapy, would be more effective than either compound alone. To answer this question, four studies were conducted to investigate the behavioral effects of combined creatine and low-dose fluoxetine treatment using the forced swim test in male and female rats. Sprague-Dawley rats were fed powdered rodent chow supplemented with 0%, 2% or 4% w/w creatine monohydrate for 5 weeks. Rats were injected with fluoxetine (5.0 or 10.0 mg/kg) or saline according to a sub-acute dosing schedule. Female rats maintained on a 4% creatine diet displayed antidepressant-like effects compared to non-supplemented females prior to fluoxetine treatment. In contrast, creatine did not alter behavior reliably in males. Following drug treatment and a second forced swim trial, the antidepressant-like profile of creatine remained significant only in females co-administered 5.0 mg/kg fluoxetine. Moreover, in females only, supplementation with 4% creatine produced a more robust antidepressant-like behavioral profile compared to either dose of fluoxetine alone. Estrous cycle data indicated that ovarian hormones influenced the antidepressant-like effects of creatine. Addressing the issue of sex differences in response to treatment may affect our understanding of creatine, its relationship with depressive behavior, and may lead to sex-specific therapeutic strategies. PMID:22429992

  19. Fluoxetine ameliorates cognitive impairments induced by chronic cerebral hypoperfusion via down-regulation of HCN2 surface expression in the hippocampal CA1 area in rats.

    Science.gov (United States)

    Luo, Pan; Zhang, Xiaoxue; Lu, Yun; Chen, Cheng; Li, Changjun; Zhou, Mei; Lu, Qing; Xu, Xulin; Shen, Guanxin; Guo, Lianjun

    2016-01-01

    Chronic cerebral hypoperfusion (CCH) causes cognitive impairments and increases the risk of Alzheimer's disease (AD) and vascular dementia (VD) through several biologically plausible pathways, yet the underlying neurobiological mechanisms are still poorly understood. In this study, we investigated whether fluoxetine, a selective serotonin reuptake inhibitor (SSRI), could play a neuroprotective role against chronic cerebral hypoperfusion injury and to clarify underlying mechanisms of its efficacy. Rats were subjected to permanent bilateral occlusion of the common carotid arteries (two-vessel occlusion, 2VO). Two weeks later, rats were treated with 30 mg/kg fluoxetine (intragastric injection, i.g.) for 6 weeks. Cognitive function was evaluated by Morris water maze (MWM) and novel objects recognition (NOR) test. Long-term potentiation (LTP) was used to address the underlying synaptic mechanisms. Western blotting was used to quantify the protein levels. Our results showed that fluoxetine treatment significantly improved the cognitive impairments caused by 2VO, accompanied with a reversion of 2VO-induced inhibitory of LTP. Furthermore, 2VO caused an up-regulation of hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2) surface expressions in the hippocampal CA1 area and fluoxetine also effectively recovered the disorder of HCN2 surface expressions, which may be a possible mechanism that fluoxetine treatment ameliorates cognitive impairments in rats with CCH. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. Initial Steps to inform selection of continuation cognitive therapy or fluoxetine for higher risk responders to cognitive therapy for recurrent major depressive disorder.

    Science.gov (United States)

    Vittengl, Jeffrey R; Anna Clark, Lee; Thase, Michael E; Jarrett, Robin B

    2017-07-01

    Responders to acute-phase cognitive therapy (A-CT) for major depressive disorder (MDD) often relapse or recur, but continuation-phase cognitive therapy (C-CT) or fluoxetine reduces risks for some patients. We tested composite moderators of C-CT versus fluoxetine's preventive effects to inform continuation treatment selection. Responders to A-CT for MDD judged to be at higher risk for relapse due to unstable or partial remission (N=172) were randomized to 8 months of C-CT or fluoxetine with clinical management and assessed, free from protocol treatment, for 24 additional months. Pre-continuation-treatment characteristics that in survival analyses moderated treatments' effects on relapse over 8 months of continuation-phase treatment (residual symptoms and negative temperament) and on relapse/recurrence over the full observation period's 32 months (residual symptoms and age) were combined to estimate the potential advantage of C-CT versus fluoxetine for individual patients. Assigning patients to optimal continuation treatment (i.e., to C-CT or fluoxetine, depending on patients' pre-continuation-treatment characteristics) resulted in absolute reduction of relapse or recurrence risk by 16-21% compared to the other non-optimal treatment. Although these novel results require replication before clinical application, selecting optimal continuation treatment (i.e., personalizing treatment) for higher risk A-CT responders may decrease risks of MDD relapse and recurrence substantively. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

  1. 12-Month Follow-Up of Fluoxetine and Cognitive Behavioral Therapy for Binge Eating Disorder

    Science.gov (United States)

    Grilo, Carlos M.; Crosby, Ross D.; Wilson, G. Terence; Masheb, Robin M.

    2012-01-01

    Objective: The longer term efficacy of medication treatments for binge-eating disorder (BED) remains unknown. This study examined the longer term effects of fluoxetine and cognitive behavioral therapy (CBT) either with fluoxetine (CBT + fluoxetine) or with placebo (CBT + placebo) for BED through 12-month follow-up after completing treatments.…

  2. Three cases of zolpidem dependence treated with fluoxetine: the serotonin hypothesis.

    Science.gov (United States)

    Liappas, Ioannis A; Malitas, Petros N; Dimopoulos, Nikolaos P; Gitsa, Olympia E; Liappas, Alexandros I; Nikolaou, Chrisoula K; Christodoulou, Georgios N

    2003-04-01

    Zolpidem is an imidazopyridine hypnotic that is believed to act selectively at alpha(1) subunit-containing gamma-aminobutyric acid type A (GABA(A)) receptors and thus to have minimal abuse and dependence potential. We present three cases of zolpidem abuse and dependence in which the drug was used not for sedation but for stimulation and anxiolysis. All of the patients were treated with fluoxetine (a selective serotonin reuptake inhibitor) and managed to discontinue the abuse and remain abstinent from the drug. The efficacy of this kind of medication on the abuse of a GABAergic agonist, in this case dependence on zolpidem, leads to a serotonergic and GABAergic system interaction hypothesis.

  3. Antidepressant behavioral effects of duloxetine and fluoxetine in the rat forced swimming test.

    Science.gov (United States)

    Ciulla, Leandro; Menezes, Honório Sampaio; Bueno, Bárbara Beatriz Moreira; Schuh, Alexandre; Alves, Rafael José Vargas; Abegg, Milena Pacheco

    2007-01-01

    To compare the effects of the antidepressant drugs duloxetine and fluoxetine on depressive behaviors in rodents. Eighteen male Wistar rats were given systemic injections of duloxetine, fluoxetine, or saline prior to a Forced Swimming Test (FST). Immobility and number of stops were measured. Rats given injections of fluoxetine displayed significantly less immobility (p = 0.02) and fewer stops than the control group (p = 0.003). Duloxetine significantly reduced the number of stops (p = 0.003), but did not effect immobility (p = 0.48). Duloxetine and fluoxetine reduced depressive behaviors in the Forced FST. However, our findings suggest that fluoxetine is more effective than duloxetine.

  4. An improved method for preparing tritium labeled fluoxetine

    Energy Technology Data Exchange (ETDEWEB)

    Hsi, R.S.P.; Stolle, W.T. [Pharmacia and Upjohn Inc., Kalamazoo, MI (United States)

    1996-12-01

    Palladium-on-charcoal catalyzed reduction of N-methyl-3-(3-bromo) phenyl-3-(4-trifluoromethyl)phenoxypropylamine (1) with tritium gas produces a mixture of the debrominated product [{sup 3}H]fluoxetine (2) and N-methyl-3-[3-{sup 3}H]phenylpropylamine (3), which results from cleavage of the benzylic carbon-oxygen bond. Carrying out this reaction in the presence of pyridine eliminates hydrogenolysis and produces [{sup 3}H]fluoxetine as the sole product. (author).

  5. Fluoxetine protects against methamphetamine‑induced lung inflammation by suppressing oxidative stress through the SERT/p38 MAPK/Nrf2 pathway in rats.

    Science.gov (United States)

    Wang, Yun; Gu, Yu-Han; Liu, Ming; Bai, Yang; Wang, Huai-Liang

    2017-02-01

    Methamphetamine (MA) abuse is a major public health and safety concern throughout the world and a growing burden on healthcare costs. The purpose of the present study was to investigate the protective effect of fluoxetine against MA‑induced chronic pulmonary inflammation and to evaluate the potential role of nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidative stress. Wistar rats were divided into control, MA and two fluoxetine‑treated groups. Rats in the MA and the two fluoxetine‑treated groups were treated daily with intraperitoneal injection of 10 mg/kg MA twice daily. Rats in the two fluoxetine‑treated groups were injected intragastrically with fluoxetine (2 and 10 mg/kg) once daily, respectively. After 5 weeks, the rats were euthanized and hematoxylin and eosin staining, immunohistochemistry, western blot analysis and redox assay were performed. It was demonstrated that chronic exposure to MA can induce pulmonary inflammation in rats, with the symptoms of inflammatory cell infiltration, crowded lung parenchyma, thickened septum and a reduced number of alveolar sacs. Fluoxetine attenuated pulmonary inflammation and the expression of interleukin‑6 and tumor necrosis factor‑α in rat lungs. Fluoxetine inhibited MA‑induced increases in the expression levels of serotonin transporter (SERT) and p‑p38 mitogen‑activated protein kinase (MAPK), and reversed the MA‑induced decrease in nuclear Nrf2 and human heme oxygenase‑1 in lungs. Fluoxetine at 10 mg/kg significantly reversed the reduced glutathione (GSH) level, the ratio of GSH/oxidized glutathione, and the reactive oxygen species level in rat lungs from the MA group. These findings suggested that fluoxetine, a SERT inhibitor, has a protective effect against MA‑induced lung inflammation by suppressing oxidative stress through the SERT/p38 MAPK/Nrf2 pathway in rats.

  6. Convergence of glycogen synthase kinase 3β and GR signaling in response to fluoxetine treatment in chronically stressed female and male rats.

    Science.gov (United States)

    Mitic, Milos; Brkic, Zeljka; Lukic, Iva; Adzic, Miroslav

    2017-08-30

    Accumulating evidence strongly suggest that impaired glucocorticoid receptor (GR) signaling is involved in stress-related mood disorders, and nominate GR as a potential target for antidepressants (ADs). It is known that different classes of ADs affects the GR action via modifying its phosphorylation, while the mechanism through which ADs alter GR phosphorylation targeted by GSK3β, a kinase modulated via serotonin neurotransmission, are unclear. On this basis, we investigated whether GSK3β-GR signaling could be a convergence point of fluoxetine action on brain function and behavior, by examining its effect on GSK3β targeted-GR phosphorylation on threonine 171 (pGR171), and expression of GR-regulated genes in the hippocampus of female and male rats exposed to chronic isolation stress. Stress induced sex-specific GSK3β-targeted phosphorylation of pGR171 in the nucleus of the hippocampus of stressed animals. Namely, while in females stress triggered coupled action of GSK3β-pGR171 signaling, in males changes in pGR171 levels did not correspond to GSK3β activity. On the other hand, fluoxetine managed to up-regulate this pathway in sex-unbiased manner. Furthermore, fluoxetine reverted stress-induced changes in most of the analyzed genes in males, CRH, 5-HT1a and p11, while in females its effect was limited to CRH. These data further suggest that pGR171 signaling affects cellular localization of GR in response to chronic stress and fluoxetine in both sexes. Collectively, our results describe a novel convergence point between GR signaling and GSK3β pathway in rat hippocampus in response to stress and fluoxetine in both sexes and its involvement in fluoxetine-regulated brain function in males. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Fluoxetine Exerts Age-Dependent Effects on Behavior and Amygdala Neuroplasticity in the Rat

    Science.gov (United States)

    Homberg, Judith R.; Olivier, Jocelien D. A.; Blom, Tom; Arentsen, Tim; van Brunschot, Chantal; Schipper, Pieter; Korte-Bouws, Gerdien; van Luijtelaar, Gilles; Reneman, Liesbeth

    2011-01-01

    The selective serotonin reuptake inhibitor (SSRI) Prozac® (fluoxetine) is the only registered antidepressant to treat depression in children and adolescents. Yet, while the safety of SSRIs has been well established in adults, serotonin exerts neurotrophic actions in the developing brain and thereby may have harmful effects in adolescents. Here we treated adolescent and adult rats chronically with fluoxetine (12 mg/kg) at postnatal day (PND) 25 to 46 and from PND 67 to 88, respectively, and tested the animals 7–14 days after the last injection when (nor)fluoxetine in blood plasma had been washed out, as determined by HPLC. Plasma (nor)fluoxetine levels were also measured 5 hrs after the last fluoxetine injection, and matched clinical levels. Adolescent rats displayed increased behavioral despair in the forced swim test, which was not seen in adult fluoxetine treated rats. In addition, beneficial effects of fluoxetine on wakefulness as measured by electroencephalography in adults was not seen in adolescent rats, and age-dependent effects on the acoustic startle response and prepulse inhibition were observed. On the other hand, adolescent rats showed resilience to the anorexic effects of fluoxetine. Exploratory behavior in the open field test was not affected by fluoxetine treatment, but anxiety levels in the elevated plus maze test were increased in both adolescent and adult fluoxetine treated rats. Finally, in the amygdala, but not the dorsal raphe nucleus and medial prefrontal cortex, the number of PSA-NCAM (marker for synaptic remodeling) immunoreactive neurons was increased in adolescent rats, and decreased in adult rats, as a consequence of chronic fluoxetine treatment. No fluoxetine-induced changes in 5-HT1A receptor immunoreactivity were observed. In conclusion, we show that fluoxetine exerts both harmful and beneficial age-dependent effects on depressive behavior, body weight and wakefulness, which may relate, in part, to differential fluoxetine

  8. Fast simultaneous electrochemical detection of tetracycline and fluoxetine in water

    NARCIS (Netherlands)

    Ardelean, Magdalena; Pode, Rodica; Schoonman, J.; Pop, Aniela; Manea, Florica

    2017-01-01

    The electrochemical methods-based protocol for simultaneous detection of tetracycline (TC) from antibiotics class and fluoxetine (FXT) from anti-depressive pharmaceuticals class, which belongs to emerging pollutants from water, was developed in this study using carbon nanofiber-epoxy composite

  9. Treatment of Transvestic Fetishism With Fluoxetine: A Case Report

    Science.gov (United States)

    Usmani, Mohammad Amir; K Gaur, Rakesh; Ahmad Azmi, Suhail; Gangwar, Sheshank

    2012-01-01

    Transvestic fetishism is having a sexual or erotic interest in cross-dressing. This case report describes a 17-year-old male with transvestic fetishism who suffered from obsessive thoughts and subsequent masturbation as compulsion. He was managed successfully with fluoxetine. PMID:24644490

  10. Protective effects of melatonin on long-term administration of fluoxetine in rats.

    Science.gov (United States)

    Khaksar, Majid; Oryan, Ahmad; Sayyari, Mansour; Rezabakhsh, Aysa; Rahbarghazi, Reza

    2017-10-02

    The degree and consequence of tissue injury are highly regarded during long-term exposure to selective antidepressant fluoxetine. Melatonin has been shown to palliate different lesions by scavenging free radicals, but its role in the reduction of the fluoxetine-induced injuries has been little known. Thirty-six mature male Wistar rats were randomly assigned into control and experimental groups. The experimental rats were included as following; 24mg/kg/bw fluoxetine for 4 weeks; 1mg/kg/bw melatonin for 4 weeks; fluoxetine+1-week melatonin, fluoxetine+2-week melatonin and fluoxetine+4-week melatonin. In the current experiment, we investigated weight gain, hematological and biochemical parameters, pathological injuries and oxidative status. We noted the positive effect of melatonin in weight loss of fluoxetine-treated rats (pfluoxetine were reversed by melatonin (pfluoxetine (pfluoxetine in inducing leukopenia, thrombocytopenia and hypochromic and macrocytic anemia which was blunted by melatonin. Both RBCs and platelets indices were also corrected. Rats received melatonin in combination with fluoxetine showed a reduction in the severity of degeneration and inflammatory changes in different tissues, brain, heart, liver, lungs, testes and kidneys as compared to the fluoxetine group. Therefore, melatonin fundamentally reversed the side effects of fluoxetine in the rat model which is comparable to human medicine. Copyright © 2017 Elsevier GmbH. All rights reserved.

  11. Fluoxetine-treated male wrasses exhibit low AVT expression.

    Science.gov (United States)

    Semsar, Katharine; Perreault, Heidi A N; Godwin, John

    2004-12-17

    In many species, increasing serotonergic activity can reduce aggression and reverse dominance relationships. These effects may in part be mediated through interactions with the arginine vasotocin/vasopressin (AVT/AVP) system. We tested this hypothesis in a territorial coral reef fish, the bluehead wrasse (Thalassoma bifasciatum), by experimentally enhancing serotonergic neurotransmission, using the selective serotonin re-uptake inhibitor (SSRI) fluoxetine. Terminal phase (TP) males received 2 weeks of nightly intraperitoneal fluoxetine injections (6 microg/g body weight) and were then tested for their aggressive response to an intruder and killed to examine AVT phenotype in the preoptic area of the hypothalamus (POA), an area important to social behavior in fishes. Our previously published study demonstrated that fluoxetine-treated males are less aggressive [H.A.N. Perreault, K. Semsar, J. Godwin, Fluoxetine treatment decreases territorial aggression in a coral reef fish, Physiol. and Behav. 79 (2003) 719-724.]. Here, further study of these same fluoxetine-treated males shows approximately twofold lower AVT mRNA expression relative to saline-treated controls in all regions of the POA (all p0.4). This study experimentally supports the hypothesis that behavioral effects of SSRIs may be mediated in part through interactions with the AVT/AVP system. These results parallel findings from rodents and humans and are consistent with an indirect neurosteroidogenic rather than a solely direct serotonergic mechanism for SSRI effects on the AVT/AVP system. Furthermore, they suggest that SSRI effects on neuroendocrine function may be best modeled in animals with sensitive stress responses such as those found in nondomesticated animals.

  12. Prozac in the water: Chronic fluoxetine exposure and predation risk interact to shape behaviors in an estuarine crab.

    Science.gov (United States)

    Peters, Joseph R; Granek, Elise F; de Rivera, Catherine E; Rollins, Matthew

    2017-11-01

    Predators exert considerable top-down pressure on ecosystems by directly consuming prey or indirectly influencing their foraging behaviors and habitat use. Prey is, therefore, forced to balance predation risk with resource reward. A growing list of anthropogenic stressors such as rising temperatures and ocean acidification has been shown to influence prey risk behaviors and subsequently alter important ecosystem processes. Yet, limited attention has been paid to the effects of chronic pharmaceutical exposure on risk behavior or as an ecological stressor, despite widespread detection and persistence of these contaminants in aquatic environments. In the laboratory, we simulated estuarine conditions of the shore crab, Hemigrapsus oregonensis, and investigated whether chronic exposure (60 days) to field-detected concentrations (0, 3, and 30 ng/L) of the antidepressant fluoxetine affected diurnal and nocturnal risk behaviors in the presence of a predator, Cancer productus . We found that exposure to fluoxetine influenced both diurnal and nocturnal prey risk behaviors by increasing foraging and locomotor activity in the presence of predators, particularly during the day when these crabs normally stay hidden. Crabs exposed to fluoxetine were also more aggressive, with a higher frequency of agonistic interactions and increased mortality due to conflicts with conspecifics. These results suggest that exposure to field-detected concentrations of fluoxetine may alter the trade-off between resource acquisition and predation risk among crabs in estuaries. This fills an important data gap, highlighting how intra- and interspecific behaviors are altered by exposure to field concentrations of pharmaceuticals; such data more explicitly identify potential ecological impacts of emerging contaminants on aquatic ecosystems and can aid water quality management.

  13. Behavioral, endocrine, and neuronal alterations in zebrafish (Danio rerio) following sub-chronic coadministration of fluoxetine and ketamine.

    Science.gov (United States)

    Pittman, Julian; Hylton, Andrew

    2015-12-01

    Most existing pharmacological treatments have focused on the "monoamine hypothesis" for targeted drug design for major depressive disorder (MDD). Many of these medications have a delayed onset-of-action and limited efficacy. Antidepressants with principal targets outside the monoamine system may offer the potential for more rapid activity with improved therapeutic benefit. Growing evidence suggests that the glutamatergic system is uniquely central to the neurobiology and treatment of MDD. Ketamine (Ketalar®) is a non-competitive glutamatergic antagonist classically used to induce sedation. However, preliminary clinical evidence has been promising with regard to its rapidly acting antidepressant profile. Zebrafish (Danio rerio) have emerged as a promising new animal model to screen the effects of numerous psychotropic compounds. This study aimed to determine if a sub-chronic low (sub-anesthetic) dose of ketamine could be used to augment the antidepressant effects of the widely used antidepressant fluoxetine (Prozac®) in adult zebrafish, employing an ethanol withdrawal model. Sub-chronic exposure to dosages of 100μg/L fluoxetine and 20mg/L of ketamine reduced anxiety/depression-like behaviors, leads to upregulation of serotonin synthesis and elevated whole-body cortisol levels. These results demonstrate the utility of zebrafish as a model for neuropharmacological research, and the possible efficacy of fluoxetine and ketamine coadministration. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. Behavioral and neurogenomic transcriptome changes in wild-derived zebrafish with fluoxetine treatment

    Science.gov (United States)

    2013-01-01

    Background Stress and anxiety-related behaviors are seen in many organisms. Studies have shown that in humans and other animals, treatment with selective serotonin reuptake inhibitors (e.g. fluoxetine) can reduce anxiety and anxiety-related behaviors. The efficacies and side effects, however, can vary between individuals. Fluoxetine can modulate anxiety in a stereospecific manner or with equal efficacy regardless of stereoisomer depending on the mechanism of action (e.g. serotonergic or GABAergic effects). Zebrafish are an emerging and valuable translational model for understanding human health related issues such as anxiety. In this study we present data showing the behavioral and whole brain transcriptome changes with fluoxetine treatment in wild-derived zebrafish and suggest additional molecular mechanisms of this widely-prescribed drug. Results We used automated behavioral analyses to assess the effects of racemic and stereoisomeric fluoxetine on male wild-derived zebrafish. Both racemic and the individual isomers of fluoxetine reduced anxiety-related behaviors relative to controls and we did not observe stereospecific fluoxetine effects. Using RNA-sequencing of the whole brain, we identified 411 genes showing differential expression with racemic fluoxetine treatment. Several neuropeptides (neuropeptide Y, isotocin, urocortin 3, prolactin) showed consistent expression patterns with the alleviation of stress and anxiety when anxiety-related behavior was reduced with fluoxetine treatment. With gene ontology and KEGG pathway analyses, we identified lipid and amino acid metabolic processes, and steroid biosynthesis among other terms to be over-enriched. Conclusion Our results demonstrate that fluoxetine reduces anxiety-related behaviors in wild-derived zebrafish and alters their neurogenomic state. We identify two biological processes, lipid and amino acid metabolic synthesis that characterize differences in the fluoxetine treated fish. Fluoxetine may be acting on

  15. The role of fluoxetine in antiviral therapy for chronic hepatitis C

    OpenAIRE

    QIN Yuan; ZHANG Ying; ZHAO Jieru

    2016-01-01

    More than 20% of chronic hepatitis C (CHC) patients receiving the antiviral therapy with interferonα(IFNα) experience depression, and fluoxetine is often used to alleviate this symptom. Fluoxetine has anti-inflammatory properties and can change the synthesis of liver lipids, but its influence on antiviral therapy for CHC and related mechanism remain unknown. Recent studies show that fluoxetine can inhibit hepatitis C virus (HCV) infection and reduce the production of reactive oxygen species (...

  16. Antidepressant behavioral effects of duloxetine and fluoxetine in the rat forced swimming test

    OpenAIRE

    Ciulla,Leandro; Menezes,Honório Sampaio; Bueno,Bárbara Beatriz Moreira; Schuh,Alexandre; Alves,Rafael José Vargas; Abegg,Milena Pacheco

    2007-01-01

    PURPOSE: To compare the effects of the antidepressant drugs duloxetine and fluoxetine on depressive behaviors in rodents. METHODS: Eighteen male Wistar rats were given systemic injections of duloxetine, fluoxetine, or saline prior to a Forced Swimming Test (FST). Immobility and number of stops were measured. RESULTS: Rats given injections of fluoxetine displayed significantly less immobility (p = 0.02) and fewer stops than the control group (p = 0.003). Duloxetine significanlty reduced the nu...

  17. Fluoxetine exerts age-dependent effects on behavior and amygdala neuroplasticity in the rat.

    Directory of Open Access Journals (Sweden)

    Judith R Homberg

    Full Text Available The selective serotonin reuptake inhibitor (SSRI Prozac® (fluoxetine is the only registered antidepressant to treat depression in children and adolescents. Yet, while the safety of SSRIs has been well established in adults, serotonin exerts neurotrophic actions in the developing brain and thereby may have harmful effects in adolescents. Here we treated adolescent and adult rats chronically with fluoxetine (12 mg/kg at postnatal day (PND 25 to 46 and from PND 67 to 88, respectively, and tested the animals 7-14 days after the last injection when (norfluoxetine in blood plasma had been washed out, as determined by HPLC. Plasma (norfluoxetine levels were also measured 5 hrs after the last fluoxetine injection, and matched clinical levels. Adolescent rats displayed increased behavioral despair in the forced swim test, which was not seen in adult fluoxetine treated rats. In addition, beneficial effects of fluoxetine on wakefulness as measured by electroencephalography in adults was not seen in adolescent rats, and age-dependent effects on the acoustic startle response and prepulse inhibition were observed. On the other hand, adolescent rats showed resilience to the anorexic effects of fluoxetine. Exploratory behavior in the open field test was not affected by fluoxetine treatment, but anxiety levels in the elevated plus maze test were increased in both adolescent and adult fluoxetine treated rats. Finally, in the amygdala, but not the dorsal raphe nucleus and medial prefrontal cortex, the number of PSA-NCAM (marker for synaptic remodeling immunoreactive neurons was increased in adolescent rats, and decreased in adult rats, as a consequence of chronic fluoxetine treatment. No fluoxetine-induced changes in 5-HT(1A receptor immunoreactivity were observed. In conclusion, we show that fluoxetine exerts both harmful and beneficial age-dependent effects on depressive behavior, body weight and wakefulness, which may relate, in part, to differential

  18. The Distribution of Fluoxetine and Norfluoxetine in Postmortem Fluids and Tissues

    National Research Council Canada - National Science Library

    Lewis, Russell J; Johnson, Robert D; Angier, Mike K

    2007-01-01

    During aviation accident investigations, postmortem specimens from the flight crews are submitted to the Federal Aviation Administration's Civil Aerospace Medical Institute for toxicological analysis. Fluoxetine (Prozac...

  19. Influence of gasoline inhalation on the enantioselective pharmacokinetics of fluoxetine in rats.

    Science.gov (United States)

    Cardoso, Juciane Lauren Cavalcanti; Lanchote, Vera Lucia; Pereira, Maria Paula Marques; Capela, Jorge Manuel Vieira; Lepera, José Salvador

    2013-03-01

    Fluoxetine is used clinically as a racemic mixture of (+)-(S) and (-)-(R) enantiomers for the treatment of depression. CYP2D6 catalyzes the metabolism of both fluoxetine enantiomers. We aimed to evaluate whether exposure to gasoline results in CYP2D inhibition. Male Wistar rats exposed to filtered air (n = 36; control group) or to 600 ppm of gasoline (n = 36) in a nose-only inhalation exposure chamber for 6 weeks (6 h/day, 5 days/week) received a single oral 10-mg/kg dose of racemic fluoxetine. Fluoxetine enantiomers in plasma samples were analyzed by a validated analytical method using LC-MS/MS. The separation of fluoxetine enantiomers was performed in a Chirobiotic V column using as the mobile phase a mixture of ethanol:ammonium acetate 15 mM. Higher plasma concentrations of the (+)-(S)-fluoxetine enantiomer were found in the control group (enantiomeric ratio AUC((+)-(S)/(-)-(R)) = 1.68). In animals exposed to gasoline, we observed an increase in AUC(0-∞) for both enantiomers, with a sharper increase seen for the (-)-(R)-fluoxetine enantiomer (enantiomeric ratio AUC((+)-(S)/(-)-(R)) = 1.07), resulting in a loss of enantioselectivity. Exposure to gasoline was found to result in the loss of enantioselectivity of fluoxetine, with the predominant reduction occurring in the clearance of the (-)-(R)-fluoxetine enantiomer (55% vs. 30%). Copyright © 2013 Wiley Periodicals, Inc.

  20. Effectiveness of cognitive behavioral therapy and fluoxetine on sexual function of women with obsessive compulsive disorder: A double-blind randomized controlled trial.

    Science.gov (United States)

    Sabetnejad, Zahra; Assarian, Fatemeh; Omidi, Abdollah; Najarzadegan, Mohammad Reza

    2016-11-01

    Obsessive compulsive disorder (OCD) is a mental health concern due to its various negative consequences, especially in sexual function. Therefore, the treatment of sexual dysfunction in women with OCD is important in order to improve the patient's marital function and mental health. To compare the sexual behavior and sexual and marital satisfaction in women with obsessive-compulsive disorder (OCD) before and after treatment with fluoxetine and cognitive behavior therapy. This randomized clinical trial was conducted at psychiatric and psychological counseling centers in Kashan (Iran) from January 2, 2014, to December 29, 2014. Fifty-eight women with OCD were included in the study. In order to compare the effectiveness of pharmacological treatment (fluoxetine) and psychological treatment, cognitive behavior therapy (CBT), 58 female patients with OCD (diagnosed based on DSM-IV-T criteria) were randomized equally to either fluoxetine (at a dose of 60-80 mg daily for 3 months) or CBT (10 45-minute sessions). OCD and sexual behavior status of the patients before and after the intervention was assessed with the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and Female Sexual Function Index (FSFI) questionnaire, respectively. The data were analyzed using SPSS version 22. To compare changes between the two groups, an independent T-test was used. Finally, the effects of all potential factors on treatment outcome were analyzed using factorial ANCOVA. The mean score for OCD in the fluoxetine group was 25.6 ± 4.8 at the beginning of the experiment and 18.79 ± 4.26 at the end of the study, while in the CBT group it was 25.6 ± 4.8 and 18.79 ± 4.26, respectively. No significant differences were found between two groups regarding obsession score changes. These scores in fluoxetine group were 58.1 and 52.8, respectively (p=0.046). There was a significant difference between the two groups in terms of sexual performance (p=0.003). In this study, our findings demonstrate a

  1. Fluoxetine: a case history of its discovery and preclinical development

    OpenAIRE

    Perez-Caballero, Laura; Torres-Sanchez, Sonia; Bravo, Lidia; Mico, Juan A.; Berrocoso, Esther

    2014-01-01

    Introduction: Depression is a multifactorial mood disorder with a high prevalence worldwide. Until now, treatments for depression have focused on the inhibition of monoaminergic reuptake sites, which augment the bioavailability of monoamines in the CNS. Advances in drug discovery have widened the therapeutic options with the synthesis of so-called selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine. Areas covered: The aim of this case history is to describe and discuss the ...

  2. Fluoxetine effects on periodontogenesis: histomorphometrical and immunohistochemical analyses in rats

    Directory of Open Access Journals (Sweden)

    Luciana Silva REGUEIRA

    Full Text Available Abstract Reports have indicated that serotonin plays an important role in cell migration and differentiation during the organogenesis of several tissues, including the oral types. Administration of selective serotonin reuptake inhibitor (SSRI drugs during pregnancy could affect the delivery of serotonin to embryonic tissues altering its development. Objective This study aimed to assess the effects of fluoxetine, a selective serotonin reuptake inhibitor, on the formation of the periodontal ligament during pregnancy and lactation in rat pups. Material and Methods Twelve pregnant rats of Wistar lineage were divided into four study groups. In the control group, 0.9% sodium chloride solution was administered orally, throughout the entire period of the 21 days of pregnancy (CG group and in the CGL group, it was administrated during pregnancy and lactation (from day 1 of pregnancy to the 21st day after birth. Fluoxetine was administered orally at the dose of 20 mg/kg in a group treated during pregnancy only (FG group, and during pregnancy and lactation (FGL group. Histometrical, histochemical and immunohistochemical analysis of the maxillary first molar periodontium region of the 24 rat pups was made under light microscopy, and periodontal ligament collagen was qualitatively evaluated under a polarizing light microscope. Results The quantity of fibroblasts (p=0.006, osteoblasts (p=0.027 and cementoblasts (p=0.001 was reduced in pups from the rats that received fluoxetine during pregnancy and lactation. No alterations were seen in the collagen fibers. Conclusion These findings suggest that periodontal tissue may be sensitive to fluoxetine, and its interference in reducing periodontal cells depends on exposure time during lactation.

  3. Effects of co-administration of fluoxetine or tianeptine with metyrapone on immobility time and plasma corticosterone concentration in rats subjected to the forced swim test.

    Science.gov (United States)

    Rogóz, Zofia; Skuza, Grazyna; Leśkiewicz, Monika; Budziszewska, Bogusława

    2008-01-01

    Major depression is frequently associated with hyperactivity of the hypothalamic-pituitary-adrenocortical axis, and glucocorticoid synthesis inhibitors have been shown to exert antidepressant action. The aim of the present study was to examine the effect of co-administration of fluoxetine or tianeptine with metyrapone on immobility time and plasma corticosterone concentration in male Wistar rats subjected to the forced swim test. Metyrapone alone (50 mg/kg, but not 25 mg/kg) reduced the immobility time of rats in the forced swim test; moreover, both doses tested (25 and 50 mg/kg), dose-dependently decreased the stress-induced plasma corticosterone concentration. Joint administration of fluoxetine or tianeptine (10 mg/kg) and metyrapone (25 mg/kg - a dose inactive per se) exhibited antidepressant-like activity in the forced swim test in rats. WAY 100636 (a 5-HT(1A) antagonist), but not prazosin (an alpha(1)-adrenergic antagonist), used in doses ineffective in the forced swim test, inhibited the antidepressant-like effect induced by co-administration of fluoxetine or tianeptine with metyrapone (25 mg/kg). Combined treatment of fluoxetine or tianeptine and metyrapone inhibited stress-induced corticosterone secretion to a similar extent as metyrapone alone. The obtained results indicate that metyrapone potentiates the antidepressant-like activity of fluoxetine or tianeptine and that, among other mechanisms, 5-HT(1A) receptors may play some role in this effect. Moreover, metyrapone exerts a beneficial effect on the stress-induced increase in plasma corticosterone concentration. These findings suggest that the co-administration of metyrapone and an antidepressant drug may be useful for the treatment of drug-resistant depression and/or depression associated with a high cortisol level.

  4. The role of clinical variables, neuropsychological performance and SLC6A4 and COMT gene polymorphisms on the prediction of early response to fluoxetine in major depressive disorder.

    Science.gov (United States)

    Gudayol-Ferré, Esteve; Herrera-Guzmán, Ixchel; Camarena, Beatriz; Cortés-Penagos, Carlos; Herrera-Abarca, Jorge E; Martínez-Medina, Patricia; Cruz, David; Hernández, Sandra; Genis, Alma; Carrillo-Guerrero, Mariana Y; Avilés Reyes, Rubén; Guàrdia-Olmos, Joan

    2010-12-01

    Major depressive disorder (MDD) is treated with antidepressants, but only between 50% and 70% of the patients respond to the initial treatment. Several authors suggested different factors that could predict antidepressant response, including clinical, psychophysiological, neuropsychological, neuroimaging, and genetic variables. However, these different predictors present poor prognostic sensitivity and specificity by themselves. The aim of our work is to study the possible role of clinical variables, neuropsychological performance, and the 5HTTLPR, rs25531, and val108/58Met COMT polymorphisms in the prediction of the response to fluoxetine after 4weeks of treatment in a sample of patient with MDD. 64 patients with MDD were genotyped according to the above-mentioned polymorphisms, and were clinically and neuropsychologically assessed before a 4-week fluoxetine treatment. Fluoxetine response was assessed by using the Hamilton Depression Rating Scale. We carried out a binary logistic regression model for the potential predictive variables. Out of the clinical variables studied, only the number of anxiety disorders comorbid with MDD have predicted a poor response to the treatment. A combination of a good performance in variables of attention and low performance in planning could predict a good response to fluoxetine in patients with MDD. None of the genetic variables studied had predictive value in our model. The possible placebo effect has not been controlled. Our study is focused on response prediction but not in remission prediction. Our work suggests that the combination of the number of comorbid anxiety disorders, an attentional variable, and two planning variables makes it possible to correctly classify 82% of the depressed patients who responded to the treatment with fluoxetine, and 74% of the patients who did not respond to that treatment. Copyright © 2010 Elsevier B.V. All rights reserved.

  5. Fluoxetine normalizes disrupted light-induced entrainment, fragmented ultradian rhythms and altered hippocampal clock gene expression in an animal model of high trait anxiety- and depression-related behavior.

    Science.gov (United States)

    Schaufler, Jörg; Ronovsky, Marianne; Savalli, Giorgia; Cabatic, Maureen; Sartori, Simone B; Singewald, Nicolas; Pollak, Daniela D

    2016-01-01

    Disturbances of circadian rhythms are a key symptom of mood and anxiety disorders. Selective serotonin reuptake inhibitors (SSRIs) - commonly used antidepressant drugs - also modulate aspects of circadian rhythmicity. However, their potential to restore circadian disturbances in depression remains to be investigated. The effects of the SSRI fluoxetine on genetically based, depression-related circadian disruptions at the behavioral and molecular level were examined using mice selectively bred for high anxiety-related and co-segregating depression-like behavior (HAB) and normal anxiety/depression behavior mice (NAB). The length of the circadian period was increased in fluoxetine-treated HAB as compared to NAB mice while the number of activity bouts and light-induced entrainment were comparable. No difference in hippocampal Cry2 expression, previously reported to be dysbalanced in untreated HAB mice, was observed, while Per2 and Per3 mRNA levels were higher in HAB mice under fluoxetine treatment. The present findings provide evidence that fluoxetine treatment normalizes disrupted circadian locomotor activity and clock gene expression in a genetic mouse model of high trait anxiety and depression. An interaction between the molecular mechanisms mediating the antidepressant response to fluoxetine and the endogenous regulation of circadian rhythms in genetically based mood and anxiety disorders is proposed.

  6. Anti-inflammatory properties of desipramine and fluoxetine

    Directory of Open Access Journals (Sweden)

    Portet Karine

    2007-05-01

    Full Text Available Abstract Background Antidepressants are heavily prescribed drugs and have been shown to affect inflammatory signals. We examined whether these have anti-inflammatory properties in animal models of septic shock and allergic asthma. We also analysed whether antidepressants act directly on peripheral cell types that participate in the inflammatory response in these diseases. Methods The antidepressants desipramine and fluoxetine were compared in vivo to the glucocorticoid prednisolone, an anti-inflammatory drug of reference. In a murine model of lipopolysaccharides (LPS-induced septic shock, animals received the drugs either before or after injection of LPS. Circulating levels of tumour necrosis factor (TNF-α and mortality rate were measured. In ovalbumin-sensitized rats, the effect of drug treatment on lung inflammation was assessed by counting leukocytes in bronchoalveolar lavages. Bronchial hyperreactivity was measured using barometric plethysmography. In vitro production of TNF-α and Regulated upon Activation, Normal T cell Expressed and presumably Secreted (RANTES from activated monocytes and lung epithelial cells, respectively, was analysed by immunoassays. Reporter gene assays were used to measure the effect of antidepressants on the activity of nuclear factor-κB and activator protein-1 which are involved in the control of TNF-α and RANTES expression. Results In the septic shock model, all three drugs given preventively markedly decreased circulating levels of TNF-α and mortality (50% mortality in fluoxetine treated group, 30% in desipramine and prednisolone treated groups versus 90% in controls. In the curative trial, antidepressants had no statistically significant effect, while prednisolone still decreased mortality (60% mortality versus 95% in controls. In ovalbumin-sensitized rats, the three drugs decreased lung inflammation, albeit to different degrees. Prednisolone and fluoxetine reduced the number of macrophages, lymphocytes

  7. Fluoxetine Dose and Administration Method Differentially Affect Hippocampal Plasticity in Adult Female Rats

    Science.gov (United States)

    Pawluski, Jodi L.; van Donkelaar, Eva; Abrams, Zipporah; Steinbusch, Harry W. M.; Charlier, Thierry D.

    2014-01-01

    Selective serotonin reuptake inhibitor medications are one of the most common treatments for mood disorders. In humans, these medications are taken orally, usually once per day. Unfortunately, administration of antidepressant medications in rodent models is often through injection, oral gavage, or minipump implant, all relatively stressful procedures. The aim of the present study was to investigate how administration of the commonly used SSRI, fluoxetine, via a wafer cookie, compares to fluoxetine administration using an osmotic minipump, with regards to serum drug levels and hippocampal plasticity. For this experiment, adult female Sprague-Dawley rats were divided over the two administration methods: (1) cookie and (2) osmotic minipump and three fluoxetine treatment doses: 0, 5, or 10 mg/kg/day. Results show that a fluoxetine dose of 5 mg/kg/day, but not 10 mg/kg/day, results in comparable serum levels of fluoxetine and its active metabolite norfluoxetine between the two administration methods. Furthermore, minipump administration of fluoxetine resulted in higher levels of cell proliferation in the granule cell layer (GCL) at a 5 mg dose compared to a 10 mg dose. Synaptophysin expression in the GCL, but not CA3, was significantly lower after fluoxetine treatment, regardless of administration method. These data suggest that the administration method and dose of fluoxetine can differentially affect hippocampal plasticity in the adult female rat. PMID:24757568

  8. SET-C versus Fluoxetine in the Treatment of Childhood Social Phobia

    Science.gov (United States)

    Beidel, Deborah C.; Turner, Samuel M.; Ammerman, Robert T.; Sallee, Floyd R.; Crosby, Lori A.; Pathak, Sanjeev

    2007-01-01

    A study examines the effectiveness of fluoxetine, pill placebo and Social Effectiveness Therapy for Children (SET-C) for children and adolescents with social phobia. The results conclude that both fluoxetine and SET-C are effective for social phobia but SET-C is better for enhancing social skills.

  9. Long-term administration of fluoxetine to improve motor recovery after stroke

    NARCIS (Netherlands)

    Berends, Hanneke I.; IJzerman, Maarten Joost; Movig, Kris L.L.; van Putten, Michel Johannes Antonius Maria

    2011-01-01

    Evaluation of: Chollet F. Tardy J., Albucher J.F. et al. Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial. Lancet Neurol. 10(2), 123–130 (2011). In this study, the authors examined the effects of administration of fluoxetine for 90 days on the

  10. Morphological and functional determinants of fluoxetine (Prozac)-induced pulmonary disease in an experimental model.

    Science.gov (United States)

    Capelozzi, Marco A; Leick-Maldonado, Edna A; Parra, Edwin R; Martins, Mílton A; Tibério, Iolanda F L C; Capelozzi, Vera L

    2007-05-14

    Fluoxetine treatment effects were determined by evaluating respiratory mechanics (elastance/resistance) and exhaled nitric oxide, as well as mononuclear and polymorphonuclear cell recruitment into the lungs, in an experimental guinea pig model. Guinea pigs were divided into four groups: Fl (fluoxetine only, n=7); Fl+Sw (fluoxetine and forced swimming, n=7); Ns+Sw (normal saline and forced swimming, n=8); and Ns (normal saline only, n=8). Treated animals received oral fluoxetine (10 mg/(kg day)) for 30 consecutive days. On day 31, all animals were anesthetized and mechanically ventilated so that respiratory system elastance and resistance, as well exhaled nitric oxide, could be determined. The lungs were then excised en bloc for histological and immunohistochemical evaluation. Forced swimming induced bronchodilation in untreated animals and bronchoconstriction in fluoxetine-treated animals. Fluoxetine treatment was also associated with mononuclear infiltration (predominantly into alveolar walls) and neutrophil recruitment. In addition, levels of exhaled nitric oxide, an inflammatory marker, were higher in fluoxetine-treated animals. Swimming-induced stress also amplified mononuclear cell recruitment to the lungs. These results show that, in this experimental model, fluoxetine treatment reproduces the pathology of chronic interstitial pneumonia in humans.

  11. Distinctive behavioral and cellular responses to fluoxetine in the mouse model for Fragile X syndrome

    Directory of Open Access Journals (Sweden)

    Marko eUutela

    2014-05-01

    Full Text Available Fluoxetine is used as a therapeutic agent for autism spectrum disorder (ASD, including Fragile X syndrome (FXS. The treatment often associates with disruptive behaviors such as agitation and disinhibited behaviors in FXS. To identify mechanisms that increase the risk to poor treatment outcome, we investigated the behavioral and cellular effects of fluoxetine on adult Fmr1 knockout (KO mice, a mouse model for FXS. We found that fluoxetine reduced anxiety-like behavior of both wild type and Fmr1 KO mice seen as shortened latency to enter the center area in the open field test. In Fmr1 KO mice, fluoxetine normalized locomotor hyperactivity but abnormally increased exploratory activity. Reduced Brain-derived neurotrophic factor (BDNF and increased TrkB receptor expression levels in the hippocampus of Fmr1 KO mice associated with inappropriate coping responses under stressful condition and abolished antidepressant activity of fluoxetine. Fluoxetine response in the cell proliferation was also missing in the hippocampus of Fmr1 KO mice when compared with wild type controls. The postnatal expression of serotonin transporter was reduced in the thalamic nuclei of Fmr1 KO mice during the time of transient innervation of somatosensory neurons suggesting that developmental changes of serotonin transporter (SERT expression were involved in the differential cellular and behavioral responses to fluoxetine in wild type and Fmr1 mice. The results indicate that changes of BDNF/TrkB signaling contribute to differential behavioral responses to fluoxetine among individuals with ASD.

  12. Fluoxetine Dose and Administration Method Differentially Affect Hippocampal Plasticity in Adult Female Rats

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    Jodi L. Pawluski

    2014-01-01

    Full Text Available Selective serotonin reuptake inhibitor medications are one of the most common treatments for mood disorders. In humans, these medications are taken orally, usually once per day. Unfortunately, administration of antidepressant medications in rodent models is often through injection, oral gavage, or minipump implant, all relatively stressful procedures. The aim of the present study was to investigate how administration of the commonly used SSRI, fluoxetine, via a wafer cookie, compares to fluoxetine administration using an osmotic minipump, with regards to serum drug levels and hippocampal plasticity. For this experiment, adult female Sprague-Dawley rats were divided over the two administration methods: (1 cookie and (2 osmotic minipump and three fluoxetine treatment doses: 0, 5, or 10 mg/kg/day. Results show that a fluoxetine dose of 5 mg/kg/day, but not 10 mg/kg/day, results in comparable serum levels of fluoxetine and its active metabolite norfluoxetine between the two administration methods. Furthermore, minipump administration of fluoxetine resulted in higher levels of cell proliferation in the granule cell layer (GCL at a 5 mg dose compared to a 10 mg dose. Synaptophysin expression in the GCL, but not CA3, was significantly lower after fluoxetine treatment, regardless of administration method. These data suggest that the administration method and dose of fluoxetine can differentially affect hippocampal plasticity in the adult female rat.

  13. Synthesis of [[sup 18]F]-(S)-fluoxetine: a selective serotonine uptake inhibitor

    Energy Technology Data Exchange (ETDEWEB)

    Hammadi, A.; Crouzel, C. (CEA, 91 - Orsay (France). Service Hospitalier Frederic Joliot)

    1993-01-01

    The (S)-N-methyl-[gamma]-[4-(trifluoromethyl)phenoxy] benzenepropanamine, an antidepressant with potential applications in the treatment of other illnesses was labelled with fluorine-18 for Positron Emission Tomography studies. The synthesis was accomplished from the [[sup 18]F]-4-chlorobenzotrifluoride where [[sup 18]F]-label was introduced via a nucleophilic aliphatic substitution reaction. [[sup 18]F]-(S)-Fluoxetine was obtained with a radiochemical yield of 9-10% (decay corrected) and a specific radioactivity of 100-150 mCi/[mu]mol (3.70-5.55 GBq/[mu]mol) in a total synthesis time of 150 min. A facile isotopic exchange reaction was demonstrated; it is expected to reduce the specific activity of the final [[sup 18]F]-product. The experimental parameters play an important role, which is discussed. (Author).

  14. Synthesis of [18F]-(S)-fluoxetine: a selective serotonine uptake inhibitor

    International Nuclear Information System (INIS)

    Hammadi, A.; Crouzel, C.

    1993-01-01

    The (S)-N-methyl-γ-[4-(trifluoromethyl)phenoxy] benzenepropanamine, an antidepressant with potential applications in the treatment of other illnesses was labelled with fluorine-18 for Positron Emission Tomography studies. The synthesis was accomplished from the [ 18 F]-4-chlorobenzotrifluoride where [ 18 F]-label was introduced via a nucleophilic aliphatic substitution reaction. [ 18 F]-(S)-Fluoxetine was obtained with a radiochemical yield of 9-10% (decay corrected) and a specific radioactivity of 100-150 mCi/μmol (3.70-5.55 GBq/μmol) in a total synthesis time of 150 min. A facile isotopic exchange reaction was demonstrated; it is expected to reduce the specific activity of the final [ 18 F]-product. The experimental parameters play an important role, which is discussed. (Author)

  15. Differential regulation of catecholamine synthesis and transport in rat adrenal medulla by fluoxetine treatment.

    Science.gov (United States)

    Spasojevic, Natasa; Jovanovic, Predrag; Dronjak, Sladjana

    2015-03-01

    We have recently shown that chronic fluoxetine treatment acted significantly increasing plasma norepinephrine and epinephrine concentrations both in control and chronically stressed adult male rats. However, possible effects of fluoxetine on catecholamine synthesis and re-uptake in adrenal medulla have been largely unknown. In the present study the effects of chronic fluoxetine treatment on tyrosine hydroxylase, a rate-limiting enzyme in catecholamine synthesis, as well as a norepinephrine transporter and vesicular monoamine transporter 2 gene expressions in adrenal medulla of animals exposed to chronic unpredictable mild stress (CUMS) for 4 weeks, were investigated. Gene expression analyses were performed using a real-time quantitative reverse transcription-PCR. Chronically stressed animals had increased tyrosine hydroxylase mRNA levels and decreased expression of both transporters. Fluoxetine increased tyrosine hydroxylase and decreased norepinephrine transporter gene expression in both unstressed and CUMS rats. These findings suggest that chronic fluoxetine treatment increased plasma catecholamine levels by affecting opposing changes in catecholamine synthesis and uptake.

  16. Effect of electrostatic interaction between fluoxetine and lipid membranes on the partitioning of fluoxetine investigated using second derivative spectrophotometry and FTIR.

    Science.gov (United States)

    Do, Tien T T; Dao, Uyen P N; Bui, Huong T; Nguyen, Trang T

    2017-10-01

    The interaction between a drug molecule and lipid bilayers is highly important regarding the pharmaceutical activity of the drug. In this study, the interaction of fluoxetine, a well-known selective serotonin reuptake inhibitor antidepressant and lipid bilayers composed of 1,2-dipalmitoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (DPPG) and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) was studied from the aspect of electrostatics using second derivative spectrophotometry and Fourier transform infrared spectroscopy (FTIR) in order to provide insights into the drug behavior. Changing pH from 7.4 to 9.5 to increases the neutral state of fluoxetine, the partitioning of fluoxetine into the zwitterionic DPPC large unilamellar vesicles (LUVs) was increased whereas it was reduced into the negatively charged DPPG LUVs. Fluoxetine was found to exhibit a disordering effect on the acyl chains of DPPC and DPPG bilayers upon its partitioning. In addition, increasing concentration of NaCl lessened the binding of fluoxetine into DPPG bilayers due to the reduction in electrostatic attraction between positively charged fluoxetine and negatively charged DPPG LUVs. In addition, the FTIR study revealed that increasing the NaCl concentration could trigger the shift to higher frequency of the CH 2 stretching as well as the notable blue shift in the PO 2 - regions of DPPG, indicating that fluoxetine had deeper penetration into DPPG LUVs. The differences in the NaCl concentration showed a negligible effect on the incorporation of fluoxetine into the zwitterionic DPPC LUVs. In summary, the electrostatic interaction plays an important role on the partitioning of a cationic amphiphilic SSIR drug into the lipid bilayers and the drug partitioning induces the lipids' conformational change. These imply a possible influence on the drug pharmacology. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Clinical efficacy and safety of fluoxetine in generalized anxiety disorder in Chinese patients

    Directory of Open Access Journals (Sweden)

    Zou C

    2013-11-01

    Full Text Available Chuan Zou,1 Xiang Ding,1 Joseph H Flaherty,2 Birong Dong1 1The Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu, People's Republic of China; 2St Louis University, St Louis, MO, USA Background: Generalized anxiety disorder (GAD is a prevalent, disabling disease and is highly comorbid with other psychiatric disorders both in Western countries and the People's Republic of China. Fluoxetine, a selective inhibitor of serotonin reuptake (SSRI, is widely utilized in the management of GAD in clinical practice despite the lack of strong evidence. This article reviews fluoxetine trials to investigate fluoxetine's efficacy and tolerability in Chinese patients with GAD. Methods: A literature review was conducted using the following databases up to and including April 2013: Chinese BioMedical Literature, China National Knowledge Infrastructure, EMBASE, MEDLINE, and PsycINFO. We selected clinical studies that utilized fluoxetine for GAD in which all participants were Chinese. Results: Fifteen open-label, non-placebo trials were identified and analyzed; eleven anxiolytics were compared with fluoxetine separately. Short-term efficacy of fluoxetine had been established in these open-label, head-to-head controlled trials. Fluoxetine had rapid onset of action (approximately 1–2 weeks and seemed to be effective in maintenance treatment. Fluoxetine was generally well-tolerated with the most common side effect of dry month and nausea. Compared to other anxiolytic agents, fluoxetine was equivalent with all of the comparative anxiolytics in terms of efficacy except mirtazapine which showed conflicting results with fluoxetine in two studies. In terms of side effects, fluoxetine was better tolerated than diazepam, doxepine, and amitriptyline, less tolerated than escitalopram, and had similar tolerability with duloxetine as well as alprazolam. Conclusion: Given the high risk of bias of the included studies, the overall small sample

  18. Fluoxetine effects on molecular, cellular and behavioral endophenotypes of depression are driven by the living environment.

    Science.gov (United States)

    Alboni, S; van Dijk, R M; Poggini, S; Milior, G; Perrotta, M; Drenth, T; Brunello, N; Wolfer, D P; Limatola, C; Amrein, I; Cirulli, F; Maggi, L; Branchi, I

    2017-04-01

    Selective serotonin reuptake inhibitors (SSRIs) represent the most common treatment for major depression. However, their efficacy is variable and incomplete. In order to elucidate the cause of such incomplete efficacy, we explored the hypothesis positing that SSRIs may not affect mood per se but, by enhancing neural plasticity, render the individual more susceptible to the influence of the environment. Consequently, SSRI administration in a favorable environment promotes a reduction of symptoms, whereas in a stressful environment leads to a worse prognosis. To test such hypothesis, we exposed C57BL/6 mice to chronic stress in order to induce a depression-like phenotype and, subsequently, to fluoxetine treatment (21 days), while being exposed to either an enriched or a stressful condition. We measured the most commonly investigated molecular, cellular and behavioral endophenotypes of depression and SSRI outcome, including depression-like behavior, neurogenesis, brain-derived neurotrophic factor levels, hypothalamic-pituitary-adrenal axis activity and long-term potentiation. Results showed that, in line with our hypothesis, the endophenotypes investigated were affected by the treatment according to the quality of the living environment. In particular, mice treated with fluoxetine in an enriched condition overall improved their depression-like phenotype compared with controls, whereas those treated in a stressful condition showed a distinct worsening. Our findings suggest that the effects of SSRI on the depression- like phenotype is not determined by the drug per se but is induced by the drug and driven by the environment. These findings may be helpful to explain variable effects of SSRI found in clinical practice and to device strategies aimed at enhancing their efficacy by means of controlling environmental conditions.

  19. Perinatal Fluoxetine Exposure Impairs the CO2 Chemoreflex. Implications for Sudden Infant Death Syndrome.

    Science.gov (United States)

    Bravo, Karina; Eugenín, Jaime L; Llona, Isabel

    2016-09-01

    High serotonin levels during pregnancy affect central nervous system development. Whether a commonly used antidepressant such as fluoxetine (a selective serotonin reuptake inhibitor) taken during pregnancy may adversely affect respiratory control in offspring has not been determined. The objective was to determine the effect of prenatal-perinatal fluoxetine exposure on the respiratory neural network in offspring, particularly on central chemoreception. Osmotic minipumps implanted into CF-1 mice on Days 5-7 of pregnancy delivered 7 milligrams per kilogram per day of fluoxetine, achieving plasma levels within the range found in patients. Ventilation was assessed in offspring at postnatal Days 0-40 using head-out body plethysmography. Neuronal activation was evaluated in the raphe nuclei and in the nucleus tractus solitarius by c-Fos immunohistochemistry during normoxic eucapnia and hypercapnia (10% CO2). Respiratory responses to acidosis were evaluated in brainstem slices. Prenatal-perinatal fluoxetine did not affect litter size, birth weight, or the postnatal growth curve. Ventilation under eucapnic normoxic conditions was similar to that of control offspring. Fluoxetine exposure reduced ventilatory responses to hypercapnia at P8-P40 (P Fluoxetine applied acutely on control slices did not modify their respiratory response to acidosis. We concluded that prenatal-perinatal fluoxetine treatment impairs central respiratory chemoreception during postnatal life. These results are relevant in understanding the pathogenesis of respiratory failures, such as sudden infant death syndrome, associated with brainstem serotonin abnormalities and the failure of respiratory chemoreflexes.

  20. Fluoxetine ameliorates cartilage degradation in osteoarthritis by inhibiting Wnt/β-catenin signaling.

    Science.gov (United States)

    Miyamoto, Kentaro; Ohkawara, Bisei; Ito, Mikako; Masuda, Akio; Hirakawa, Akihiro; Sakai, Tadahiro; Hiraiwa, Hideki; Hamada, Takashi; Ishiguro, Naoki; Ohno, Kinji

    2017-01-01

    Abnormal activation of the Wnt/β-catenin signaling is implicated in the osteoarthritis (OA) pathology. We searched for a pre-approved drug that suppresses abnormally activated Wnt/β-catenin signaling and has a potency to reduce joint pathology in OA. We introduced the TOPFlash reporter plasmid into HCS-2/8 human chondrosarcoma cells to estimate the Wnt/β-catenin activity in the presence of 10 μM each compound in a panel of pre-approved drugs. We found that fluoxetine, an antidepressant in the class of selective serotonin reuptake inhibitors (SSRI), down-regulated Wnt/β-catenin signaling in human chondrosarcoma cells. Fluoxetine inhibited both Wnt3A- and LiCl-induced loss of proteoglycans in chondrogenically differentiated ATDC5 cells. Fluoxetine increased expression of Sox9 (the chondrogenic master regulator), and decreased expressions of Axin2 (a marker for Wnt/β-catenin signaling) and Mmp13 (matrix metalloproteinase 13). Fluoxetine suppressed a LiCl-induced increase of total β-catenin and a LiCl-induced decrease of phosphorylated β-catenin in a dose-dependent manner. An in vitro protein-binding assay showed that fluoxetine enhanced binding of β-catenin with Axin1, which is a scaffold protein forming the degradation complex for β-catenin. Fluoxetine suppressed LiCl-induced β-catenin accumulation in human OA chondrocytes. Intraarticular injection of fluoxetine in a rat OA model ameliorated OA progression and suppressed β-catenin accumulation.

  1. Effect of using fluoxetine at different time windows on neurological functional prognosis after ischemic stroke.

    Science.gov (United States)

    Guo, Yi; He, Yitao; Tang, Bingshan; Ma, Kefu; Cai, Zhili; Zeng, Siling; Zhang, Ying; Jiang, Xin

    2016-01-01

    To evaluate the effect of using fluoxetine at different time intervals after ischemic stroke on neurological functional prognosis in China. The patients enrolled were randomly allocated to three groups. Group A received fluoxetine 20 mg/day immediately; group B received fluoxetine 20 mg/day 7 days after enrollment; and group C did not receive fluoxetine. The therapeutic duration of fluoxetine was 90 days and the follow-up period was 180 days. The mean NIHSS score at day 90 was significantly lower in group A than group C (P = 0.005), while at day 180, the mean score in group A was significantly lower than groups B and C (P = 0.035, P = 0.000), respectively. The mean BI score at day 90 was significantly higher in group A than group C (P = 0.001), while at day 180, the mean score in group A was significantly higher than groups B and C (P = 0.036, P = 0.000), respectively. Regression analysis indicated that lower NIHSS score and higher BI score at day 180 were attributed to the early administration of fluoxetine. In patients with ischemic stroke, early administration of fluoxetine may improve the neurological functional prognosis.

  2. Fluoxetine augments ventilatory CO2 sensitivity in Brown Norway but not Sprague Dawley rats.

    Science.gov (United States)

    Hodges, Matthew R; Echert, Ashley E; Puissant, Madeleine M; Mouradian, Gary C

    2013-04-01

    The Brown Norway (BN; BN/NHsdMcwi) rat exhibits a deficit in ventilatory CO2 sensitivity and a modest serotonin (5-HT) deficiency. Here, we tested the hypothesis that the selective serotonin reuptake inhibitor fluoxetine would augment CO2 sensitivity in BN but not Sprague Dawley (SD) rats. Ventilation during room air or 7% CO2 exposure was measured before, during and after 3 weeks of daily injections of saline or fluoxetine (10mg/(kgday)) in adult male BN and SD rats. Fluoxetine had minimal effects on room air breathing in BN and SD rats (p>0.05), although tidal volume (VT) was reduced in BN rats (peffects of fluoxetine on CO2 sensitivity in SD rats, but fluoxetine increased minute ventilation, breathing frequency and VT during hypercapnia in BN rats (pCO2 response was reversible upon withdrawal of fluoxetine. Brain levels of biogenic amines were largely unaffected, but 5-HIAA and the ratio of 5-HIAA/5-HT were reduced (peffective 5-HT reuptake inhibition. Thus, fluoxetine increases ventilatory CO2 sensitivity in BN but not SD rats, further suggesting altered 5-HT system function may contribute to the inherently low CO2 sensitivity in the BN rat. Copyright © 2013 Elsevier B.V. All rights reserved.

  3. Fluoxetine augments ventilatory CO2 sensitivity in Brown Norway but not Sprague Dawley rats

    OpenAIRE

    Hodges, Matthew R.; Echert, Ashley E.; Puissant, Madeleine M.; Mouradian, Gary C.

    2013-01-01

    The Brown Norway (BN; BN/NHsdMcwi) rat exhibits a deficit in ventilatory CO2 sensitivity and a modest serotonin (5-HT) deficiency. Here, we tested the hypothesis that the selective serotonin reuptake inhibitor fluoxetine would augment CO2 sensitivity in BN but not Sprague Dawley (SD) rats. Ventilation during room air or 7 % CO2 exposure was measured before, during and after 3 weeks of daily injections of saline or fluoxetine (10 mg/kg/day) in adult male BN and SD rats. Fluoxetine had minimal ...

  4. miR-16 and Fluoxetine Both Reverse Autophagic and Apoptotic Change in Chronic Unpredictable Mild Stress Model Rats

    Directory of Open Access Journals (Sweden)

    Yang Yang

    2017-07-01

    Full Text Available In the clinic selective serotonin reuptake inhibitors (SSRIs, like Fluoxetine, remain the primary treatment for major depression. It has been suggested that miR-16 regulates serotonin transporters (SERT via raphe nuclei and hippocampal responses to antidepressants. However, the underlying mechanism and regulatory pathways are still obtuse. Here, a chronic unpredicted mild stress (CUMS depression model in rats was established, and then raphe nuclei miR-16 and intragastric Fluoxetine injections were administered for a duration of 3 weeks. An open field test and sucrose preference quantification displayed a significant decrease in the CUMS groups when compare to the control groups, however these changes were attenuated by both miR-16 and Fluoxetine treatments. A dual-luciferase reporter assay system verified that hsa-miR-16 inhibitory effects involve the targeting of 3′UTR on the 5-HTT gene. Expression levels of miR-16 and BDNF in the hippocampus were examined with RT-PCR, and it was found that increased 5-HT2a receptor expression induced by CUMS can be decreased by miR-16 and Fluoxetine administration. Immunofluorescence showed that expression levels of neuron NeuN and MAP-2 in CUMS rats were lower. Apoptosis and autophagy levels were evaluated separately through relative expression of Bcl-2, Caspase-3, Beclin-1, and LC3II. Furthermore, CUMS was found to decrease levels of hippocampal mTOR, PI3K, and AKT. These findings indicate that apoptosis and autophagy related pathways could be involved in the effectiveness of antidepressants, in which miR-16 participates in the regulation of, and is likely to help integrate rapid therapeutic strategies to alleviate depression clinically. These findings indicate that miR-16 participates in the regulation of apoptosis and autophagy and could account for some part of the therapeutic effect of SSRIs. This discovery has the potential to further the understanding of SSRIs and accelerate the development of new

  5. Transient Serotonin Toxicity Evoked by Combination of Electroconvulsive Therapy and Fluoxetine

    Directory of Open Access Journals (Sweden)

    René Klysner

    2014-01-01

    Full Text Available The serotonin syndrome has been described only in rare instances for electroconvulsive therapy combined with an antidepressant medication. We describe a case of serotonin toxicity induced by electroconvulsive therapy in combination with fluoxetine.

  6. Role of anti-depressant fluoxetine in the puva treatment of psoriasis vulgaris

    Directory of Open Access Journals (Sweden)

    Mitra A

    2001-11-01

    Full Text Available Severity of psoriasis vulgaris is known to be modified by psychological stress. The objective of this study was to evaluate the role of fluoxetine in the PU VA treatment of psoriasis. Twenty patients with progressive disease having more than thirty per cent body area involvement were included in a randomized, double blinded, placebo- controlled, age and sex matched study. All patients were on PUVA treatment, half of patients were given fluoxetine 20 mgs daily whereas the ten were given placebo. Assessment was done by Psoriasis Area and Severity Index (PASI scoring after every 5 exposures of PUVA treatment till 20 treatments. All ten patients who took fluoxetine along with PUVA treatment showed better response and quicker remission. Fluoxetine may be used as an adjuvant in PUVA treatment of psoriasis.

  7. A concise total synthesis of (R)-fluoxetine, a potent and selective serotonin reuptake inhibitor

    International Nuclear Information System (INIS)

    Fatima, Angelo de; Lapis, Alexandre Augusto M.; Pilli, Ronaldo A.

    2005-01-01

    (R)-Fluoxetine, potent and selective serotonin reuptake inhibitor, has been synthesized in six steps, 50% overall yield and 99% ee from benzaldehyde via catalytic asymmetric allylation with Maruoka's catalyst. (author)

  8. A concise total synthesis of (R)-fluoxetine, a potent and selective serotonin reuptake inhibitor

    Energy Technology Data Exchange (ETDEWEB)

    Fatima, Angelo de; Lapis, Alexandre Augusto M.; Pilli, Ronaldo A. [Universidade Estadual de Campinas, SP (Brazil). Inst. de Quimica]. E-mail: pilli@iqm.unicamp.br

    2005-05-15

    (R)-Fluoxetine, potent and selective serotonin reuptake inhibitor, has been synthesized in six steps, 50% overall yield and 99% ee from benzaldehyde via catalytic asymmetric allylation with Maruoka's catalyst. (author)

  9. Effects of chronic fluoxetine treatment on neurogenesis and tryptophan hydroxylase expression in adolescent and adult rats

    NARCIS (Netherlands)

    Klomp, Anne; Václavů, Lena; Meerhoff, Gideon F.; Reneman, Liesbeth; Lucassen, Paul J.

    2014-01-01

    The antidepressant drug fluoxetine (Prozac) has been increasingly prescribed to children and adolescents with depressive disorders despite a lack of thorough understanding of its therapeutic effects in the paediatric population and of its putative neurodevelopmental effects. Within the framework of

  10. Role of anti-depressant fluoxetine in the puva treatment of psoriasis vulgaris

    Directory of Open Access Journals (Sweden)

    Mitra A

    2003-03-01

    Full Text Available Severity of Psoriasis Vulgaris is known to be modified by psychological stress. The objective of this study was to evaluate the role of Fluoxetine in the PUVA treatment of Psoriasis. Twenty patients with progressive disease having more than thirty per cent body area involvement were included in a randomized, double blinded, placebo-controlled, age and sex matched study. All patients were on PUVAtreatment; half of the patients were given Fluoxetine 20 mgms daily whereas the other ten were given placebo. Assessment was done by Psoriasis Area and Severity Index (PASI scoring after every 5 exposures of PUVA treatment till 20 treatments. All ten patients who took Fluoxetine along with PUVA treatment showed better response and quicker remission. Fluoxetine may be used as an adjuvant in PUVA treatment of Psoriasis.

  11. Estradiol or fluoxetine alters depressive behavior and tryptophan hydroxylase in rat raphe.

    Science.gov (United States)

    Yang, Fu-Zhong; Wu, Yan; Zhang, Wei-Guo; Cai, Yi-Yun; Shi, Shen-Xun

    2010-03-10

    The effects of 17beta-estradiol and fluoxetine on behavior of ovariectomized rats subjected to the forced swimming test and the expression of tryptophan hydroxylase (TPH) in dorsal and median raphe were investigated, respectively through time sampling technique of behavior scoring and immunohistochemistry. Both estradiol and fluoxetine increased swimming and decreased immobility in the forced swimming test. The forced swimming stress decreased integrated optical density of TPH-positive regions in dorsal and median raphe. Both estradiol and fluoxetine administration prevented integrated optical density of TPH-positive regions from being decreased by forced swimming stress. These observations suggest that both estradiol and fluoxetine have protective bearing on ovariectomized rats enduring forced swimming stress.

  12. Parkinsonisme na toevoeging van fluoxetine aan behandeling met neuroleptica of carbamazepine

    NARCIS (Netherlands)

    Touw, D J; Gernaat, H B; van der Woude, J

    1992-01-01

    This article describes three patients who developed parkinsonism when fluoxetine was added to their existing medication (neuroleptics or carbamazepine). Based on published pharmacological and neuroanatomical research we postulate a serotonin-dopamine antagonism to be operative in the development of

  13. Comparison of neurogenic effects of fluoxetine, duloxetine and running in mice

    NARCIS (Netherlands)

    Marlatt, M.W.; Lucassen, P.J.; van Praag, H.

    2010-01-01

    Hippocampal neurogenesis can be regulated by extrinsic factors, such as exercise and antidepressants. While there is evidence that the selective serotonin reuptake inhibitor (SSRI) fluoxetine enhances neurogenesis, the new dual serotonergic-noradrenergic reuptake inhibitor (SNRI) duloxetine has not

  14. Effects of fluoxetine on changes of pain sensitivity in chronic stress model rats.

    Science.gov (United States)

    Lian, Yan-Na; Chang, Jin-Long; Lu, Qi; Wang, Yi; Zhang, Ying; Zhang, Feng-Min

    2017-06-09

    Exposure to stress could facilitate or inhibit pain responses (stress-induced hyperalgesia or hypoalgesia, respectively). Fluoxetine is a selective serotonin (5-HT) reuptake inhibitor antidepressant. There have been contradictory reports on whether fluoxetine produces antinociceptive effects. The purpose of this study was to elucidate changes in pain sensitivity after chronic stress exposure, and the effects of fluoxetine on these changes. We measured thermal, mechanical, and formalin-induced acute and inflammatory pain by using the tail-flick, von Frey, and formalin tests respectively. The results showed that rats exposed to chronic stress exhibited thermal and formalin-induced acute and inflammatory hypoalgesia and transient mechanical hyperalgesia. Furthermore, fluoxetine promoted hypoalgesia in thermal and inflammatory pain and induced mechanical hyperalgesia. Our results indicate that the 5-HT system could be involved in hypoalgesia of thermal and inflammatory pain and induce transient mechanical hyperalgesia after stress exposure. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Sprague-Dawley and Fischer Female Rats Differ in Acute Effects of Fluoxetine on Sexual Behavior

    Science.gov (United States)

    Miryala, C.S.J.; Hiegel, C.; Uphouse, L.

    2012-01-01

    Introduction The selective serotonin reuptake inhibitor (SSRI), fluoxetine, leads to sexual dysfunction in a substantial proportion of women. In studies with the Fischer inbred rat, the 5-HT1A receptor has been implicated in this sexual dysfunction. Whether this association with 5-HT1A receptors holds for other rat strains is not known. Aim The effects of acute fluoxetine on sexual behavior in two strains of rats that differ in their response to a 5-HT1A receptor agonist were examined. Whether the strain difference is comparable in naturally cycling and hormonally primed, ovariectomized rats was determined. Main Outcome Measures Lordosis to mount ratios, lordosis quality, and proceptive behaviors were quantified. Sprague-Dawley and Fischer females were compared on each of these measures. The IC50 for inhibition of lordosis behavior was determined. Methods Proestrous rats and ovariectomized rats, hormonally primed with estradiol benzoate and progesterone, were treated with varying doses of fluoxetine. Sexual behavior was examined before and after treatment with the SSRI. Results In both the intact and the hormonally-primed, ovariectomized model, Sprague-Dawley females were less sensitive to the effects of fluoxetine on sexual behavior. In both groups, fluoxetine showed dose-dependency in behavioral inhibition, but a higher dose was required for Sprague-Dawley than for Fischer females. Naturally cycling, proestrous rats required a higher dose of fluoxetine than hormonally-primed ovariectomized rats to produce significant inhibition of sexual behavior. Thus, the strain difference in the response to fluoxetine does not parallel strain differences in the response to a 5-HT1A receptor agonist. Conclusions Acute treatment with fluoxetine inhibits lordosis behavior in both Fischer and Sprague-Dawley females and the strain difference cannot be explained by reported strain differences in the response to a 5-HT1A receptor agonist. Fluoxetine’s inhibition of female rat

  16. Transient Serotonin Toxicity Evoked by Combination of Electroconvulsive Therapy and Fluoxetine

    DEFF Research Database (Denmark)

    Klysner, René; Bjerg Bendsen, Birgitte; Hansen, Maja Soon

    2014-01-01

    The serotonin syndrome has been described only in rare instances for electroconvulsive therapy combined with an antidepressant medication. We describe a case of serotonin toxicity induced by electroconvulsive therapy in combination with fluoxetine.......The serotonin syndrome has been described only in rare instances for electroconvulsive therapy combined with an antidepressant medication. We describe a case of serotonin toxicity induced by electroconvulsive therapy in combination with fluoxetine....

  17. Behavioral and neurogenomic transcriptome changes in wild-derived zebrafish with fluoxetine treatment

    OpenAIRE

    Wong, Ryan Y; Oxendine, Sarah E; Godwin, John

    2013-01-01

    Background Stress and anxiety-related behaviors are seen in many organisms. Studies have shown that in humans and other animals, treatment with selective serotonin reuptake inhibitors (e.g. fluoxetine) can reduce anxiety and anxiety-related behaviors. The efficacies and side effects, however, can vary between individuals. Fluoxetine can modulate anxiety in a stereospecific manner or with equal efficacy regardless of stereoisomer depending on the mechanism of action (e.g. serotonergic or GABAe...

  18. Effects of chronic fluoxetine treatment on neurogenesis and tryptophan hydroxylase expression in adolescent and adult rats

    OpenAIRE

    Klomp, A.; Václavů, L.; Meerhoff, G.F.; Reneman, L.; Lucassen, P.J.

    2014-01-01

    The antidepressant drug fluoxetine (Prozac) has been increasingly prescribed to children and adolescents with depressive disorders despite a lack of thorough understanding of its therapeutic effects in the paediatric population and of its putative neurodevelopmental effects. Within the framework of PRIOMEDCHILD ERA-NET, we investigated; a) effects of chronic fluoxetine treatment on adult hippocampal neurogenesis, a structural readout relevant for antidepressant action and hippocampal developm...

  19. Differential weight restoration on olanzapine versus fluoxetine in identical twins with anorexia nervosa

    OpenAIRE

    Duvvuri, V; Cromley, T; Klabunde, M; Boutelle, K; Kaye, WH

    2012-01-01

    Objective: No studies have compared the response to selective serotonin reuptake inhibitors and atypical antipsychotics in anorexia nervosa. This case study examines such a comparison. Method: This report describes a case of 12-year-old identical twins with anorexia nervosa, one of whom was treated with olanzapine and the other with fluoxetine, while undergoing family therapy. Results: Twin A treated with fluoxetine went from 75 to 84.4% ideal body weight, while Twin B treated with olanzapine...

  20. Metabolic mapping of the effects of the antidepressant fluoxetine on the brains of congenitally helpless rats.

    Science.gov (United States)

    Shumake, Jason; Colorado, Rene A; Barrett, Douglas W; Gonzalez-Lima, F

    2010-07-09

    Antidepressants require adaptive brain changes before efficacy is achieved, and they may impact the affectively disordered brain differently than the normal brain. We previously demonstrated metabolic disturbances in limbic and cortical regions of the congenitally helpless rat, a model of susceptibility to affective disorder, and we wished to test whether administration of fluoxetine would normalize these metabolic differences. Fluoxetine was chosen because it has become a first-line drug for the treatment of affective disorders. We hypothesized that fluoxetine antidepressant effects may be mediated by decreasing metabolism in the habenula and increasing metabolism in the ventral tegmental area. We measured the effects of fluoxetine on forced swim behavior and regional brain cytochrome oxidase activity in congenitally helpless rats treated for 2 weeks with fluoxetine (5mg/kg, i.p., daily). Fluoxetine reduced immobility in the forced swim test as anticipated, but congenitally helpless rats responded in an atypical manner, i.e., increasing climbing without affecting swimming. As hypothesized, fluoxetine reduced metabolism in the habenula and increased metabolism in the ventral tegmental area. In addition, fluoxetine reduced the metabolism of the hippocampal dentate gyrus and dorsomedial prefrontal cortex. This study provided the first detailed mapping of the regional brain effects of an antidepressant drug in congenitally helpless rats. All of the effects were consistent with previous studies that have metabolically mapped the effects of serotonergic antidepressants in the normal rat brain, and were in the predicted direction of metabolic normalization of the congenitally helpless rat for all affected brain regions except the prefrontal cortex. Copyright (c) 2010 Elsevier B.V. All rights reserved.

  1. Metabolic mapping of the effects of the antidepressant fluoxetine on the brains of congenitally helpless rats

    OpenAIRE

    Shumake, Jason; Colorado, Rene A.; Barrett, Douglas W.; Gonzalez-Lima, F.

    2010-01-01

    Antidepressants require adaptive brain changes before efficacy is achieved, and they may impact the affectively disordered brain differently than the normal brain. We previously demonstrated metabolic disturbances in limbic and cortical regions of the congenitally helpless rat, a model of susceptibility to affective disorder, and we wished to test whether administration of fluoxetine would normalize these metabolic differences. Fluoxetine was chosen because it has become a first-line drug for...

  2. Peer social interaction is facilitated in juvenile rhesus monkeys treated with fluoxetine.

    Science.gov (United States)

    Golub, Mari S; Hogrefe, Casey E; Bulleri, Alicia M

    2016-06-01

    Fluoxetine improves social interactions in children with autism, social anxiety and social phobia. It is not known whether this effect is mediated directly or indirectly by correcting the underlying pathology. Genetics may also influence the drug effect. Polymorphisms of the MAOA (monoamine oxidase A) gene interact with fluoxetine to influence metabolic profiles in juvenile monkeys. Juvenile nonhuman primates provide an appropriate model for studying fluoxetine effects and drug*gene interactions in children. Male rhesus monkeys 1-3 years of age living in permanent social pairs were treated daily with a therapeutic dose of fluoxetine or vehicle (n = 16/group). Both members of each social pair were assigned to the same treatment group. They were observed for social interactions with their familiar cagemate over a 2-year dosing period. Subjects were genotyped for MAOA variable number of tandem repeats (VNTR) polymorphisms categorized for high or low transcription rates (hi-MAOA, low-MAOA). Fluoxetine-treated animals spent 30% more time in social interaction than vehicle controls. Fluoxetine significantly increased the duration of quiet interactions, the most common type of interaction, and also of immature sexual behavior typical of rhesus in this age group. Specific behaviors affected depended on MAOA genotype of the animal and its social partner. When given fluoxetine, hi-MOAO monkeys had more social invitation and initiation behaviors and low-MAOA subjects with low-MAOA partners had more grooming and an increased frequency of some facial and vocal expressive behaviors. Fluoxetine may facilitate social interaction in children independent of remediation of psychopathology. Common genetic variants may modify this effect. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. On the interaction between fluoxetine and lipid membranes: Effect of the lipid composition

    Science.gov (United States)

    Pham, Vy T.; Nguyen, Trinh Q.; Dao, Uyen P. N.; Nguyen, Trang T.

    2018-02-01

    Molecular interaction between the antidepressant fluoxetine and lipid bilayers was investigated in order to provide insights into the drug's incorporation to lipid membranes. In particular, the effects of lipid's unsaturation degree and cholesterol content on the partitioning of fluoxetine into large unilamellar vesicles (LUVs) comprised of unsaturated 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and saturated 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) were evaluated using second derivative spectrophotometry and Attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR). It was found that fluoxetine partitioned to a greater extent into the liquid-crystalline DOPC LUVs than into the solid-gel DPPC LUVs. The lipid physical state dependence of drug partitioning was verified by increasing the temperature in which the partition coefficient of fluoxetine significantly increased upon the change of the lipid phase from solid-gel to liquid-crystalline. The incorporation of 28 mol% cholesterol into the LUVs exerted a significant influence on the drug partitioning into both DOPC and DPPC LUVs. The ATR-FTIR study revealed that fluoxetine perturbed the conformation of DOPC more strongly than that of DPPC due to the cis-double bonds in the lipid acyl chains. Fluoxetine possibly bound to the carbonyl moiety of the lipids through the hydrogen bonding formation while displaced some water molecules surrounding the PO2- regions of the lipid head groups. Cholesterol, however, could lessen the interaction between fluoxetine and the carbonyl groups of both DOPC and DPPC LUVs. These findings provided a better understanding of the role of lipid structure and cholesterol on the interaction between fluoxetine and lipid membranes, shedding more light into the drug's therapeutic action.

  4. Metabolomic identification of biochemical changes induced by fluoxetine and imipramine in a chronic mild stress mouse model of depression

    Science.gov (United States)

    Zhao, Jing; Jung, Yang-Hee; Jang, Choon-Gon; Chun, Kwang-Hoon; Kwon, Sung Won; Lee, Jeongmi

    2015-03-01

    Metabolomics was applied to a C57BL/6N mouse model of chronic unpredictable mild stress (CMS). Such mice were treated with two antidepressants from different categories: fluoxetine and imipramine. Metabolic profiling of the hippocampus was performed using gas chromatography-mass spectrometry analysis on samples prepared under optimized conditions, followed by principal component analysis, partial least squares-discriminant analysis, and pair-wise orthogonal projections to latent structures discriminant analyses. Body weight measurement and behavior tests including an open field test and the forced swimming test were completed with the mice as a measure of the phenotypes of depression and antidepressive effects. As a result, 23 metabolites that had been differentially expressed among the control, CMS, and antidepressant-treated groups demonstrated that amino acid metabolism, energy metabolism, adenosine receptors, and neurotransmitters are commonly perturbed by drug treatment. Potential predictive markers for treatment effect were identified: myo-inositol for fluoxetine and lysine and oleic acid for imipramine. Collectively, the current study provides insights into the molecular mechanisms of the antidepressant effects of two widely used medications.

  5. Chronic fluoxetine treatment induces anxiolytic responses and altered social behaviors in medaka, Oryzias latipes.

    Science.gov (United States)

    Ansai, Satoshi; Hosokawa, Hiroshi; Maegawa, Shingo; Kinoshita, Masato

    2016-04-15

    Medaka (Oryzias latipes) is a small freshwater teleost that is an emerging model system for neurobehavioral research and toxicological testing. The selective serotonin reuptake inhibitor class of antidepressants such as fluoxetine is one of the widely prescribed drugs, but little is known about the effects of these drugs on medaka behaviors. To assess the behavioral effects of fluoxetine, we chronically administrated fluoxetine to medaka adult fish and analyzed the anxiety-related and social behaviors using five behavioral paradigms (diving, open-field, light-dark transition, mirror-biting, and social interaction) with an automated behavioral testing system. Fish chronically treated with fluoxetine exhibited anxiolytic responses such as an overall increased time spent in the top area in the diving test and an increased time spent in center area in the open-field test. Analysis of socially evoked behavior showed that chronic fluoxetine administration decreased the number of mirror biting times in the mirror-biting test and increased latency to first contact in the social interaction test. Additionally, chronic fluoxetine administration reduced the horizontal locomotor activity in the open-field test but not the vertical activity in the diving test. These investigations are mostly consistent with previous reports in the other teleost species and rodent models. These results indicate that behavioral assessment in medaka adult fish will become useful for screening of effects of pharmaceutical and toxicological compounds in animal behaviors. Copyright © 2016 Elsevier B.V. All rights reserved.

  6. Chronic effects of fluoxetine, a selective inhibitor of serotonin uptake, on neurotransmitter receptors

    International Nuclear Information System (INIS)

    Wong, D.T.; Reid, L.R.; Bymaster, F.P.; Threlkeld, P.G.

    1985-01-01

    Fluoxetine administration to rats dose of 10mg/kg i.p. daily up to 12 or 24 days failed to change the concentration-dependent binding of [ 3 H]WB4101, [ 3 H]clonidine and [ 3 H]dihydroalprenolol to α 1 -, α 2 - and β-adrenergic receptors, respectively; [ 3 H]quinuclidinyl benzilate to muscarinic receptors; [ 3 H]pyrilamine to histamine H 1 receptors and [ 3 H]naloxone to opiate receptors. Persistent and significant decreases in receptor number (Bsub(max) value) without changes in the dissociation constant (Ksub(D) value) of [ 3 H]5-HT binding in cortical membranes were observed upon chronic treatment with fluoxetine administered either by intraperitoneal injection or incorporation in the diet. A detectable reduction of 5-HT 1 receptor number occured after once-daily injections of fluoxetine at 10mg/kg i.p. within 49 hours. After pretreatment for 3 days with p-chlorophenylalanine, an inhibitor of 5-HT synthesis, followed by repeated administration of fluoxetine, 5-HT 1 receptor numbers were higher than those of normal rats, suggesting a dependence on synaptic concentration of 5-HT for fluoxetine to affect a receptor down-regulation. These studies provide further evidence for the selectivity of fluoxetine as an inhibitor of 5-HT reuptake, resulting in a selective down-regulation of 5-HT 1 receptors in the cerebal cortex of rat brain. (Author)

  7. Chronic fluoxetine treatment increases daytime melatonin synthesis in the rodent

    Directory of Open Access Journals (Sweden)

    Gillian W Reierson

    2009-09-01

    Full Text Available Gillian W Reierson, Claudio A Mastronardi, Julio Licinio, Ma-Li WongCenter on Pharmacogenomics, Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL, USAAbstract: Circadian rhythm disturbances can occur as part of the clinical symptoms of major depressive disorder and have been found to resolve with antidepressant therapy. The pineal gland is relevant to circadian rhythms as it secretes the hormone melatonin following activation of the cyclic adenosine monophosphate (cAMP signaling cascade and of arylalkylamine N-acetyltransferase (AA-NAT, the rate-limiting enzyme for its synthesis. Cyclic AMP is synthesized by adenylate cyclases (AC and degraded by phosphodiesterases (PDEs. Little is known about the contribution of the PDE system to antidepressant-induced alterations in pineal cAMP signaling and melatonin synthesis. In the present study we used enzyme immunoassay to measure plasma melatonin levels and pineal cAMP levels and as well as quantitative real-time polymerase chain reaction to measure pineal expression of PDE, AC, and AA-NAT genes in rats chronically treated with the prototypic antidepressant fluoxetine. We found elevated melatonin synthesis with increased pineal AA-NAT gene expression and daytime plasma melatonin levels and downregulated cAMP signaling with increased PDE and unchanged AC pineal gene expression, and decreased content of pineal cAMP. We conclude that chronic fluoxetine treatment increases daytime plasma melatonin and pineal AA-NAT gene expression despite downregulated pineal cAMP signaling in the rodent.Keywords: antidepressant, melatonin, pineal, nucleotides, cyclic, phosphodiesterase, rat

  8. Maillard reaction of lactose and fluoxetine hydrochloride, a secondary amine.

    Science.gov (United States)

    Wirth, D D; Baertschi, S W; Johnson, R A; Maple, S R; Miller, M S; Hallenbeck, D K; Gregg, S M

    1998-01-01

    Analysis of commercially available generic formulations of fluoxetine HCl revealed the presence of lactose as the most common excipient. We show that such formulations are inherently less stable than formulations with starch as the diluent due to the Maillard reaction between the drug, a secondary amine hydrochloride, and lactose. The Amadori rearrangement product was isolated and characterized; the characterization was aided by reduction with sodium borohydride and subsequent characterization of this reduced adduct. The lactose-fluoxetine HCl reaction was examined in aqueous ethanol and in the solid state, in which factors such as water content, lubricant concentration, and temperature were found to influence the degradation. N-Formylfluoxetine was identified as a major product of this Maillard reaction and it is proposed that N-formyl compounds be used as markers for this drug-excipient interaction since they are easy to prepare synthetically. Many characteristic volatile products of the Maillard reaction have been identified by GC/MS, including furaldehyde, maltol, and 2,3-dihydro-3,5-dihydroxy-6-methyl-4 H-pyran-4-one. Close similarity between the degradation products of simple mixtures and formulated generic products was found; however, at least one product decomposed at a rate nearly 10 times that predicted from the simple models. Maillard products have also been identified in unstressed capsules. The main conclusion is that drugs which are secondary amines (not just primary amines as sometimes reported) undergo the Maillard reaction with lactose under pharmaceutically relevant conditions. This finding should be considered during the selection of excipients and stability protocols for drugs which are secondary amines or their salts, just as it currently is for primary amines.

  9. Fluoxetine Increases Hippocampal Neurogenesis and Induces Epigenetic Factors But Does Not Improve Functional Recovery after Traumatic Brain Injury

    Science.gov (United States)

    Wang, Yonggang; Neumann, Melanie; Hansen, Katharina; Hong, Shuwhey M.; Kim, Sharon; Noble-Haeusslein, Linda J.

    2011-01-01

    Abstract The selective serotonin reuptake inhibitor fluoxetine induces hippocampal neurogenesis, stimulates maturation and synaptic plasticity of adult hippocampal neurons, and reduces motor/sensory and memory impairments in several CNS disorders. In the setting of traumatic brain injury (TBI), its effects on neuroplasticity and function have yet to be thoroughly investigated. Here we examined the efficacy of fluoxetine after a moderate to severe TBI, produced by a controlled cortical impact. Three days after TBI or sham surgery, mice were treated with fluoxetine (10 mg/kg/d) or vehicle for 4 weeks. To evaluate the effects of fluoxetine on neuroplasticity, hippocampal neurogenesis and epigenetic modification were studied. Stereologic analysis of the dentate gyrus revealed a significant increase in doublecortin-positive cells in brain-injured animals treated with fluoxetine relative to controls, a finding consistent with enhanced hippocampal neurogenesis. Epigenetic modifications, including an increase in histone 3 acetylation and induction of methyl-CpG-binding protein, a transcription factor involved in DNA methylation, were likewise seen by immunohistochemistry and quantitative Western immunoblots, respectively, in brain-injured animals treated with fluoxetine. To determine if fluoxetine improves neurological outcomes after TBI, gait function and spatial learning and memory were assessed by the CatWalk-assisted gait test and Barnes maze test, respectively. No differences in these parameters were seen between fluoxetine- and vehicle-treated animals. Thus while fluoxetine enhanced neuroplasticity in the hippocampus after TBI, its chronic administration did not restore locomotor function or ameliorate memory deficits. PMID:21175261

  10. Fluoxetine prevents the memory deficits and reduction in hippocampal cell proliferation caused by valproic acid.

    Science.gov (United States)

    Welbat, Jariya Umka; Sangrich, Preeyanuch; Sirichoat, Apiwat; Chaisawang, Pornthip; Chaijaroonkhanarak, Wunnee; Prachaney, Parichat; Pannangrong, Wanassanun; Wigmore, Peter

    2016-12-01

    Valproic acid (VPA), a commonly used antiepileptic drug, has been reported to cause cognitive impairments in patients. In a previous study, using a rodent model, we showed that VPA treatment impaired cognition which was associated with a reduction in the cell proliferation required for hippocampal neurogenesis. The antidepressant fluoxetine has been shown to increase hippocampal neurogenesis and to reverse the memory deficits found in a number of pathological conditions. In the present study we investigated the protective effects of fluoxetine treatment against the impairments in memory and hippocampal cell proliferation produced by VPA. Male Sprague Dawley rats received daily treatment with fluoxetine (10mg/kg) by oral gavage for 21days. Some rats were co-administered with VPA (300mg/kg, twice daily i.p. injections) for 14days from day 8 to day 21 of the fluoxetine treatment. Spatial memory was tested using the novel object location (NOL) test. The number of proliferating cells present in the sub granular zone of the dentate gyrus was quantified using Ki67 immunohistochemistry at the end of the experiment. Levels of the receptor Notch1, the neurotrophic factor BDNF and the neural differentiation marker DCX were determined by Western blotting. VPA-treated rats showed memory deficits, a decrease in the number of proliferating cells in the sub granular zone and decreases in the levels of Notch1 and BDNF but not DCX compared to control animals. These changes in behavior, cell proliferation and Notch1 and BDNF were prevented in animals which had received both VPA and fluoxetine. Rats receiving fluoxetine alone did not show a significant difference in the number of proliferating cells or behavior compared to controls. These results demonstrated that the spatial memory deficits and reduction of cell proliferation produced by VPA can be ameliorated by the simultaneous administration of the antidepressant fluoxetine. Crown Copyright © 2016. Published by Elsevier B

  11. Fluoxetine Ameliorates Behavioral and Neuropathological Deficits in a Transgenic Model Mouse of α-synucleinopathy

    Science.gov (United States)

    Ubhi, Kiren; Inglis, Chandra; Mante, Michael; Patrick, Christina; Adame, Anthony; Spencer, Brian; Rockenstein, Edward; May, Verena; Winkler, Juergen; Masliah, Eliezer

    2013-01-01

    The term α-synucleinopathies refers to a group of age-related neurological disorders including Parkinson’s disease (PD), Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA) that display an abnormal accumulation of alpha-synuclein (α-syn). In contrast to the neuronal α-syn accumulation observed in PD and DLB, MSA is characterized by a widespread oligodendrocytic α-syn accumulation. Transgenic mice expressing human α-syn under the oligodendrocyte-specific myelin basic protein promoter (MBP1-hαsyn tg mice) model many of the behavioral and neuropathological alterations observed in MSA. Fluoxetine, a selective serotonin reuptake inhibitor, has been shown to be protective in toxin-induced models of PD, however its effects in an in vivo transgenic model of α-synucleinopathy remain unclear. In this context, this study examined the effect of fluoxetine in the MBP1-hαsyn tg mice, a model of MSA. Fluoxetine adminstration ameliorated motor deficits in the MBP1-hαsyn tg mice, with a concomitant decrease in neurodegenerative pathology in the basal ganglia, neocortex and hippocampus. Fluoxetine adminstration also increased levels of the neurotrophic factors, GDNF (glial-derived neurotrophic factor) and BDNF (brain-derived neurotrophic factor) in the MBP1-hαsyn tg mice compared to vehicle-treated tg mice. This fluoxetine-induced increase in GDNF and BDNF protein levels was accompanied by activation of the ERK signaling pathway. The effects of fluoxetine adminstration on myelin and serotonin markers were also examined. Collectively these results indicate that fluoxetine may represent a novel therapeutic intervention for MSA and other neurodegenerative disorders. PMID:22281106

  12. Fluoxetine improves functional work capacity in women with premenstrual dysphoric disorder.

    Science.gov (United States)

    Steiner, M; Brown, E; Trzepacz, P; Dillon, J; Berger, C; Carter, D; Reid, R; Stewart, D

    2003-02-01

    Interference with social and occupational functioning is a key criterion for premenstrual dysphoric disorder (PMDD) and distinguishes it from the less severe premenstrual syndrome (PMS). We conducted a post hoc analysis of the results of a previously reported study evaluating the efficacy of fluoxetine in the management of PMDD, to determine the extent to which women with PMDD perceived impairment in their functional work capacity during the luteal phase of their menstrual cycle. The effects of two doses of fluoxetine vs placebo in alleviating PMDD symptoms and restoring normal work capacity during this period were assessed. We measured baseline follicular vs luteal phase presence of 8 patient-rated functional work capacity-related symptoms on the Premenstrual Tension Scale-Self Rated in 320 women who met diagnostic criteria for late luteal phase dysphoric disorder, now known as PMDD. Women were then randomized to double-blind treatment with either fluoxetine 20 mg/d, fluoxetine 60 mg/d, or placebo daily for 6 menstrual cycles. All 8 work capacity-related symptoms were more likely to be present in the baseline luteal phase than in the baseline follicular phase. A statistically significant improvement from baseline to the average treatment score for the work capacity subscale was detected for both fluoxetine groups compared to the placebo group. This beneficial response to fluoxetine was evident by the first cycle of treatment. Our results demonstrate that fluoxetine at a relatively low dose of 20 mg/d quickly reduced symptoms that negatively affect work capacity and was well tolerated.

  13. Fluoxetine ameliorates behavioral and neuropathological deficits in a transgenic model mouse of α-synucleinopathy.

    Science.gov (United States)

    Ubhi, Kiren; Inglis, Chandra; Mante, Michael; Patrick, Christina; Adame, Anthony; Spencer, Brian; Rockenstein, Edward; May, Verena; Winkler, Juergen; Masliah, Eliezer

    2012-04-01

    The term α-synucleinopathies refers to a group of age-related neurological disorders including Parkinson's disease (PD), Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA) that display an abnormal accumulation of alpha-synuclein (α-syn). In contrast to the neuronal α-syn accumulation observed in PD and DLB, MSA is characterized by a widespread oligodendrocytic α-syn accumulation. Transgenic mice expressing human α-syn under the oligodendrocyte-specific myelin basic protein promoter (MBP1-hαsyn tg mice) model many of the behavioral and neuropathological alterations observed in MSA. Fluoxetine, a selective serotonin reuptake inhibitor, has been shown to be protective in toxin-induced models of PD, however its effects in an in vivo transgenic model of α-synucleinopathy remain unclear. In this context, this study examined the effect of fluoxetine in the MBP1-hαsyn tg mice, a model of MSA. Fluoxetine administration ameliorated motor deficits in the MBP1-hαsyn tg mice, with a concomitant decrease in neurodegenerative pathology in the basal ganglia, neocortex and hippocampus. Fluoxetine administration also increased levels of the neurotrophic factors, GDNF (glial-derived neurotrophic factor) and BDNF (brain-derived neurotrophic factor) in the MBP1-hαsyn tg mice compared to vehicle-treated tg mice. This fluoxetine-induced increase in GDNF and BDNF protein levels was accompanied by activation of the ERK signaling pathway. The effects of fluoxetine administration on myelin and serotonin markers were also examined. Collectively these results indicate that fluoxetine may represent a novel therapeutic intervention for MSA and other neurodegenerative disorders. Copyright © 2011 Elsevier Inc. All rights reserved.

  14. Serotoninergic manipulation, meal-induced satiety and eating pattern: effect of fluoxetine in obese female subjects.

    Science.gov (United States)

    Lawton, C L; Wales, J K; Hill, A J; Blundell, J E

    1995-07-01

    Twelve nondepressed healthy female obese subjects (BMI > 30 kg/m2) took part in a study which conformed to a double-blind randomized crossover design. Each subject acted as her own control across 2 weeks of treatment with either 60 mg of the 5-HT reuptake inhibitor fluoxetine or matching placebo. On days 7 and 14 of both treatment phases subjects were provided with fixed energy lunch meals high in either CHO or fat. The effect of these meals on satiety during the fluoxetine and placebo phases was assessed by a battery of procedures. Subjects felt less hungry after consuming the high CHO meal than after consuming the high-fat meal. They also felt less hungry when taking fluoxetine than when taking the placebo. Analysis of energy intake from the test meal revealed a main effect of prior lunch meal type (high CHO or high fat) and a main effect of drug treatment. Subjects consumed an average of 574 kcal following the high CHO meal compared to 689 kcal following the high-fat meal. Subjects also consumed an average of 532 kcal when taking fluoxetine compared to 730 kcal when taking the placebo. Fluoxetine did not exert any significant effects on macronutrient selection. Mean daily energy intake, calculated from food diary records, was 1881 kcal when subjects were taking the placebo compared to 1460 kcal when taking fluoxetine (a reduction of 22.4%). Fluoxetine treatment produced a significant weight loss of 1.97 kg over the two weeks of treatment compared to a weight loss of only 0.04 kg on placebo.

  15. 5-HT(1A) receptor antagonism reverses and prevents fluoxetine-induced sexual dysfunction in rats.

    Science.gov (United States)

    Sukoff Rizzo, Stacey J; Pulicicchio, Claudine; Malberg, Jessica E; Andree, Terrance H; Stack, Gary P; Hughes, Zoë A; Schechter, Lee E; Rosenzweig-Lipson, Sharon

    2009-09-01

    Sexual dysfunction associated with antidepressant treatment continues to be a major compliance issue for antidepressant therapies. 5-HT(1A) antagonists have been suggested as beneficial adjunctive treatment in respect of antidepressant efficacy; however, the effects of 5-HT(1A) antagonism on antidepressant-induced side-effects has not been fully examined. The present study was conducted to evaluate the ability of acute or chronic treatment with 5-HT(1A) antagonists to alter chronic fluoxetine-induced impairments in sexual function. Chronic 14-d treatment with fluoxetine resulted in a marked reduction in the number of non-contact penile erections in sexually experienced male rats, relative to vehicle-treated controls. Acute administration of the 5-HT(1A) antagonist WAY-101405 resulted in a complete reversal of chronic fluoxetine-induced deficits on non-contact penile erections at doses that did not significantly alter baselines. Chronic co-administration of the 5-HT(1A) antagonists WAY-100635 or WAY-101405 with fluoxetine prevented fluoxetine-induced deficits in non-contact penile erections in sexually experienced male rats. Moreover, withdrawal of WAY-100635 from co-treatment with chonic fluoxetine, resulted in a time-dependent reinstatement of chronic fluoxetine-induced deficits in non-contact penile erections. Additionally, chronic administration of SSA-426, a molecule with dual activity as both a SSRI and 5-HT(1A) antagonist, did not produce deficits in non-contact penile erections at doses demonstrated to have antidepressant-like activity in the olfactory bulbectomy model. Taken together, these data suggest that 5-HT(1A) antagonist treatment may have utility for the management of SSRI-induced sexual dysfunction.

  16. Fluoxetine ameliorates cartilage degradation in osteoarthritis by inhibiting Wnt/β-catenin signaling.

    Directory of Open Access Journals (Sweden)

    Kentaro Miyamoto

    Full Text Available Abnormal activation of the Wnt/β-catenin signaling is implicated in the osteoarthritis (OA pathology. We searched for a pre-approved drug that suppresses abnormally activated Wnt/β-catenin signaling and has a potency to reduce joint pathology in OA. We introduced the TOPFlash reporter plasmid into HCS-2/8 human chondrosarcoma cells to estimate the Wnt/β-catenin activity in the presence of 10 μM each compound in a panel of pre-approved drugs. We found that fluoxetine, an antidepressant in the class of selective serotonin reuptake inhibitors (SSRI, down-regulated Wnt/β-catenin signaling in human chondrosarcoma cells. Fluoxetine inhibited both Wnt3A- and LiCl-induced loss of proteoglycans in chondrogenically differentiated ATDC5 cells. Fluoxetine increased expression of Sox9 (the chondrogenic master regulator, and decreased expressions of Axin2 (a marker for Wnt/β-catenin signaling and Mmp13 (matrix metalloproteinase 13. Fluoxetine suppressed a LiCl-induced increase of total β-catenin and a LiCl-induced decrease of phosphorylated β-catenin in a dose-dependent manner. An in vitro protein-binding assay showed that fluoxetine enhanced binding of β-catenin with Axin1, which is a scaffold protein forming the degradation complex for β-catenin. Fluoxetine suppressed LiCl-induced β-catenin accumulation in human OA chondrocytes. Intraarticular injection of fluoxetine in a rat OA model ameliorated OA progression and suppressed β-catenin accumulation.

  17. Intrauterine and lactation exposure to fluoxetine blunted in the offspring the aortic adaptive response induced by acute restraint stress.

    Science.gov (United States)

    Marques, Bruno V D; Higashi, Carolina M; da S Novi, Daniella R B; Zanluqui, Nagela G; Gregório, Thais F; Pinge-Filho, Phileno; Gerardin, Daniela C C; Pelosi, Gislaine G; Moreira, Estefânia G; Ceravolo, Graziela S

    2017-10-15

    Selective serotonin reuptake inhibitors are the most widely prescribed antidepressants to women during pregnancy. Maternal treatment with fluoxetine can expose fetuses and neonates to higher levels of serotonin that plays a role in stress response. Thus, the aim of the study was to evaluate whether maternal treatment with fluoxetine interferes with aorta reactivity of adult male offspring after acute restraint stress. Wistar rats were gavaged with fluoxetine (5mg/kg/day) or water (control) during pregnancy and lactation. The experiments were performed in adult male offspring, treated or not with reserpine (4mg/Kg, ip, 28h before the experimental protocol). Fluoxetine and control rats were submitted to a single restraint stress session (ST) for 1h. Curves to phenylephrine were performed in thoracic aorta with endothelium. Aortic nitric oxide (NOx) were evaluated by the Griess method. The aortic contraction induced by phenylephrine was similar between control and fluoxetine rats. The acute stress reduced contraction in aorta of control ST compared to control, and L-NAME equaled this response. In fluoxetine rats, ST did not change the aortic constriction. Reserpine treatment restored the vasoconstriction in control ST, but did not interfere with aortic contraction in control, fluoxetine or fluoxetine ST. The NOx concentration was higher in aortas from control ST than control rats, and reserpine reduced NOx levels of control ST. The NOx concentration was similar between fluoxetine and fluoxetine ST rats, treated or not with reserpine. In conclusion, maternal treatment with fluoxetine blunted acute restraint stress-induced NO system activation and aortic adaptation in adult offspring. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Does curcumin or pindolol potentiate fluoxetine′s antidepressant effect by a pharmacokinetic or pharmacodynamic interaction?

    OpenAIRE

    H.A.S. Murad; M. I. Suliaman; H. Abdallah; May Abdulsattar

    2014-01-01

    This study was designed to study potentiation of fluoxetine′s antidepressant effect by curcumin or pindolol. Twenty eight groups of mice (n=8) were used in three sets of experiments. In the first set, 9 groups were subjected to the forced swimming test after being treated intraperitoneally with three vehicles, fluoxetine (5 and 20 mg/kg), curcumin (20 mg/kg), pindolol (32 mg/kg), curcumin+fluoxetine (5 mg/kg) and pindolol+fluoxetine (5 mg/kg). One hour after the test, serum and brain fluoxeti...

  19. Enantioselective analysis of fluoxetine in pharmaceutical formulations by capillary zone electrophoresis

    Directory of Open Access Journals (Sweden)

    Melania Cârcu-Dobrin

    2017-03-01

    Full Text Available Fluoxetine is an antidepressant, a selective serotonin reuptake inhibitor (SSRI used primarily in the treatment of major depression, panic disorder and obsessive compulsive disorder. Chiral separation of racemic fluoxetine is necessary due to its enantioselective metabolism. In order to develop a suitable method for chiral separation of fluoxetine, cyclodextrin (CD modified capillary electrophoresis (CE was employed. A large number of native and derivatized, neutral and ionized CD derivatives were screened to find the optimal chiral selector. As a result of this process, heptakis(2,3,6-tri-O-methyl-β-CD (TRIMEB was selected for enantiomeric discrimination. A factorial analysis study was performed by orthogonal experimental design in which several factors are varied at the same time to optimize the separation method. The optimized method (50 mM phosphate buffer, pH = 5.0, 10 mM TRIMEB, 15 °C, + 20 kV, 50 mbar/1 s, detection at 230 nm was successful for baseline separation of fluoxetine enantiomers within 5 min. Our method was validated according to ICH guidelines and proved to be sensitive, linear, accurate and precise for the chiral separation of fluoxetine.

  20. An HDAC-dependent epigenetic mechanism that enhances the efficacy of the antidepressant drug fluoxetine

    Science.gov (United States)

    Schmauss, C.

    2015-01-01

    Depression is a prevalent and debilitating psychiatric illnesses. However, currently prescribed antidepressant drugs are only efficacious in a limited group of patients. Studies on Balb/c mice suggested that histone deacetylase (HDAC) inhibition may enhance the efficacy of the widely-prescribed antidepressant drug fluoxetine. This study shows that reducing HDAC activity in fluoxetine-treated Balb/c mice leads to robust antidepressant and anxiolytic effects. While reducing the activity of class I HDACs 1 and 3 led to antidepressant effects, additional class II HDAC inhibition was necessary to exert anxiolytic effects. In fluoxetine-treated mice, HDAC inhibitors increased enrichment of acetylated histone H4 protein and RNA polymerase II at promotor 3 of the brain-derived neurotrophic factor (Bdnf) gene and increased Bdnf transcription from this promotor. Reducing Bdnf-stimulated tropomyosin kinase B receptor activation in fluoxetine-treated mice with low HDAC activity abolished the behavioral effects of fluoxetine, suggesting that the HDAC-triggered epigenetic stimulation of Bdnf expression is critical for therapeutic efficacy. PMID:25639887

  1. Fluoxetine vs. placebo for the treatment of recurrent vasovagal syncope with anxiety sensitivity.

    Science.gov (United States)

    Flevari, Panayota; Leftheriotis, Dionyssios; Repasos, Evangelos; Katsaras, Dimitrios; Katsimardos, Andreas; Lekakis, John

    2017-01-01

    The optimal medical therapy of patients with vasovagal syncope (VVS) remains controversial. Fluoxetine is effective against anxiety and panic disorders, while its use has shown promising results for VVS. Anxiety sensitivity is a personality trait observed in a considerable proportion of patients with VVS, associated with predisposition to anxiety and panic disorders. Our aim was to examine whether fluoxetine exerts beneficial effects regarding VVS prevention in the subset of patients with anxiety sensitivity. We assessed 106 patients with typical history of recurrent VVS, without other comorbidities, and a diagnostic, positive head-up tilt test. A psychiatric examination ruled out clinical psychiatric disease. Their psychological, stress-related profile was assessed by the Anxiety Sensitivity Index (ASI) questionnaire, a 16-item questionnaire, assessing fear of anxiety-related sensations, previously studied in VVS. Patients scoring positive for ASI (n = 60, 57% of the population) were randomized in a 2:1 fashion to receive either 10-40 mg fluoxetine daily (n = 40) or placebo (n = 20), and were followed-up for 1 year. A significant difference was observed between patients receiving fluoxetine and those with placebo, regarding the distribution of syncope-free time during the study (P Fluoxetine is superior to placebo against syncope in these patients. This drug may be a first-line pharmacological treatment for this difficult-to-treat group. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.

  2. Fluoxetine induces vasodilatation of cerebral arterioles by co-modulating NO/muscarinic signalling

    Science.gov (United States)

    Ofek, Keren; Schoknecht, Karl; Melamed-Book, Naomi; Heinemann, Uwe; Friedman, Alon; Soreq, Hermona

    2012-01-01

    Ischaemic stroke patients treated with Selective Serotonin Reuptake Inhibitors (SSRI) show improved motor, cognitive and executive functions, but the underlying mechanism(s) are incompletely understood. Here, we report that cerebral arterioles in the rat brain superfused with therapeutically effective doses of the SSRI fluoxetine showed consistent, dose-dependent vasodilatation (by 1.2 to 1.6-fold), suppressible by muscarinic and nitric oxide synthase (NOS) antagonists [atropine, NG-nitro-l-arginine methyl ester (l-NAME)] but resistant to nicotinic and serotoninergic antagonists (mecamylamine, methylsergide). Fluoxetine administered 10–30 min. following experimental vascular photo-thrombosis increased arterial diameter (1.3–1.6), inducing partial, but lasting reperfusion of the ischaemic brain. In brain endothelial b.End.3 cells, fluoxetine induced rapid muscarinic receptor-dependent increases in intracellular [Ca2+] and promoted albumin- and eNOS-dependent nitric oxide (NO) production and HSP90 interaction. In vitro, fluoxetine suppressed recombinant human acetylcholinesterase (rhAChE) activity only in the presence of albumin. That fluoxetine induces vasodilatation of cerebral arterioles suggests co-promotion of endothelial muscarinic and nitric oxide signalling, facilitated by albumin-dependent inhibition of serum AChE. PMID:22697296

  3. Fluoxetine-induced inhibition of synaptosomal [3H]5-HT release: Possible Ca2+-channel inhibition

    International Nuclear Information System (INIS)

    Stauderman, K.A.; Gandhi, V.C.; Jones, D.J.

    1992-01-01

    Fluoxetine, a selective 5-Ht uptake inhibitor, inhibited 15 mM K + -induced [ 3 H]5-HT release from rat spinal cord and cortical synaptosomes at concentrations > 0.5 uM. This effect reflected a property shared by another selective 5-HT uptake inhibitor paroxetine but not by less selective uptake inhibitors such as amitriptyline, desipramine, imipramine or nortriptyline. Inhibition of release by fluoxetine was inversely related to both the concentration of K + used to depolarize the synaptosomes and the concentration of external Ca 2+ . Experiments aimed at determining a mechanism of action revealed that fluoxetine did not inhibit voltage-independent release of [ 3 H]5-HT release induced by the Ca 2+ -ionophore A 23187 or Ca 2+ -independent release induced by fenfluramine. Moreover the 5-HT autoreceptor antagonist methiothepin did not reverse the inhibitory actions of fluoxetine on K + -induced release. Further studies examined the effects of fluoxetine on voltage-dependent Ca 2+ channels and Ca 2+ entry

  4. The role of fluoxetine in antiviral therapy for chronic hepatitis C

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    QIN Yuan

    2016-09-01

    Full Text Available More than 20% of chronic hepatitis C (CHC patients receiving the antiviral therapy with interferonα(IFNα experience depression, and fluoxetine is often used to alleviate this symptom. Fluoxetine has anti-inflammatory properties and can change the synthesis of liver lipids, but its influence on antiviral therapy for CHC and related mechanism remain unknown. Recent studies show that fluoxetine can inhibit hepatitis C virus (HCV infection and reduce the production of reactive oxygen species (ROS and lipid accumulation in Huh7.5 cells; in addition, it can promote the antiviral effect mediated by IFNα through activating STAT1 and JNK signaling pathways and thus reduce HCV viral load and the level of alanine aminotransferase in CHC patients. Fluoxetine elevates PPAR response element activity in CHC patients, and its inhibitory effect on HCV infection and lipid accumulation were partly reversed by antagonists including PPARβ/γ, suggesting that fluoxetine inhibits HCV infection, ROS production, and lipid accumulation through regulating PPARβ/γ and JNK/STAT pathways.

  5. Differential regulation of catecholamine synthesis and transport in rat adrenal medulla by fluoxetine treatment

    Directory of Open Access Journals (Sweden)

    NATASA SPASOJEVIC

    2015-03-01

    Full Text Available We have recently shown that chronic fluoxetine treatment acted significantly increasing plasma norepinephrine and epinephrine concentrations both in control and chronically stressed adult male rats. However, possible effects of fluoxetine on catecholamine synthesis and re-uptake in adrenal medulla have been largely unknown. In the present study the effects of chronic fluoxetine treatment on tyrosine hydroxylase, a rate-limiting enzyme in catecholamine synthesis, as well as a norepinephrine transporter and vesicular monoamine transporter 2 gene expressions in adrenal medulla of animals exposed to chronic unpredictable mild stress (CUMS for 4 weeks, were investigated. Gene expression analyses were performed using a real-time quantitative reverse transcription-PCR. Chronically stressed animals had increased tyrosine hydroxylase mRNA levels and decreased expression of both transporters. Fluoxetine increased tyrosine hydroxylase and decreased norepinephrine transporter gene expression in both unstressed and CUMS rats. These findings suggest that chronic fluoxetine treatment increased plasma catecholamine levels by affecting opposing changes in catecholamine synthesis and uptake.

  6. Fluoxetine versus Vitex agnus castus extract in the treatment of premenstrual dysphoric disorder.

    Science.gov (United States)

    Atmaca, Murad; Kumru, Selahattin; Tezcan, Ertan

    2003-04-01

    Clinical trials have demonstrated that serotonin reuptake inhibitors (SRIs) and the extract of Vitex agnus castus are effective for the treatment of premenstrual dysphoric disorder (PMDD). However, to the best of our knowledge, there has been no study comparing the efficacy of the SRIs with Vitex agnus castus (AC) extract. Therefore, the aim of the present study was to compare the efficacy of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), with that of the AC extract, a natural choice. After a period of 2 screening months to screen the patients for suitability, 41 patients with PMDD according to DSM-IV were recruited into the study. The patients were randomized to fluoxetine or AC for 2 months of single-blind, rater- blinded and prospective treatment period. The outcome measures included the Penn daily symptom report (DSR), the Hamilton depression rating scale (HAM-D), and the clinical global impression-severity of illness (CGI-SI) and -improvement (CGI-I) scales. At endpoint, using the clinical criterion for improvement, a similar percentage of patients responded to fluoxetine (68.4%, n = 13) and AC (57.9%, n = 11). There was no statistically significant difference between the groups with respect to the rate of responders. This preliminary study suggests that patients with PMDD respond well to treatment with both fluoxetine and AC. However, fluoxetine was more effective for psychological symptoms while the extract diminished the physical symptoms. Copyright 2002 John Wiley & Sons, Ltd.

  7. Long-term consequences of chronic fluoxetine exposure on the expression of myelination-related genes in the rat hippocampus

    Science.gov (United States)

    Kroeze, Y; Peeters, D; Boulle, F; van den Hove, D L A; van Bokhoven, H; Zhou, H; Homberg, J R

    2015-01-01

    The selective serotonin reuptake inhibitor (SSRI) fluoxetine is widely prescribed for the treatment of symptoms related to a variety of psychiatric disorders. After chronic SSRI treatment, some symptoms remediate on the long term, but the underlying mechanisms are not yet well understood. Here we studied the long-term consequences (40 days after treatment) of chronic fluoxetine exposure on genome-wide gene expression. During the treatment period, we measured body weight; and 1 week after treatment, cessation behavior in an SSRI-sensitive anxiety test was assessed. Gene expression was assessed in hippocampal tissue of adult rats using transcriptome analysis and several differentially expressed genes were validated in independent samples. Gene ontology analysis showed that upregulated genes induced by chronic fluoxetine exposure were significantly enriched for genes involved in myelination. We also investigated the expression of myelination-related genes in adult rats exposed to fluoxetine at early life and found two myelination-related genes (Transferrin (Tf) and Ciliary neurotrophic factor (Cntf)) that were downregulated by chronic fluoxetine exposure. Cntf, a neurotrophic factor involved in myelination, showed regulation in opposite direction in the adult versus neonatally fluoxetine-exposed groups. Expression of myelination-related genes correlated negatively with anxiety-like behavior in both adult and neonatally fluoxetine-exposed rats. In conclusion, our data reveal that chronic fluoxetine exposure causes on the long-term changes in expression of genes involved in myelination, a process that shapes brain connectivity and contributes to symptoms of psychiatric disorders. PMID:26393488

  8. Essential Segmental Myoclonus Responding Well To Fluoxetine A case Report

    Directory of Open Access Journals (Sweden)

    Bhattacharyya K B

    1999-01-01

    Full Text Available We report a case of essential segmental myoclonus a 10 year old girl who presented with continuing movement of both the shoulder girdle muscles for 6 months. The movements were exacerbated with the hands raised above the head or in the outstretched posture and were persisting during sleep. There was no abnormal palatal movement. Additionally there was a rhythmical clicking sound arising from the shoulders that could be felt and ausculated with the stethoscope. CT scan of brain and MRI of cervical spine were non-contributory, EMG showed muscle activates at about 50 per second in the shoulder girdle muscles. Cine-radiography of shoulder joints showed the head of humerus hitting against the spine of the scapula rhythmically. Spinal tap was non-contributory. The diagnosis or essential segmental myoclonus was entertained and the subject with fluoxetine, a selective serotonin reuptake inhibitor with remarkable response. The possible mechanism of action of agents modulating the serotonergic system in the brain for the management of myoclonus has been reviewed and their role suggested.

  9. Differential behavioral effects of the antidepressants reboxetine, fluoxetine, and moclobemide in a modified forced swim test following chronic treatment.

    Science.gov (United States)

    Cryan, John F; Page, Michelle E; Lucki, Irwin

    2005-11-01

    The forced swim test (FST) is the most widely used model for assessing potential antidepressant activity in rodents following acute or short-term treatment. However, few studies have compared the effects of short- and long-term antidepressant treatment on behaviors in the test, despite the need to treat patients chronically to produce clinical effects. The current studies examined whether antidepressants from different classes produce different behavioral effects following short-term treatment and whether such effects change following administration for a longer duration. The effects of administering short-term (3 days) and long-term (14 days) treatments of antidepressants from three different chemical classes with distinct mechanisms of action via osmotic minipump were examined: the selective norepinephrine reuptake inhibitor reboxetine (10 and 60 mg kg(-1) day(-1)), the selective serotonin reuptake inhibitor fluoxetine (2.5 and 15 mg kg(-1) day(-1)), and the reversible inhibitor of monoamine oxidase moclobemide (2.5 and 15 mg kg(-1) day(-1)). All testing was carried out in a 15-min test with no preswim session in order to negate any confounding aspect of an induction procedure. The majority of antidepressant-sensitive behavioral changes were observed in the first 5 min of the test. The low dose of reboxetine failed to alter behavior in the test after 3 days but significantly decreased immobility and increased climbing behavior following administration for 14 days, whereas the high dose of reboxetine was equally effective following 3 and 14 days of treatment. In a similar fashion, the low dose of fluoxetine failed to alter behavior in the test following 3 days, but showed an augmented response on immobility and increased swimming following administration for 14 days. The high dose of fluoxetine was slightly more effective at reducing immobility following administration for 14 days than 3 days. The low dose of moclobemide decreased immobility and increased climbing

  10. Mouse Strain Affects Behavioral and Neuroendocrine Stress Responses Following Administration of Probiotic Lactobacillus rhamnosus JB-1 or Traditional Antidepressant Fluoxetine

    Directory of Open Access Journals (Sweden)

    Karen-Anne McVey Neufeld

    2018-05-01

    Full Text Available Currently, there is keen interest in the development of alternative therapies in the treatment of depression. Given the explosion of research focused on the microbiota-gut-brain axis, consideration has turned to the potential of certain probiotics to improve patient outcomes for those suffering from mood disorders. Here we examine the abilities of a known antidepressant, fluoxetine, and the probiotic Lactobacillus rhamnosus JB-1™, to attenuate responses to two established criteria for depressive-like behavior in animal models, the tail suspension test (TST and the corticosterone response to an acute restraint stressor. We examine two different strains of mice known to differ in the extent to which they express both anxiety-like behavior and measures of despair—BALB/c and Swiss Webster—with respectively high and normal behavioral phenotypes for each. While adult male BALB/c mice responded with increased antidepressive-like behavior to both fluoxetine and L. rhamnosus JB-1 in both the TST and the corticosterone stress response, SW mice did not respond to either treatment as compared to controls. These findings highlight the importance of investigating putative antidepressants in mouse strains known to express face validity for some markers of depression. Clinical studies examining the activity of L. rhamnosus JB-1 in patients suffering from mood disorders are warranted, as well as further pre-clinical work examining how interactions between host genotype and intestinal microbial alterations may impact behavioral responses. This study adds to the literature supporting the possibility that modifying the intestinal microbiota via probiotics represents a promising potential therapeutic breakthrough in the treatment of psychiatric disease.

  11. Mouse Strain Affects Behavioral and Neuroendocrine Stress Responses Following Administration of Probiotic Lactobacillus rhamnosus JB-1 or Traditional Antidepressant Fluoxetine.

    Science.gov (United States)

    McVey Neufeld, Karen-Anne; Kay, Sebastian; Bienenstock, John

    2018-01-01

    Currently, there is keen interest in the development of alternative therapies in the treatment of depression. Given the explosion of research focused on the microbiota-gut-brain axis, consideration has turned to the potential of certain probiotics to improve patient outcomes for those suffering from mood disorders. Here we examine the abilities of a known antidepressant, fluoxetine, and the probiotic Lactobacillus rhamnosus JB-1™, to attenuate responses to two established criteria for depressive-like behavior in animal models, the tail suspension test (TST) and the corticosterone response to an acute restraint stressor. We examine two different strains of mice known to differ in the extent to which they express both anxiety-like behavior and measures of despair-BALB/c and Swiss Webster-with respectively high and normal behavioral phenotypes for each. While adult male BALB/c mice responded with increased antidepressive-like behavior to both fluoxetine and L. rhamnosus JB-1 in both the TST and the corticosterone stress response, SW mice did not respond to either treatment as compared to controls. These findings highlight the importance of investigating putative antidepressants in mouse strains known to express face validity for some markers of depression. Clinical studies examining the activity of L. rhamnosus JB-1 in patients suffering from mood disorders are warranted, as well as further pre-clinical work examining how interactions between host genotype and intestinal microbial alterations may impact behavioral responses. This study adds to the literature supporting the possibility that modifying the intestinal microbiota via probiotics represents a promising potential therapeutic breakthrough in the treatment of psychiatric disease.

  12. Effects of chronic fluoxetine treatment on neurogenesis and tryptophan hydroxylase expression in adolescent and adult rats.

    Science.gov (United States)

    Klomp, Anne; Václavů, Lena; Meerhoff, Gideon F; Reneman, Liesbeth; Lucassen, Paul J

    2014-01-01

    The antidepressant drug fluoxetine (Prozac) has been increasingly prescribed to children and adolescents with depressive disorders despite a lack of thorough understanding of its therapeutic effects in the paediatric population and of its putative neurodevelopmental effects. Within the framework of PRIOMEDCHILD ERA-NET, we investigated; a) effects of chronic fluoxetine treatment on adult hippocampal neurogenesis, a structural readout relevant for antidepressant action and hippocampal development; b) effects on tryptophan hydroxylase (TPH) expression, a measure of serotonin synthesis; c) whether treatment effects during adolescence differed from treatment at an adult age, and d) whether they were subregion-specific. Stereological quantification of the number of proliferating (Ki-67+) cells and of the number of young migratory neurons (doublecortin+), revealed a significant age-by-treatment interaction effect, indicating that fluoxetine affects both proliferation and neurogenesis in adolescent-treated rats differently than it does in adult-treated rats. In terms of subregional differences, fluoxetine enhanced proliferation mainly in the dorsal parts of the hippocampus, and neurogenesis in both the suprapyramidal and infrapyramidal blades of the dentate gyrus in adolescent-treated rats, while no such differences were seen in adult-treated rats. Fluoxetine exerted similar age-by-treatment interaction effects on TPH cells mainly in the ventral portion of the dorsal raphe nucleus. We conclude that fluoxetine exerts divergent effects on structural plasticity and serotonin synthesis in adolescent versus adult-treated rats. These preliminary data indicate a differential sensitivity of the adolescent brain to this drug and thus warrant further research into their behavioural and translational aspects. Together with recent related findings, they further call for caution in prescribing these drugs to the adolescent population.

  13. Effects of chronic fluoxetine treatment on neurogenesis and tryptophan hydroxylase expression in adolescent and adult rats.

    Directory of Open Access Journals (Sweden)

    Anne Klomp

    Full Text Available The antidepressant drug fluoxetine (Prozac has been increasingly prescribed to children and adolescents with depressive disorders despite a lack of thorough understanding of its therapeutic effects in the paediatric population and of its putative neurodevelopmental effects. Within the framework of PRIOMEDCHILD ERA-NET, we investigated; a effects of chronic fluoxetine treatment on adult hippocampal neurogenesis, a structural readout relevant for antidepressant action and hippocampal development; b effects on tryptophan hydroxylase (TPH expression, a measure of serotonin synthesis; c whether treatment effects during adolescence differed from treatment at an adult age, and d whether they were subregion-specific. Stereological quantification of the number of proliferating (Ki-67+ cells and of the number of young migratory neurons (doublecortin+, revealed a significant age-by-treatment interaction effect, indicating that fluoxetine affects both proliferation and neurogenesis in adolescent-treated rats differently than it does in adult-treated rats. In terms of subregional differences, fluoxetine enhanced proliferation mainly in the dorsal parts of the hippocampus, and neurogenesis in both the suprapyramidal and infrapyramidal blades of the dentate gyrus in adolescent-treated rats, while no such differences were seen in adult-treated rats. Fluoxetine exerted similar age-by-treatment interaction effects on TPH cells mainly in the ventral portion of the dorsal raphe nucleus. We conclude that fluoxetine exerts divergent effects on structural plasticity and serotonin synthesis in adolescent versus adult-treated rats. These preliminary data indicate a differential sensitivity of the adolescent brain to this drug and thus warrant further research into their behavioural and translational aspects. Together with recent related findings, they further call for caution in prescribing these drugs to the adolescent population.

  14. A double-masked, placebo-controlled study of fluoxetine for hypochondriasis.

    Science.gov (United States)

    Fallon, Brian A; Petkova, Eva; Skritskaya, Natalia; Sanchez-Lacay, Arturo; Schneier, Franklin; Vermes, Donna; Cheng, Jianfeng; Liebowitz, Michael R

    2008-12-01

    This study assessed the efficacy, durability, and tolerability of fluoxetine for hypochondriasis, a disorder for which controlled pharmacological trials are scarce. Fifty-seven patients with hypochondriasis were enrolled: 12 discontinued during the placebo run-in, and 45 were randomized to either fluoxetine or placebo for 12 weeks (acute treatment). Responder status was defined as a Clinical Global Impression rating for hypochondriasis of much or very much improved. Secondary outcome measures included severity of hypochondriasis, somatization, anxiety, and depression. Responders to acute treatment entered a 12-week maintenance phase to week 24. Sustained responders at week 24 entered a 12-week double-masked discontinuation phase. Primary analysis used the intent-to-treat sample. More patients responded with improvement in hypochondriasis when given fluoxetine compared with placebo, starting at week 8 (50.0% vs 19.0%, P = 0.03) and continuing to week 12 (62.5% vs 33.3%, P = 0.05). Mean dose at week 12 dose was 51.4 mg (SD, +/-23 mg). The acute treatment response was maintained to week 24 with more responders in the fluoxetine compared with the placebo group (54.2% vs 23.8%, P = 0.04). Significant improvement was not noted on the continuous secondary outcomes measures of hypochondriasis, with the exception of the Clinical Global Impression hypochondriasis severity scale at week 24. Likelihood of response was not associated with severity of psychiatric comorbidity. Durability of response after controlled drug discontinuation could not be reasonably assessed, given the small sample size of patients who entered the discontinuation phase (n = 10). Fluoxetine was well tolerated, with no significant differences in discontinuation due to side effects between treatment groups. Fluoxetine is a moderately effective and well-tolerated treatment for hypochondriasis.

  15. Adolescent fluoxetine exposure produces enduring, sex-specific alterations of visual discrimination and attention in rats.

    Science.gov (United States)

    LaRoche, Ronee B; Morgan, Russell E

    2007-01-01

    Over the past two decades the use of selective serotonin reuptake inhibitors (SSRIs) to treat behavioral disorders in children has grown rapidly, despite little evidence regarding the safety and efficacy of these drugs for use in children. Utilizing a rat model, this study investigated whether post-weaning exposure to a prototype SSRI, fluoxetine (FLX), influenced performance on visual tasks designed to measure discrimination learning, sustained attention, inhibitory control, and reaction time. Additionally, sex differences in response to varying doses of fluoxetine were examined. In Experiment 1, female rats were administered (P.O.) fluoxetine (10 mg/kg ) or vehicle (apple juice) from PND 25 thru PND 49. After a 14 day washout period, subjects were trained to perform a simultaneous visual discrimination task. Subjects were then tested for 20 sessions on a visual attention task that consisted of varied stimulus delays (0, 3, 6, or 9 s) and cue durations (200, 400, or 700 ms). In Experiment 2, both male and female Long-Evans rats (24 F, 24 M) were administered fluoxetine (0, 5, 10, or 15 mg/kg) then tested in the same visual tasks used in Experiment 1, with the addition of open-field and elevated plus-maze testing. Few FLX-related differences were seen in the visual discrimination, open field, or plus-maze tasks. However, results from the visual attention task indicated a dose-dependent reduction in the performance of fluoxetine-treated males, whereas fluoxetine-treated females tended to improve over baseline. These findings indicate that enduring, behaviorally-relevant alterations of the CNS can occur following pharmacological manipulation of the serotonin system during postnatal development.

  16. Comparing effects of citalopram with fluoxetine on sleep quality in patients with major depressive disorder.

    Science.gov (United States)

    Shahsavand-Ananloo, E; Berenji, F; Sadeghniiat, K; Alimadadi, A; Zahiroddin, A R; Tabatabaee, M; Abbasi-Asl, M; Ghaeli, P

    2013-05-01

    Sleep disturbance is a common complaint in major depressive disorder (MDD) including impairment of both subjective and objective parameters. All antidepressants affect sleep architecture and quality. This trial was designed to compare the effects of short-term use of citalopram with fluoxetine on sleep quality (SQ) of patients with MDD based on Diagnostic and Statistical Manual for Mental Disorders - Text Revision 4th edition (DSM-IV-TR) criteria. Patients who met the study criteria entered this open-label study. Sleep quality and depression severity were evaluated by using Pittsburgh Sleep Quality Index (PSQI) and Beck Depression Inventory-II (BDI-II), respectively. Patients could not have received any antidepressant for at least one month prior entering the study. Subjects were assigned to receive either fluoxetine or citalopram for 8 weeks. The relationships between SQ and severity of depression were also studied at weeks 4 and 8. Data was analyzed by using SPSS 11.5 version. Nineteen patients received fluoxetine 20-40 mg/day and 21 received citalopram 20-40 mg/day. After 4 and 8 weeks treatment with both fluoxetine and citalopram, significant improvements in SQ were noted in both groups. However, no significant difference between the two groups was observed. Additionally, a significant and positive correlation between improvements in SQ and depression was noted after 8 weeks treatment with citalopram but not with fluoxetine. This study noted that both citalopram and fluoxetine improved SQ in outpatients with MDD after 8 weeks without any significant difference between the 2 groups.

  17. Fluoxetine treatment induces dose dependent alterations in depression associated behavior and neural plasticity in female mice

    OpenAIRE

    Hodes, Georgia E.; Hill-Smith, Tiffany E.; Lucki, Irwin

    2010-01-01

    Antidepressant induced increases in neurogenesis and neurotrophin mobilization in rodents and primates are proposed to be necessary for behavioral efficacy. The current study examines the relationship between the effects of fluoxetine treatment on behavior, cell proliferation and the neurotrophin BDNF in females. Female MRL/MpJ mice were treated acutely (5 and 10 mg/kg) or chronically (2.5, 5 and 10 mg/kg b.i.d.) with fluoxetine and tested in the tail suspension test (TST) and or novelty indu...

  18. Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial.

    Science.gov (United States)

    Chollet, François; Tardy, Jean; Albucher, Jean-François; Thalamas, Claire; Berard, Emilie; Lamy, Catherine; Bejot, Yannick; Deltour, Sandrine; Jaillard, Assia; Niclot, Philippe; Guillon, Benoit; Moulin, Thierry; Marque, Philippe; Pariente, Jérémie; Arnaud, Catherine; Loubinoux, Isabelle

    2011-02-01

    Hemiplegia and hemiparesis are the most common deficits caused by stroke. A few small clinical trials suggest that fluoxetine enhances motor recovery but its clinical efficacy is unknown. We therefore aimed to investigate whether fluoxetine would enhance motor recovery if given soon after an ischaemic stroke to patients who have motor deficits. In this double-blind, placebo-controlled trial, patients from nine stroke centres in France who had ischaemic stroke and hemiplegia or hemiparesis, had Fugl-Meyer motor scale (FMMS) scores of 55 or less, and were aged between 18 years and 85 years were eligible for inclusion. Patients were randomly assigned, using a computer random-number generator, in a 1:1 ratio to fluoxetine (20 mg once per day, orally) or placebo for 3 months starting 5-10 days after the onset of stroke. All patients had physiotherapy. The primary outcome measure was the change on the FMMS between day 0 and day 90 after the start of the study drug. Participants, carers, and physicians assessing the outcome were masked to group assignment. Analysis was of all patients for whom data were available (full analysis set). This trial is registered with ClinicalTrials.gov, number NCT00657163. 118 patients were randomly assigned to fluoxetine (n=59) or placebo (n=59), and 113 were included in the analysis (57 in the fluoxetine group and 56 in the placebo group). Two patients died before day 90 and three withdrew from the study. FMMS improvement at day 90 was significantly greater in the fluoxetine group (adjusted mean 34·0 points [95% CI 29·7-38·4]) than in the placebo group (24·3 points [19·9-28·7]; p=0·003). The main adverse events in the fluoxetine and placebo groups were hyponatraemia (two [4%] vs two [4%]), transient digestive disorders including nausea, diarrhoea, and abdominal pain (14 [25%] vs six [11%]), hepatic enzyme disorders (five [9%] vs ten [18%]), psychiatric disorders (three [5%] vs four [7%]), insomnia (19 [33%] vs 20 [36%]), and partial

  19. Methylphenidate-induced erections in a prepubertal child.

    LENUS (Irish Health Repository)

    Kelly, B D

    2013-02-01

    Methylphenidate is a medication used routinely in the management of attention deficit hyperactivity disorder. We report a case of a prepubertal child who developed unwanted erections after commencing a response-adjusted dosing regimen of sustained release methylphenidate. Despite priapism being a rare adverse reaction associated with methylphenidate, physicians and parents need to be aware as it can have significant long-term complications.

  20. Developmental exposure to fluoxetine modulates the serotonin system in hypothalamus.

    Directory of Open Access Journals (Sweden)

    Cecilia Berg

    Full Text Available The selective serotonin reuptake inhibitor (SSRI fluoxetine (FLU, Prozac® is commonly prescribed for depression in pregnant women. This results in SSRI exposure of the developing fetus. However, there are knowledge gaps regarding the impact of SSRI exposure during development. Given the role of serotonin in brain development and its cross-talk with sex hormone function, we investigated effects of developmental exposure to pharmacologically relevant concentrations of FLU (3 and 30 nM (measured on brain neurotransmitter levels, gonadal differentiation, aromatase activity in brain and gonads, and the thyroid system, using the Xenopus tropicalis model. Tadpoles were chronically exposed (8 weeks until metamorphosis. At metamorphosis brains were cryosectioned and levels of serotonin, dopamine, norepinephrine, and their metabolites 5-hydroxyindoleacetic acid, 3,4-dihydroxyphenylacetic acid, and homovanillic acid were measured in discrete regions (telencephalon, hypothalamus and the reticular formation of the cryosections using high-performance liquid chromatography. Exposure to 30 nM FLU increased the concentration of 5-hydroxyindoleacetic acid in hypothalamus compared with controls. FLU exposure did not affect survival, time to metamorphosis, thyroid histology, gonadal sex differentiation, or aromatase activity implying that the effect on the serotonergic neurotransmitter system in the hypothalamus region was specific. The FLU concentration that impacted the serotonin system is lower than the concentration measured in umbilical cord serum, suggesting that the serotonin system of the developing brain is highly sensitive to in utero exposure to FLU. To our knowledge this is the first study showing effects of developmental FLU exposure on brain neurochemistry. Given that SSRIs are present in the aquatic environment the current results warrant further investigation into the neurobehavioral effects of SSRIs in aquatic wildlife.

  1. Long-term fluoxetine treatment induces input-specific LTP and LTD impairment and structural plasticity in the CA1 hippocampal subfield.

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    Francisco J Rubio

    2013-05-01

    Full Text Available Antidepressant drugs are usually administered for long time for the treatment of major depressive disorder. However, they are also prescribed in several additional psychiatric conditions as well as during long term maintenance treatments. Antidepressants induce adaptive changes in several forebrain structures which include modifications at glutamatergic synapses. We recently found that repetitive administration of the selective serotonin reuptake inhibitor fluoxetine to naϊve adult male rats induced an increase of mature, mushroom-type dendritic spines in several forebrain regions. This was associated with an increase of GluA2-containing α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors (AMPA-Rs in telencephalic postsynaptic densities. To unravel the functional significance of such a synaptic re-arrangement, we focused on glutamate neurotransmission in the hippocampus. We evaluated the effect of four weeks of treatment with 0.7 mg/kg of fluoxetine on long-term potentiation (LTP and long-term depression (LTD in the Schaffer collateral-CA1 synapses and the perforant path-CA1 synapses. Recordings in hippocampal slices revealed profound deficits in LTP and LTD at Schaffer collateral-CA1 synapses associated to increased spine density and enhanced presence of mushroom-type spines, as revealed by Golgi staining. However, the same treatment had neither an effect on spine morphology, nor on LTP and LTD at perforant path-CA1 synapses. Cobalt staining experiments revealed decreased AMPA-R Ca2+ permeability in the stratum radiatum together with increased GluA2-containing, Ca2+-impermeable AMPA-Rs. Therefore, 4 weeks of fluoxetine treatment promoted structural and functional adaptations in CA1 neurons in a pathway-specific manner that were selectively associated with impairment of activity-dependent plasticity at Schaffer collateral-CA1 synapses.

  2. Alterations on the morphology, nitric oxide synthesis and activity of platelets reproduced in rats as possible biomarkers for depression are reversed by fluoxetine.

    Science.gov (United States)

    González-Trujano, María Eva; Alvarado-Vásquez, Noé; Mendoza-Sotelo, José; López, Guadalupe; Estrada-Camarena, Erika; Martínez-Mota, Lucia; Moreno, Julia

    2012-08-01

    Biochemical markers associated with the prognosis of depression in humans are being described in the literature, whereas experimental studies in animal models in search for antidepressant strategies are lacking. The aim of this study was to evaluate platelet morphology, platelet activity and nitric oxide (NO) synthesis as possible biomarkers of depressive-like behavior by using FST alone and in the presence of fluoxetine. Naïve rats were compared to those receiving vehicle or fluoxetine at 10mg/kg i.p. in acute, subchronic and chronic administration in the FST. After behavioral assessment, platelets were isolated from blood samples and analyzed by flow cytometry to determine the platelet mitochondrial membrane potential and NO synthesis. In addition, HPLC and electron microscopy were used to examine 5-HT and tryptophan levels and morphology of platelets, respectively. Rats receiving vehicle and exposed to FST showed depressive-like behavior at all the times tested; after chronic FST rats showed a similar pattern of alteration in platelet morphology and in the studied as possible biochemical markers as those previously recognized in depressive humans. Depressive-like behavior in rats exposed to FST was prevented in the presence of fluoxetine administration at all the times tested and associated with the prevention of alterations in platelet morphology, platelet activity and NO synthesis, and/or in 5-HT concentrations. The results of the present study suggest that platelet function and morphology might be relevant markers for the prognosis of depression and the search for functional treatments. Besides, the relevance of FST as model to study this psychiatric illness is reinforced. Copyright © 2012 Elsevier Inc. All rights reserved.

  3. Thirty-five Day Fluoxetine Treatment Limits Sensory-Motor Deficit and Biochemical Disorders in a Rat Model of Decompression Sickness

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    Caroline Cosnard

    2017-09-01

    Full Text Available According to the OECD statistical base for 2014, anti-depressants will, on average, be distributed at a rate of 62 daily doses per 1,000 inhabitants for the 25 countries surveyed (Health at a glance: Europe 2014; OECD Health Statistics; World Health Organization and OECD Health Statistics, 2014. Divers must be concerned. On another hand, divers are potentially exposed to decompression sickness including coagulation inflammation and ischemia, which can result in neurological lesions or even death. The purpose of this study is to assess whether chronic treatment with anti-depressants may represent a contraindication to the practice of an at-risk activity, such as, scuba diving, or even presents a benefit by attenuating the severity of the symptoms. We study for the first time the effect of a 35-day fluoxetine treatment (20 mg/kg on the occurrence of decompression sickness in laboratory rats (n = 79. Following exposure to the hazardous protocol, there is a significant correlation between the type of treatment and the clinical status of the rats in favor of a better clinical prognosis for the rats treated with fluoxetine with a significantly higher number of No DCS status and a lower number of Severe DCS status in the Flux, compared to Controls. The treatment modifies the rat performances both significantly and favorably during the physical and behavioral tests, just like their biological and biochemical constants. After decompression, rats under treatment display lower sensory-motor deficit and lowers biochemical disorders. From a biological point of view, we conclude fluoxetine should not be seen as a contraindication for diving on the basis of anticipated increased physiological risk.

  4. Fluoxetine regulates mTOR signalling in a region-dependent manner in depression-like mice

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    Liu, Xiao-Long; Luo, Liu; Mu, Rong-Hao; Liu, Bin-Bin; Geng, Di; Liu, Qing; Yi, Li-Tao

    2015-01-01

    Previous studies have demonstrated that the mammalian target of rapamycin (mTOR) signaling pathway has an important role in ketamine-induced, rapid antidepressant effects despite the acute administration of fluoxetine not affecting mTOR phosphorylation in the brain. However, the effects of long-term fluoxetine treatment on mTOR modulation have not been assessed to date. In the present study, we examined whether fluoxetine, a type of commonly used antidepressant agent, alters mTOR signaling following chronic administration in different brain regions, including the frontal cortex, hippocampus, amygdala and hypothalamus. We also investigated whether fluoxetine enhanced synaptic protein levels in these regions via the activation of the mTOR signaling pathway and its downstream regulators, p70S6K and 4E-BP-1. The results indicated that chronic fluoxetine treatment attenuated the chronic, unpredictable, mild stress (CUMS)-induced mTOR phosphorylation reduction in the hippocampus and amygdala of mice but not in the frontal cortex or the hypothalamus. Moreover, the CUMS-decreased PSD-95 and synapsin I levels were reversed by fluoxetine, and these effects were blocked by rapamycin only in the hippocampus. In conclusion, our findings suggest that chronic treatment with fluoxetine can induce synaptic protein expression by activating the mTOR signaling pathway in a region-dependent manner and mainly in the hippocampus. PMID:26522512

  5. Fluoxetine during development reverses the effects of prenatal stress on depressive-like behavior and hippocampal neurogenesis in adolescence.

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    Rayen, Ine; van den Hove, Daniël L; Prickaerts, Jos; Steinbusch, Harry W; Pawluski, Jodi L

    2011-01-01

    Depression during pregnancy and the postpartum period is a growing health problem, which affects up to 20% of women. Currently, selective serotonin reuptake inhibitor (SSRIs) medications are commonly used for treatment of maternal depression. Unfortunately, there is very little research on the long-term effect of maternal depression and perinatal SSRI exposure on offspring development. Therefore, the aim of this study was to determine the role of exposure to fluoxetine during development on affective-like behaviors and hippocampal neurogenesis in adolescent offspring in a rodent model of maternal depression. To do this, gestationally stressed and non-stressed Sprague-Dawley rat dams were treated with either fluoxetine (5 mg/kg/day) or vehicle beginning on postnatal day 1 (P1). Adolescent male and female offspring were divided into 4 groups: 1) prenatal stress+fluoxetine exposure, 2) prenatal stress+vehicle, 3) fluoxetine exposure alone, and 4) vehicle alone. Adolescent offspring were assessed for anxiety-like behavior using the Open Field Test and depressive-like behavior using the Forced Swim Test. Brains were analyzed for endogenous markers of hippocampal neurogenesis via immunohistochemistry. Results demonstrate that maternal fluoxetine exposure reverses the reduction in immobility evident in prenatally stressed adolescent offspring. In addition, maternal fluoxetine exposure reverses the decrease in hippocampal cell proliferation and neurogenesis in maternally stressed adolescent offspring. This research provides important evidence on the long-term effect of fluoxetine exposure during development in a model of maternal adversity.

  6. Randomized, double-blind, placebo-controlled trial of fluoxetine treatment for elderly patients with dysthymic disorder.

    Science.gov (United States)

    Devanand, D P; Nobler, Mitchell S; Cheng, Jocelyn; Turret, Nancy; Pelton, Gregory H; Roose, Steven P; Sackeim, Harold A

    2005-01-01

    The authors compared the efficacy and side effects of fluoxetine and placebo in elderly outpatients with dysthymic disorder. Patients were randomly assigned to fluoxetine (20 mg-60 mg/day) or placebo for 12 weeks in a double-blind trial. Of 90 randomized patients, 71 completed the trial. In the intent-to-treat sample, random regression analyses of the Hamilton Rating Scale for Depression (Ham-D; 24-item) and Cornell Dysthymia Rating Scale (CDRS) scores at each visit produced significant time x treatment group interactions favoring the fluoxetine group. Analysis of percentage change in Ham-D scores yielded no effect for treatment group, but a similar analysis of percentage change in CDRS scores yielded a main effect for treatment group, favoring fluoxetine over placebo. In the intent-to-treat sample, response rates were 27.3% for fluoxetine and 19.6% for placebo. In the completer sample, response rates were 37.5% for fluoxetine and 23.1% for placebo. Fluoxetine had limited efficacy in elderly dysthymic patients. The clinical features of elderly dysthymic patients are typically distinct from those of dysthymic disorder in young adults, and the findings suggest that treatments effective for young adult dysthymic patients may not be as useful in elderly dysthymic patients. Further research is needed to identify efficacious treatments for elderly patients with dysthymic disorder, and investigative tools such as electronic/computerized brain scans and neuropsychological testing may help identify the factors that moderate antidepressant treatment response and resistance.

  7. Fluoxetine during development reverses the effects of prenatal stress on depressive-like behavior and hippocampal neurogenesis in adolescence.

    Directory of Open Access Journals (Sweden)

    Ine Rayen

    Full Text Available Depression during pregnancy and the postpartum period is a growing health problem, which affects up to 20% of women. Currently, selective serotonin reuptake inhibitor (SSRIs medications are commonly used for treatment of maternal depression. Unfortunately, there is very little research on the long-term effect of maternal depression and perinatal SSRI exposure on offspring development. Therefore, the aim of this study was to determine the role of exposure to fluoxetine during development on affective-like behaviors and hippocampal neurogenesis in adolescent offspring in a rodent model of maternal depression. To do this, gestationally stressed and non-stressed Sprague-Dawley rat dams were treated with either fluoxetine (5 mg/kg/day or vehicle beginning on postnatal day 1 (P1. Adolescent male and female offspring were divided into 4 groups: 1 prenatal stress+fluoxetine exposure, 2 prenatal stress+vehicle, 3 fluoxetine exposure alone, and 4 vehicle alone. Adolescent offspring were assessed for anxiety-like behavior using the Open Field Test and depressive-like behavior using the Forced Swim Test. Brains were analyzed for endogenous markers of hippocampal neurogenesis via immunohistochemistry. Results demonstrate that maternal fluoxetine exposure reverses the reduction in immobility evident in prenatally stressed adolescent offspring. In addition, maternal fluoxetine exposure reverses the decrease in hippocampal cell proliferation and neurogenesis in maternally stressed adolescent offspring. This research provides important evidence on the long-term effect of fluoxetine exposure during development in a model of maternal adversity.

  8. Differential Rearing Alters Forced Swim Test Behavior, Fluoxetine Efficacy, and Post-Test Weight Gain in Male Rats

    Science.gov (United States)

    Arndt, David L.; Peterson, Christy J.; Cain, Mary E.

    2015-01-01

    Environmental factors play a key role in the etiology of depression. The rodent forced swim test (FST) is commonly used as a preclinical model of depression, with increases in escape-directed behavior reflecting antidepressant effects, and increases in immobility reflecting behavioral despair. Environmental enrichment leads to serotonergic alterations in rats, but it is unknown whether these alterations may influence the efficacy of common antidepressants. Male Sprague-Dawley rats were reared in enriched (EC), standard (SC), or isolated (IC) conditions. Following the rearing period, fluoxetine (10 or 20 mg/kg, i.p.) was administered 23.5 hrs, 5 hrs, and 1 hr before locomotor and FST measures. Following locomotor testing and FST exposure, rats were weighed to assess fluoxetine-, FST-, and environmental condition-induced moderations in weight gain. Results revealed an antidepressant effect of environmental enrichment and a depressant effect of isolation. Regardless of significant fluoxetine effects on locomotor activity, fluoxetine generally decreased swimming and increased immobility in all three environmental conditions, with IC-fluoxetine (10 mg/kg) rats and EC-fluoxetine (20 mg/kg) rats swimming less than vehicle counterparts. Subchronic 20 mg/kg fluoxetine also induced significant weight loss, and differential rearing appeared to moderate weight gain following FST stress. These results suggest that differential rearing has the ability to alter FST behaviors, fluoxetine efficacy, and post-stressor well-being. Moreover, 20 mg/kg fluoxetine, administered subchronically, may lead to atypical effects of those commonly observed in the FST, highlighting the importance and impact of both environmental condition and dosing regimen in common animal models of depression. PMID:26154768

  9. Effects of acute or repeated paroxetine and fluoxetine treatment on affective behavior in male and female adolescent rats

    Science.gov (United States)

    Amodeo, Leslie R.; Greenfield, Venuz Y.; Humphrey, Danielle E.; Varela, Veronica; Pipkin, Joseph A.; Eaton, Shannon E.; Johnson, Jelesa D.; Plant, Christopher P.; Harmony, Zachary R.; Wang, Li; Crawford, Cynthia A.

    2015-01-01

    Rationale The SSRI antidepressant fluoxetine is one of the few drugs that is effective at treating depression in adolescent humans. In contrast, the SSRI paroxetine has limited efficacy and is more at risk for inducing suicidal behavior. Objective The purpose of the present study was to more fully characterize the differential actions of paroxetine and fluoxetine. Methods In Experiment 1, male and female rats were injected with paroxetine (2.5 or 10 mg/kg), fluoxetine (10 mg/kg), or vehicle for 10 days starting on postnatal day (PD) 35, and affective behaviors were assessed using sucrose preference and elevated plus maze tasks. A separate set of rats were used to examine monoamine levels. In Experiment 2, rats were injected with paroxetine (2.5, 5 or 10 mg/kg), fluoxetine (5, 10 or 20 mg/kg), or vehicle during the same time frame as Experiment 1 and anxiety-like behaviors were measured using elevated plus maze, light/dark box, and acoustic startle. Results Repeated SSRI treatment failed to alter sucrose preference, although both paroxetine and fluoxetine reduced time spent in the open arms of the elevated plus maze and light compartment of the light/dark box. Paroxetine, but not fluoxetine, enhanced acoustic startle and interfered with habituation. Serotonin turnover was decreased by both acute and repeated fluoxetine treatment but unaltered by paroxetine administration. Discussion These results show that repeated treatment with paroxetine and fluoxetine has dissociable actions in adolescent rats. In particular, paroxetine, but not fluoxetine, increases acoustic startle at low doses and may increase sensitivity to environmental stressors. PMID:26141193

  10. Fluoxetine and vitamin C synergistically inhibits blood-spinal cord barrier disruption and improves functional recovery after spinal cord injury.

    Science.gov (United States)

    Lee, Jee Y; Choi, Hae Y; Yune, Tae Y

    2016-10-01

    Recently we reported that fluoxetine (10 mg/kg) improves functional recovery by attenuating blood spinal cord barrier (BSCB) disruption after spinal cord injury (SCI). Here we investigated whether a low-dose of fluoxetine (1 mg/kg) and vitamin C (100 mg/kg), separately not possessing any protective effect, prevents BSCB disruption and improves functional recovery when combined. After a moderate contusion injury at T9 in rat, a low-dose of fluoxetine and vitamin C, or the combination of both was administered intraperitoneally immediately after SCI and further treated once a day for 14 d. Co-treatment with fluoxetine and vitamin C significantly attenuated BSCB permeability at 1 d after SCI. When only fluoxetine or vitamin C was treated after injury, however, there was no effect on BSCB disruption. Co-treatment with fluoxetine and vitamin C also significantly inhibited the expression and activation of MMP-9 at 8 h and 1 d after injury, respectively, and the infiltration of neutrophils (at 1 d) and macrophages (at 5 d) and the expression of inflammatory mediators (at 2 h, 6 h, 8 h or 24 h after injury) were significantly inhibited by co-treatment with fluoxetine and vitamin C. Furthermore, the combination of fluoxetine and vitamin C attenuated apoptotic cell death at 1 d and 5 d and improved locomotor function at 5 weeks after SCI. These results demonstrate the synergistic effect combination of low-dose fluoxetine and vitamin C on BSCB disruption after SCI and furthermore support the effectiveness of the combination treatment regimen for the management of acute SCI. Copyright © 2016 Elsevier Ltd. All rights reserved.

  11. Fluoxetine protection in decompression sickness in mice is enhanced by blocking TREK-1 potassium channel with the spadin antidepressant.

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    Nicolas eVallée

    2016-02-01

    Full Text Available In mice, disseminated coagulation, inflammation and ischemia induce neurological damages that can lead to the death. These symptoms result from circulating bubbles generated by a pathogenic decompression. An acute fluoxetine treatment or the presence of the TREK-1 potassium channel increased the survival rate when mice are subjected to an experimental dive/decompression protocol. This is a paradox because fluoxetine is a blocker of TREK-1 channels. First, we studied the effects of an acute dose of fluoxetine (50mg/kg in wild-type (WT and TREK-1 deficient mice (Knockout homozygous KO and heterozygous HET. Then, we combined the same fluoxetine treatment with a five-day treatment by spadin, in order to specifically block TREK-1 activity (KO-like mice. KO and KO-like mice could be regarded as antidepressed models.167 mice (45 WTcont 46 WTflux 30 HETflux and 46 KOflux constituting the flux-pool and 113 supplementary mice (27 KO-like 24 WTflux2 24 KO-likeflux 21 WTcont2 17 WTno dive constituting the spad-pool were included in this study. Only 7% of KO-TREK-1 treated with fluoxetine (KOflux and 4% of mice treated with both spadin and fluoxetine (KO-likeflux died from decompression sickness (DCS symptoms. These values are much lower than those of WT control (62% or KO-like mice (41%. After the decompression protocol, mice showed a significant consumption of their circulating platelets and leukocytes.Spadin antidepressed mice were more likely to declare DCS. Nevertheless, which had both blocked TREK-1 channel and were treated with fluoxetine were better protected against DCS. We conclude that the protective effect of such an acute dose of fluoxetine is enhanced when TREK-1 is inhibited. We confirmed that antidepressed models may have worse DCS outcomes, but a concomitant fluoxetine treatment not only decreases DCS severity but increases the survival rate.

  12. Mesolimbic effects of the antidepressant fluoxetine in Holtzman rats, a genetic strain with increased vulnerability to stress

    Science.gov (United States)

    Padilla, Eimeira; Shumake, Jason; Barrett, Douglas W.; Sheridan, Eva C.; Gonzalez-Lima, F.

    2011-01-01

    This is the first metabolic mapping study of the effects of fluoxetine after learned helplessness training. Antidepressants are the most commonly prescribed medications, but the regions underlying treatment effects in affectively disordered brains are poorly understood. We hypothesized the antidepressant action of fluoxetine would produce adaptations in mesolimbic regions after two weeks of treatment. We used Holtzman rats, a genetic strain showing susceptibility to novelty-evoked hyperactivity and stress-evoked helplessness, to map regional brain metabolic effects caused by fluoxetine treatment. Animals underwent learned helplessness, and subsequently immobility time was scored in the forced swim test (FST). On the next day, animals began receiving two weeks of fluoxetine (5 mg/kg/day) or vehicle and were retested in the FST at the end of drug treatment. Antidepressant behavioral effects of fluoxetine were analyzed using a ratio of immobility during pre- and post-treatment FST sessions. Brains were analyzed for regional metabolic activity using quantitative cytochrome oxidase histochemistry as in our previous study using congenitally helpless rats. Fluoxetine exerted a protective effect against FST-induced immobility behavior in Holtzman rats. Fluoxetine also caused a significant reduction in the mean regional metabolism of the nucleus accumbens shell and the ventral hippocampus as compared to vehicle-treated subjects. Additional networks affected by fluoxetine treatment included the prefrontal-cingulate cortex and brainstem nuclei linked to depression (e.g. habenula, dorsal raphe and interpeduncular nucleus). We concluded that corticolimbic regions such as the prefrontal-cingulate cortex, nucleus accumbens, ventral hippocampus and key brainstem nuclei represent important contributors to the neural network mediating fluoxetine antidepressant action. PMID:21376019

  13. Differential Rearing Alters Forced Swim Test Behavior, Fluoxetine Efficacy, and Post-Test Weight Gain in Male Rats.

    Directory of Open Access Journals (Sweden)

    David L Arndt

    Full Text Available Environmental factors play a key role in the etiology of depression. The rodent forced swim test (FST is commonly used as a preclinical model of depression, with increases in escape-directed behavior reflecting antidepressant effects, and increases in immobility reflecting behavioral despair. Environmental enrichment leads to serotonergic alterations in rats, but it is unknown whether these alterations may influence the efficacy of common antidepressants. Male Sprague-Dawley rats were reared in enriched (EC, standard (SC, or isolated (IC conditions. Following the rearing period, fluoxetine (10 or 20 mg/kg, i.p. was administered 23.5 hrs, 5 hrs, and 1 hr before locomotor and FST measures. Following locomotor testing and FST exposure, rats were weighed to assess fluoxetine-, FST-, and environmental condition-induced moderations in weight gain. Results revealed an antidepressant effect of environmental enrichment and a depressant effect of isolation. Regardless of significant fluoxetine effects on locomotor activity, fluoxetine generally decreased swimming and increased immobility in all three environmental conditions, with IC-fluoxetine (10 mg/kg rats and EC-fluoxetine (20 mg/kg rats swimming less than vehicle counterparts. Subchronic 20 mg/kg fluoxetine also induced significant weight loss, and differential rearing appeared to moderate weight gain following FST stress. These results suggest that differential rearing has the ability to alter FST behaviors, fluoxetine efficacy, and post-stressor well-being. Moreover, 20 mg/kg fluoxetine, administered subchronically, may lead to atypical effects of those commonly observed in the FST, highlighting the importance and impact of both environmental condition and dosing regimen in common animal models of depression.

  14. Differential Rearing Alters Forced Swim Test Behavior, Fluoxetine Efficacy, and Post-Test Weight Gain in Male Rats.

    Science.gov (United States)

    Arndt, David L; Peterson, Christy J; Cain, Mary E

    2015-01-01

    Environmental factors play a key role in the etiology of depression. The rodent forced swim test (FST) is commonly used as a preclinical model of depression, with increases in escape-directed behavior reflecting antidepressant effects, and increases in immobility reflecting behavioral despair. Environmental enrichment leads to serotonergic alterations in rats, but it is unknown whether these alterations may influence the efficacy of common antidepressants. Male Sprague-Dawley rats were reared in enriched (EC), standard (SC), or isolated (IC) conditions. Following the rearing period, fluoxetine (10 or 20 mg/kg, i.p.) was administered 23.5 hrs, 5 hrs, and 1 hr before locomotor and FST measures. Following locomotor testing and FST exposure, rats were weighed to assess fluoxetine-, FST-, and environmental condition-induced moderations in weight gain. Results revealed an antidepressant effect of environmental enrichment and a depressant effect of isolation. Regardless of significant fluoxetine effects on locomotor activity, fluoxetine generally decreased swimming and increased immobility in all three environmental conditions, with IC-fluoxetine (10 mg/kg) rats and EC-fluoxetine (20 mg/kg) rats swimming less than vehicle counterparts. Subchronic 20 mg/kg fluoxetine also induced significant weight loss, and differential rearing appeared to moderate weight gain following FST stress. These results suggest that differential rearing has the ability to alter FST behaviors, fluoxetine efficacy, and post-stressor well-being. Moreover, 20 mg/kg fluoxetine, administered subchronically, may lead to atypical effects of those commonly observed in the FST, highlighting the importance and impact of both environmental condition and dosing regimen in common animal models of depression.

  15. Effects of Gingko biloba Extract on Tissue Distribution of Fluoxetine and Venlafaxine in Rats

    Directory of Open Access Journals (Sweden)

    Saad Abdulrahman Hussain

    2015-09-01

    Full Text Available Objective: There are many concerns about the interactions of herbal products with conventional drugs, which are mostly used as multiple drug treatment approach. The present study was designed to evaluate the effect of long-term use of Ginkgo biloba extract (GK on the absorption and tissue distribution of fluoxetine and venlafaxine. Materials and Methods: Forty-six Wistar rats are utilized and allocated into eight groups; 2 groups administered the vehicle and saved as control; 4 groups are treated with 100 and 200 mg/kg of GK extract for 30 days; 2 groups are treated with 40mg/kg verapamil for 10 days. The liver, kidney and brain distribution of fluoxetine and venlafaxine were evaluated after single oral doses using HPLC method. Results: 200 mg/kg GK increases fluoxetine concentrations in all studied organs, while GK 100mg/kg increases venlafaxine levels in kidney tissue and not affected in the other two organs. Conclusion: Thirty days treatment with GK (100 mg/kg increases kidney availability of venlafaxine, while 200 mg GK dose increases fluoxetine availability in the liver, kidney and brain tissues after single oral doses. [J Intercult Ethnopharmacol 2015; 4(3.000: 234-238

  16. Fluoxetine Exerts Age-Dependent Effects on Behavior and Amygdala Neuroplasticity in the Rat

    NARCIS (Netherlands)

    Homberg, Judith R.; Olivier, Jocelien D. A.; Blom, Tom; Arentsen, Tim; van Brunschot, Chantal; Schipper, Pieter; Korte-Bouws, Gerdien; van Luijtelaar, Gilles; Reneman, Liesbeth

    2011-01-01

    The selective serotonin reuptake inhibitor (SSRI) Prozac (R) (fluoxetine) is the only registered antidepressant to treat depression in children and adolescents. Yet, while the safety of SSRIs has been well established in adults, serotonin exerts neurotrophic actions in the developing brain and

  17. Fluoxetine exerts age-dependent effects on behavior and amygdala neuroplasticity in the rat.

    NARCIS (Netherlands)

    Homberg, J.R.; Olivier, J.D.A.; Blom, T.; Arentsen, T.; Brunschot, C. van; Schipper, P.; Korte-Bouws, G.A.; Luijtelaar, E.L.J.M. van; Reneman, L.

    2011-01-01

    The selective serotonin reuptake inhibitor (SSRI) Prozac(R) (fluoxetine) is the only registered antidepressant to treat depression in children and adolescents. Yet, while the safety of SSRIs has been well established in adults, serotonin exerts neurotrophic actions in the developing brain and

  18. Single dose of fluoxetine increases muscle activation in chronic stroke patients.

    NARCIS (Netherlands)

    van Genderen, Hanneke Irene; Nijlant, Juliette M.M.; van Putten, Michel Johannes Antonius Maria; Movig, Kris L.L.; IJzerman, Maarten Joost

    2009-01-01

    Objectives: This pilot study explores the influence of a single dose of fluoxetine (20 mg) on the muscle activation patterns and functional ability of the muscles in the lower part of the arm in chronic stroke patients. Methods: A crossover, placebo-controlled clinical trial was conducted in 10

  19. Fluoxetine Exerts Age-Dependent Effects on Behavior and Amygdala Neuroplasticity in the Rat

    NARCIS (Netherlands)

    Homberg, J.R.; Olivier, J.D.A.; Blom, T.; Arentsen, T.; Brunschot, C. van; Schipper, P.; Korte-Bouws, G.A.; Luijtelaar, E.L.J.M. van; Reneman, L.

    2011-01-01

    The selective serotonin reuptake inhibitor (SSRI) Prozac® (fluoxetine) is the only registered antidepressant to treat depression in children and adolescents. Yet, while the safety of SSRIs has been well established in adults, serotonin exerts neurotrophic actions in the developing brain and thereby

  20. Synthesis of 14C- and 3H-labeled fluoxetine, a selective serotonin uptake inhibitor

    International Nuclear Information System (INIS)

    Robertson, D.W.; Krushinski, J.H.; Wong, D.T.; Kau, D.

    1987-01-01

    Fluoxetine (N-methyl-γ-(4-(trifluoromethyl)phenoxy) benzenepropanamine) is a potent, highly selective serotonin uptake inhibitor that is useful in treating a variety of major psychiatric derangements. We have synthesized this compound in 14 C- and 3 H-labeled forms. The tritium label was introduced in the final step by catalytic dehalogenation of the brominated fluoxetine precursor. Reaction conditions could be controlled such that catalytic hydrogenolysis of the labile C-O benzylic bond was minimized. Following HPLC purification, [ 3 H]-fluoxetine was obtained in a state of high radiochemical purity (98%) and specific activity (20.4 Ci/mmol). The 14 C-label was introduced in the final step via a nucleophilic aromatic substitution reaction between the sodium salt of α-(2-(methylamino)ethyl)benzenemethanol and uniformly ring-labeled p-chlorobenzotrifluoride. Following purification by flash chromatography, [ 14 C]-fluoxetine was obtained in 98.3% radiochemical purity with a specific activity of 5.52 mCi/mmol. (author)

  1. Fluoxetine Induces Proliferation and Inhibits Differentiation of Hypothalamic Neuroprogenitor Cells In Vitro

    Science.gov (United States)

    Sousa-Ferreira, Lígia; Aveleira, Célia; Botelho, Mariana; Álvaro, Ana Rita; Pereira de Almeida, Luís; Cavadas, Cláudia

    2014-01-01

    A significant number of children undergo maternal exposure to antidepressants and they often present low birth weight. Therefore, it is important to understand how selective serotonin reuptake inhibitors (SSRIs) affect the development of the hypothalamus, the key center for metabolism regulation. In this study we investigated the proliferative actions of fluoxetine in fetal hypothalamic neuroprogenitor cells and demonstrate that fluoxetine induces the proliferation of these cells, as shown by increased neurospheres size and number of proliferative cells (Ki-67+ cells). Moreover, fluoxetine inhibits the differentiation of hypothalamic neuroprogenitor cells, as demonstrated by decreased number of mature neurons (Neu-N+ cells) and increased number of undifferentiated cells (SOX-2+ cells). Additionally, fluoxetine-induced proliferation and maintenance of hypothalamic neuroprogenitor cells leads to changes in the mRNA levels of appetite regulator neuropeptides, including Neuropeptide Y (NPY) and Cocaine-and-Amphetamine-Regulated-Transcript (CART). This study provides the first evidence that SSRIs affect the development of hypothalamic neuroprogenitor cells in vitro with consequent alterations on appetite neuropeptides. PMID:24598761

  2. Daily high doses of fluoxetine for weight loss and improvement in lifestyle before bariatric surgery

    NARCIS (Netherlands)

    Dolfing, JG; Wolffenbuttel, BHR; Oei, HI; ten Hoor-Aukerna, NM; Schweitzer, DH

    Background: The number of gastric restrictive bariatric operations is increasing each year, but about one-fifth of patients will become disappointed due to unsatisfactory weight reduction or annoying complications. We questioned whether weight reduction by taking high doses of fluoxetine improves

  3. Fluoxetine and Norfluoxetine Revisited: New Insights into the Electrochemical and Spectroscopic Properties

    Science.gov (United States)

    Garrido, E. Manuela; Garrido, Jorge; Calheiros, Rita; Marques, M. Paula M.; Borges, Fernanda

    2009-08-01

    The extent to which humans and wildlife are exposed to the vast array of anthropogenic chemicals and their degradation products, along with related naturally occurring compounds, is nowadays an important issue. The study of the physical-chemical properties of the compounds and/or degradation products is an important subject because some of them are intrinsically related to its resistance to degradation and/or bioaccumulation. Accordingly, the study of the electrochemical behavior of the selective serotonin reuptake inhibitor fluoxetine and its main metabolite norfluoxetine was investigated. The identification of the oxidation processes was done via two fluoxetine analogues, 1-(benzyloxy)-4-(trifluoromethyl)benzene and N-methyl-3-phenylpropan-1-amine hydrochloride. The oxidative processes occurring in fluoxetine are pH-dependent and were ascribed to the chemical moieties present in the molecule: the secondary amine group and the substituted aromatic nucleus. To perform an unequivocal ascription, the structural preferences of the drug and metabolite were also determined, by Raman spectroscopy coupled to quantum mechanical calculations (at the DFT level). The analytical data obtained in this work will allow the development of a rapid and unequivocal spectroscopic procedure suitable for fluoxetine identification, as well as to distinguish between the drug and its main metabolite.

  4. Molecular basis for selective serotonin reuptake inhibition by the antidepressant agent fluoxetine (prozac)

    DEFF Research Database (Denmark)

    Andersen, Jacob; Stuhr-Hansen, Nicolai; Zachariassen, Linda Grønborg

    2014-01-01

    X-ray crystal structures of LeuBAT, an engineered monoamine-like version of the bacterial amino acid transporter LeuT. However, the binding orientation of fluoxetine is reversed in our experimentally supported model compared with the LeuBAT structures, emphasizing the need for careful experimental...

  5. Chronic administration of fluoxetine and pro-inflammatory cytokine change in a rat model of depression.

    Science.gov (United States)

    Lu, Yanxia; Ho, Cyrus S; Liu, Xin; Chua, Anna N; Wang, Wei; McIntyre, Roger S; Ho, Roger C

    2017-01-01

    This study evaluated the chronic effects of fluoxetine, a commonly prescribed SSRI antidepressant, on the peripheral and central levels of inflammatory cytokines including IL-1β, IL-6, TNF-α and IL-17 over a 4-interval in a rat model of chronic mild stress (CMS) which resembles the human experience of depression. Twenty-four Sprague-Dawley rats were randomly assigned to CMS+vehicle (n = 9), CMS+fluoxetine (n = 9) and the control (n = 6) groups. Sucrose preference and forced swim tests were performed to assess behavioral change. Blood samples were collected on day 0, 60, 90 and 120 for measurement of cytokine levels in plasma. On day 120, the brain was harvested and central level of cytokines was tested using Luminex. Four months of fluoxetine treatment resulted in changes in the sucrose preference and immobility time measurements, commensurate with antidepressant effects. The CMS+vehicle group exhibited elevated plasma levels of IL-1β, IL-17, and TNF-α on day 60 or 120. Rats treated with fluoxetine demonstrated lower IL-1β in plasma and brain after 90 and 120-day treatment respectively (pfluoxetine by reducing central and peripheral levels of IL-1β in the alleviation of depressive symptoms.

  6. Fluoxetine and imipramine: are there differences in cost-utility for depression in primary care?

    Science.gov (United States)

    Serrano-Blanco, Antoni; Suárez, David; Pinto-Meza, Alejandra; Peñarrubia, Maria T; Haro, Josep Maria

    2009-02-01

    Depressive disorders generate severe personal burden and high economic costs. Cost-utility analyses of the different therapeutical options are crucial to policy-makers and clinicians. Previous cost-utility studies, comparing selective serotonin reuptake inhibitors and tricyclic antidepressants, have used modelling techniques or have not included indirect costs in the economic analyses. To determine the cost-utility of fluoxetine compared with imipramine for treating depressive disorders in primary care. A 6-month randomized prospective naturalistic study comparing fluoxetine with imipramine was conducted in three primary care centres in Spain. One hundred and three patients requiring antidepressant treatment for a DSM-IV depressive disorder were included in the study. Patients were randomized either to fluoxetine (53 patients) or to imipramine (50 patients) treatment. Patients were treated with antidepressants according to their general practitioner's usual clinical practice. Outcome measures were the quality of life tariff of the European Quality of Life Questionnaire: EuroQoL-5D (five domains), direct costs, indirect costs and total costs. Subjects were evaluated at the beginning of treatment and after 1, 3 and 6 months. Incremental cost-utility ratios (ICUR) were obtained. To address uncertainty in the ICUR's sampling distribution, non-parametric bootstrapping was carried out. Taking into account adjusted total costs and incremental quality of life gained, imipramine dominated fluoxetine with 81.5% of the bootstrap replications in the dominance quadrant. Imipramine seems to be a better cost-utility antidepressant option for treating depressive disorders in primary care.

  7. The effect of subchronic fluoxetine treatment on learning and memory in adolescent rats

    DEFF Research Database (Denmark)

    Sass, Amdi; Wörtwein, Gitta

    2012-01-01

    Selective serotonin re-uptake inhibitors are increasingly used for the treatment of adolescents with behavioural disorders. However, the effect of this class of drugs during this sensitive period of brain development has not been extensively investigated. In this study we examine the effect of su...... in dorsal dentate gyrus and subgranular zone in young adulthood. This calls for further studies examining the long-term effects of this class of antidepressants on adolescent brain development and behaviour....... of subchronic treatment with the selective serotonin re-uptake inhibitor, fluoxetine (10mg/kg/day, i.p.) throughout adolescence (postnatal day 28-60) on learning and memory in the rat. Learning and memory were assessed at two time points: during adolescence, while the animals were being treated with fluoxetine...... and in young adulthood, 40 days after the termination of fluoxetine treatment. Fluoxetine treated rats were compared to a saline injected control group with respect to spatial navigation in the water maze, object recognition and object-in-place recognition memory. Additionally open field behaviour was examined...

  8. Moderators of fluoxetine treatment response for children and adolescents with comorbid depression and substance use disorders.

    Science.gov (United States)

    Hirschtritt, Matthew E; Pagano, Maria E; Christian, Kelly M; McNamara, Nora K; Stansbrey, Robert J; Lingler, Jacqui; Faber, Jon E; Demeter, Christine A; Bedoya, Denise; Findling, Robert L

    2012-06-01

    Our recent 8-week, randomized, placebo-controlled trial of fluoxetine in adolescents (ages 12-17 years) with comorbid depression and substance use disorder (SUD) did not detect a significant antidepressant treatment effect. The purpose of this secondary analysis was to explore moderators of the effect of fluoxetine in this sample. Static moderators measured at baseline were depression chronicity and hopelessness severity; time-varying moderators measured at baseline and weekly during the 8-week trial period were alcohol and marijuana use severity. Treatment effects on depression outcomes were examined among moderating subgroups in random effects regression models. Subjects assigned to fluoxetine treatment with chronic depression at baseline (p = .04) or no more than moderate alcohol use during the trial (p = .04) showed significantly greater decline in depression symptoms in comparison to placebo-assigned subgroups. The current analysis suggests that youth with chronic depression and no more than moderate alcohol consumption are likely to respond better to treatment with fluoxetine compared with placebo than youth with transient depression and heavy alcohol use. Copyright © 2012 Elsevier Inc. All rights reserved.

  9. Inhibition of tryptophan - pyrrolase activity and elevation of brain tryptophan concentration by fluoxetine in rats

    International Nuclear Information System (INIS)

    Bano, S.; Sherkheli, M.A

    2003-01-01

    Objective: To investigate in-vitro as well as in-vivo effects of various doses of fluoxetine (SSRI) on tryptophan metabolism in rates. Results: In in-vitro (10 - 1000 mM) as well in-vivo (0.5 - 30 mg/kg body wt.) studies, fluoxetine showed a statistically significant inhibition of rat liver tryptophan pyrrolase (tryptophan-2,3-dioxygenase; EC 1.13.11.11) activity. Significant increases were noted at 10 and 30 mg/kg doses in brain, serum (total and free) and liver L-tryptophan concentrations. Similarly, serum non-esterified free fatty acids showed a significant increase at both doses. There was no effect on serum glucose and albumin concentrations. Conclusion: It is suggested that major mechanism of action of fluoxetine is that of elevating brain tryptophan concentration and hence 5-HT synthesis by increasing the availability of circulating tryptophan to the brain secondarily to inhibition of major tryptophan degrading enzyme, hepatic tryptophan pyrrolase. It is assumed that fluoxetine inhibits the binding of apoenzyme form of tryptophan pyrrolase with its cofactor haem. The results are discussed in relation to possible involvement of disturbed hepatic tryptophan metabolism in depressive illness. (author)

  10. FLUOXETINE INCREASES INSULIN ACTION IN OBESE NONDIABETIC AND IN OBESE NON-INSULIN-DEPENDENT DIABETIC INDIVIDUALS

    NARCIS (Netherlands)

    Potter van Loon, B. J.; Radder, J. K.; Froelich, M.; Krans, H. M.; Zwinderman, A. H.; Meinders, A. E.

    1992-01-01

    Insulin resistance contributes to the metabolic defects in non-insulin-dependent diabetes mellitus (NIDDM). Anorectic agents have been shown to improve insulin action in NIDDM, irrespective of weight reduction. The serotonin-reuptake inhibiting agent fluoxetine has recently been recognized as an

  11. Ecotoxicological assessments show sucralose and fluoxetine affect the aquatic plant, Lemna minor

    Energy Technology Data Exchange (ETDEWEB)

    Amy-Sagers, Cherisse; Reinhardt, Keith; Larson, Danelle M., E-mail: danellelarson77@gmail.com

    2017-04-15

    Highlights: • Sucralose increased leaf area and photosynthetic capacity of Lemna minor. • Sucralose increased δ {sup 13}C of Lemna, indicating substantial uptake and assimilation. • 100 μg/L-fluoxetine decreased Lemna minor growth and asexual reproduction. - Abstract: Pharmaceuticals and personal care products (PPCP) are prevalent in aquatic systems, yet the fate and impacts on aquatic plants needs quantification for many compounds. We measured and detected sucralose (an artificial sweetener), fluoxetine (an antidepressant), and other PPCP in the Portneuf River in Idaho, USA, where Lemna minor (an aquatic plant in the environment and used in ecotoxicology studies) naturally occurs. Sucralose was hypothesized to negatively affect photosynthesis and growth of L. minor because sucralose is a chlorinated molecule that may be toxic or unusable for plant metabolism. A priori hypotheses were not created for fluoxetine due to lack of previous studies examining its impacts on plants. We conducted laboratory ecotoxicological assessments for a large range of concentrations of sucralose and fluoxetine on L. minor physiology and photosynthetic function. Frond green leaf area, root length, growth rate, photosynthetic capacity, and plant carbon isotopic composition (discrimination relative to a standard; δ{sup 13}C) were measured among treatments ranging from 0 to 15000 nmol/L-sucralose and 0–323 nmol/L-fluoxetine. Contrary to our predictions, sucralose significantly increased green leaf area, photosynthetic capacity, and δ {sup 13}C of L. minor at environmentally relevant concentrations. The increase of δ {sup 13}C from sucralose amendments and an isotope-mixing model indicated substantial sucralose uptake and assimilation within the plant. Unlike humans who cannot break down and utilize sucralose, we documented that L. minor—a mixotrophic plant—can use sucralose as a sugar substitute to increase its green leaf area and photosynthetic capacity. Fluoxetine

  12. Ecotoxicological assessments show sucralose and fluoxetine affect the aquatic plant, Lemna minor

    International Nuclear Information System (INIS)

    Amy-Sagers, Cherisse; Reinhardt, Keith; Larson, Danelle M.

    2017-01-01

    Highlights: • Sucralose increased leaf area and photosynthetic capacity of Lemna minor. • Sucralose increased δ "1"3C of Lemna, indicating substantial uptake and assimilation. • 100 μg/L-fluoxetine decreased Lemna minor growth and asexual reproduction. - Abstract: Pharmaceuticals and personal care products (PPCP) are prevalent in aquatic systems, yet the fate and impacts on aquatic plants needs quantification for many compounds. We measured and detected sucralose (an artificial sweetener), fluoxetine (an antidepressant), and other PPCP in the Portneuf River in Idaho, USA, where Lemna minor (an aquatic plant in the environment and used in ecotoxicology studies) naturally occurs. Sucralose was hypothesized to negatively affect photosynthesis and growth of L. minor because sucralose is a chlorinated molecule that may be toxic or unusable for plant metabolism. A priori hypotheses were not created for fluoxetine due to lack of previous studies examining its impacts on plants. We conducted laboratory ecotoxicological assessments for a large range of concentrations of sucralose and fluoxetine on L. minor physiology and photosynthetic function. Frond green leaf area, root length, growth rate, photosynthetic capacity, and plant carbon isotopic composition (discrimination relative to a standard; δ"1"3C) were measured among treatments ranging from 0 to 15000 nmol/L-sucralose and 0–323 nmol/L-fluoxetine. Contrary to our predictions, sucralose significantly increased green leaf area, photosynthetic capacity, and δ "1"3C of L. minor at environmentally relevant concentrations. The increase of δ "1"3C from sucralose amendments and an isotope-mixing model indicated substantial sucralose uptake and assimilation within the plant. Unlike humans who cannot break down and utilize sucralose, we documented that L. minor—a mixotrophic plant—can use sucralose as a sugar substitute to increase its green leaf area and photosynthetic capacity. Fluoxetine significantly

  13. Differential Peripheral Proteomic Biosignature of Fluoxetine Response in a Mouse Model of Anxiety/Depression

    Directory of Open Access Journals (Sweden)

    Indira Mendez-David

    2017-08-01

    Full Text Available The incorporation of peripheral biomarkers in the treatment of major depressive disorders (MDD could improve the efficiency of treatments and increase remission rate. Peripheral blood mononuclear cells (PBMCs represent an attractive biological substrate allowing the identification of a drug response signature. Using a proteomic approach with high-resolution mass spectrometry, the present study aimed to identify a biosignature of antidepressant response (fluoxetine, a Selective Serotonin Reuptake Inhibitor in PBMCs in a mouse model of anxiety/depression. Following determination of an emotionality score, using complementary behavioral analysis of anxiety/depression across three different tests (Elevated Plus Maze, Novelty Suppressed Feeding, Splash Test, we showed that a 4-week corticosterone treatment (35 μg/ml, CORT model in C57BL/6NTac male mice induced an anxiety/depressive-like behavior. Then, chronic fluoxetine treatment (18 mg/kg/day for 28 days in the drinking water reduced corticosterone-induced increase in emotional behavior. However, among 46 fluoxetine-treated mice, only 30 of them presented a 50% decrease in emotionality score, defining fluoxetine responders (CORT/Flx-R. To determine a peripheral biological signature of fluoxetine response, proteomic analysis was performed from PBMCs isolated from the “most” affected corticosterone/vehicle (CORT/V, corticosterone/fluoxetine responders and non-responders (CORT/Flx-NR animals. In comparison to CORT/V, a total of 263 proteins were differently expressed after fluoxetine exposure. Expression profile of these proteins showed a strong similarity between CORT/Flx-R and CORT/Flx-NR (R = 0.827, p < 1e-7. Direct comparison of CORT/Flx-R and CORT/Flx-NR groups revealed 100 differently expressed proteins, representing a combination of markers associated either with the maintenance of animals in a refractory state, or associated with behavioral improvement. Finally, 19 proteins showed a

  14. Sub-chronic exposure to fluoxetine in juvenile oysters (Crassostrea gigas): uptake and biological effects.

    Science.gov (United States)

    Di Poi, Carole; Evariste, Lauris; Séguin, Alexis; Mottier, Antoine; Pedelucq, Julie; Lebel, Jean-Marc; Serpentini, Antoine; Budzinski, Hélène; Costil, Katherine

    2016-03-01

    The bioconcentration potential of fluoxetine (FLX) and its biological effects were investigated in juvenile Pacific oyster exposed for 28 days to environmentally relevant concentrations of FLX (1 ng L(-1), 100 ng L(-1) and up to 10 μg L(-1)). FLX bioaccumulated in oyster flesh resulting in 28-day bioconcentration factors greater than 2,000 and 10,000 by referring to wet and dry weights, respectively. Nevertheless, FLX did not induce oyster mortality, delayed gametogenesis, or lead to adverse histopathological alterations. At the two highest concentrations, despite non-optimal trophic conditions, FLX stimulated shell growth but only in a transient manner, suggesting a role of serotonin in the regulation of feeding and metabolism in bivalves. Those high concentrations seemed to drive bell-shaped responses of catalase and glutathione S-transferase activities throughout the exposure period, which may indicate the activation of antioxidant enzyme synthesis and then an enhanced catabolic rate or direct inhibition of those enzymes. However, no clear oxidative stress was detected because no strong differences in thiobarbituric acid-reactive substance (TBARS) content (i.e. lipid peroxidation) were observed between oyster groups, suggesting that cellular defence mechanisms were effective. These results demonstrate the importance of considering additional biomarkers of oxidative stress to obtain a comprehensive overview of the FLX-induced changes in marine bivalves exposed under realistic conditions. Considering the battery of biomarkers used, FLX appears to induce little or no effects on oyster physiology even at a concentration of 10 μg L(-1). These results do not confirm the lowest observed effect concentration (LOEC) values reported by some authors in other mollusc species.

  15. Effects of Fluoxetine on Neural Functional Prognosis after Ischemic Stroke: A Randomized Controlled Study in China.

    Science.gov (United States)

    He, Yi-Tao; Tang, Bing-Shan; Cai, Zhi-Li; Zeng, Si-Ling; Jiang, Xin; Guo, Yi

    2016-04-01

    We investigated the effects of fluoxetine on the short-term and long-term neural functional prognoses after ischemic stroke. In this prospective randomized controlled single-blind clinical study in China, eligible patients afflicted with ischemic stroke were randomized into control and treatment groups. Patients in the treatment group received fluoxetine in addition to the basic therapies in the control group over a period of 90 days. The follow-up period was 180 days. We evaluated the effects of fluoxetine on the National Institutes of Health Stroke Scale (NIHSS) score and Barthel Index (BI) score after ischemic stroke through single- and multiple-factor analysis. The mean NIHSS score on day 180 after treatment was significantly lower in the treatment group than in the control group (P = .009). The mean BI scores on days 90 and 180 were significantly higher in the treatment group (P = .026) than in the control group (P = .011). The improvements in the NIHSS and BI scores on days 90 and 180 compared with baseline in the treatment group were all significantly greater than that in the control group (P = .033, P = .013, P = .013, P = .019, respectively). Treatment with fluoxetine was an independent factor affecting the NIHSS and BI scores on day 180 after treatment. Treatment with fluoxetine for 90 days after ischemic stroke can improve the long-term neural functional outcomes. Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  16. Technetium-99m DTPA inhalation scintigraphy in patients treated with fluoxetine and maprotiline: preliminary results

    International Nuclear Information System (INIS)

    Kaya, G.C.; Durak, H.; Oezdogan, Oe.; Sayit, E.; Degirmenci, B.; Derebek, E.

    2000-01-01

    Drug-metabolising enzymatic activities have been detected in tracheobronchiolar, bronchiolar and alveolar regions in the lungs. Induction of phospholipidosis by amine drugs such as clorphentermine has also been shown. This study aimed to investigate the effect of fluoxetine and maprotiline, which contain amine groups in their structure, on pulmonary epithelial membrane permeability. Twenty-seven patients (mean age 36±12 years) with various psychiatric problems, of whom 17 were treated with fluoxetine and 10 with maprotiline, were included in this study. Technetium-99m diethylene triamine penta-acetic acid (DTPA) aerosol inhalation scintigraphy was performed before and after 4-6 weeks of therapy. Following the inhalation of 1480 MBq 99m Tc-DTPA for 3 min, lung images in a 64 x 64 matrix were obtained every minute for 30 min. Regions of interest were drawn around the periphery of the lungs and on the major airways. Clearance half-times (T 1/2 ) were calculated by placing a mono-exponential fit on the curves. Penetration index (PI) was calculated on the first-minute image. There was no difference between the clearance rates of 99m Tc-DTPA before and after therapy for either the fluoxetine or the maprotiline group. After therapy, a significant decrease in PI was found in patients treated with fluoxetine (PI values before and after therapy: 0.53±0.03 and 0.49±0.05 respectively, P≤0.05). This finding might have been due to the induction of increased synaptic serotonin (5-HT) by fluoxetine, which acts by inhibiting the re-uptake of 5-HT on presynaptic membranes. Bronchoconstriction of small and medium airways may be caused by direct and indirect effects of 5-HT on smooth muscle contraction. (orig.)

  17. Fluoxetine Regulates Neurogenesis In Vitro Through Modulation of GSK-3β/β-Catenin Signaling

    Science.gov (United States)

    Hui, Jiaojie; Zhang, Jianping; Kim, Hoon; Tong, Chang; Ying, Qilong; Li, Zaiwang; Mao, Xuqiang; Shi, Guofeng; Yan, Jie; Zhang, Zhijun

    2015-01-01

    Background: It is generally accepted that chronic treatment with antidepressants increases hippocampal neurogenesis, but the molecular mechanisms underlying their effects are unknown. Recently, glycogen synthase kinase-3 beta (GSK-3β)/β-catenin signaling was shown to be involved in the mechanism of how antidepressants might influence hippocampal neurogenesis. Methods: The aim of this study was to determine whether GSK-3β/β-catenin signaling is involved in the alteration of neurogenesis as a result of treatment with fluoxetine, a selective serotonin reuptake inhibitor. The mechanisms involved in fluoxetine’s regulation of GSK-3β/β-catenin signaling pathway were also examined. Results: Our results demonstrated that fluoxetine increased the proliferation of embryonic neural precursor cells (NPCs) by up-regulating the phosphorylation of Ser9 on GSK-3β and increasing the level of nuclear β-catenin. The overexpression of a stabilized β-catenin protein (ΔN89 β-catenin) significantly increased NPC proliferation, while inhibition of β-catenin expression in NPCs led to a significant decrease in the proliferation and reduced the proliferative effects induced by fluoxetine. The effects of fluoxetine-induced up-regulation of both phosphorylation of Ser9 on GSK-3β and nuclear β-catenin were significantly prevented by the 5-hydroxytryptamine-1A (5-HT1A) receptor antagonist WAY-100635. Conclusions: The results demonstrate that fluoxetine may increase neurogenesis via the GSK-3β/β-catenin signaling pathway that links postsynaptic 5-HT1A receptor activation. PMID:25522429

  18. Technetium-99m DTPA inhalation scintigraphy in patients treated with fluoxetine and maprotiline: preliminary results

    Energy Technology Data Exchange (ETDEWEB)

    Kaya, G.C.; Durak, H.; Oezdogan, Oe.; Sayit, E.; Degirmenci, B.; Derebek, E. [Dokuz Eyluel Univ., Izmir (Turkey). School of Medicine; Yemez, B.; Turhal, Ue. [Dept. of Psychiatry, Dokuz Eylul Univ. School of Medicine, Izmir (Turkey)

    2000-09-01

    Drug-metabolising enzymatic activities have been detected in tracheobronchiolar, bronchiolar and alveolar regions in the lungs. Induction of phospholipidosis by amine drugs such as clorphentermine has also been shown. This study aimed to investigate the effect of fluoxetine and maprotiline, which contain amine groups in their structure, on pulmonary epithelial membrane permeability. Twenty-seven patients (mean age 36{+-}12 years) with various psychiatric problems, of whom 17 were treated with fluoxetine and 10 with maprotiline, were included in this study. Technetium-99m diethylene triamine penta-acetic acid (DTPA) aerosol inhalation scintigraphy was performed before and after 4-6 weeks of therapy. Following the inhalation of 1480 MBq {sup 99m}Tc-DTPA for 3 min, lung images in a 64 x 64 matrix were obtained every minute for 30 min. Regions of interest were drawn around the periphery of the lungs and on the major airways. Clearance half-times (T{sub 1/2}) were calculated by placing a mono-exponential fit on the curves. Penetration index (PI) was calculated on the first-minute image. There was no difference between the clearance rates of {sup 99m}Tc-DTPA before and after therapy for either the fluoxetine or the maprotiline group. After therapy, a significant decrease in PI was found in patients treated with fluoxetine (PI values before and after therapy: 0.53{+-}0.03 and 0.49{+-}0.05 respectively, P{<=}0.05). This finding might have been due to the induction of increased synaptic serotonin (5-HT) by fluoxetine, which acts by inhibiting the re-uptake of 5-HT on presynaptic membranes. Bronchoconstriction of small and medium airways may be caused by direct and indirect effects of 5-HT on smooth muscle contraction. (orig.)

  19. Biochemical and locomotor responses of Carcinus maenas exposed to the serotonin reuptake inhibitor fluoxetine.

    Science.gov (United States)

    Mesquita, Sofia Raquel; Guilhermino, Lúcia; Guimarães, Laura

    2011-10-01

    The aim of this study was to assess the effects of the widely used anti-depressant fluoxetine on behaviour (locomotion), moulting, neuromuscular transmission, energy production and anti-oxidant defences' efficiency of the epibenthic crab Carcinus maenas. Crabs were individually exposed to fluoxetine concentrations for 7d. Effects on locomotion were assessed at the end of the exposure using an open field test adapted to C. maenas in the present study. Tissue samples were later collected to evaluate fluoxetine effects on physiological functions using the activity of key enzymes and other parameters as biomarkers, namely: N-acetyl-β-glucosaminidase (NAGase) in the epidermis (moulting) and the hepatopancreas; cholinesterases (ChE) in muscle (neuromuscular cholinergic transmission); NADP(+)-dependent isocitrate dehydrogenase (IDH) and lactate dehydrogenease (LDH) in muscle (energy production); glutathione S-transferases (GST) in hepatopancreas (biotransformation and oxidative stress system); glutathione reductase (GR), and glutathione peroxidade (GPx), total glutathione levels (TG) and lipid peroxidation levels in the hepatopancreas (anti-oxidant defences and oxidative damage). Because no information on C. maenas NAGase activity was previously available, its variation during the moult cycle was also investigated. The results showed that locomotion was significantly increased at fluoxetine concentrations equal or above 120 μg L⁻¹, with animals spending more time moving, walking longer distances than controls. Levels of NAGase activity were found to vary in relation to C. maenas moult cycle, but no alterations were observed after exposure to fluoxetine. Significant increases in the activity of ChE, GST and GR enzymes, and the levels of TG were found, with a lowest observed effect concentration (LOEC) of 120 μg L⁻¹. Effects on locomotion were significantly and positively correlated to those induced on ChE activity. The results raise concern when hypothesising

  20. Effects of serotonin and fluoxetine on blood glucose regulation in two decapod species

    Directory of Open Access Journals (Sweden)

    Santos E.A.

    2001-01-01

    Full Text Available One of the best known crustacean hormones is the crustacean hyperglycemic hormone (CHH. However, the mechanisms involved in hormone release in these animals are poorly understood, and thus constitute the central objective of the present study. Different groups of crustaceans belonging to diverse taxa (Chasmagnathus granulata, a grapsid crab and Orconectes limosus, an astacid were injected with serotonin, fluoxetine, or a mixture of both, and glycemic values (C. granulata and O. limosus and CHH levels (O. limosus were determined after 2 h in either submerged animals or animals exposed to atmospheric air. Both serotonin and fluoxetine caused significant hyperglycemia (P<0.05 after injection into the blood sinus of the two species, an effect enhanced after exposure to atmospheric air. In C. granulata blood glucose increased from 6.1 to 43.3 and 11.4 mg/100 ml in submerged animals and from 5.7 to 55.2 and 22.5 mg/100 ml in air-exposed animals after treatment with serotonin and fluoxetine, respectively. In O. limosus the increases were from 1.2 to 59.7 and 135.2 mg/100 ml in submerged animals and from 2.5 to 200.3 and 193.6 mg/100 ml in air-exposed animals after treatment with serotonin and fluoxetine, respectively. Serotonin and fluoxetine also caused a significant increase in the circulating levels of CHH in O. limosus, from 11.9 to 43 and 45.7 fmol/ml in submerged animals and from 13.2 to 32.6 and 45.7 fmol/ml in air-exposed animals, respectively, thus confirming their action as neuroregulators in these invertebrates.

  1. Fluoxetine increases suicide ideation less than placebo during treatment of adults with minor depressive disorder.

    Science.gov (United States)

    Garlow, Steven J; Kinkead, Becky; Thase, Michael E; Judd, Lewis L; Rush, A John; Yonkers, Kimberly A; Kupfer, David J; Frank, Ellen; Schettler, Pamela J; Rapaport, Mark Hyman

    2013-09-01

    Some reports suggest an increase in suicide ideations and behaviors in patients treated with antidepressants. This is an analysis of the impact of fluoxetine on suicide ideations in outpatients with minor depressive disorder. Research subjects were adult outpatients with minor depressive disorder (N = 162), who received fluoxetine or placebo in a prospective, 12-week, double-blind randomized trial. The research participants were evaluated weekly with standard rating scales that included four suicide-related items: item 3 of the Hamilton Rating Scale for Depression (HRSD), item 18 of Inventory of Depressive Symptomatology (IDS-C), and items 15 and 59 of the Hopkins Symptom Checklist (SCL-90). Clinically significant intensification of suicide ideation was defined as an increase of ≥2 points on any of these items. Overall 60/162 subjects (37%) had an increase of ≥1 point during treatment and 17/162 (10.5%) of ≥2 points on at least one suicide item, with 12/81 (14.8%) placebo and 5/81 (6.2%) fluoxetine-treated subjects having a ≥2 point gain. Of the study participants with baseline suicide ideation, 9/22 (40.9%) placebo and 3/24 (12.5%) fluoxetine treated had ≥2 point increase (p = 0.04). Survival analysis revealed that subjects on placebo were significantly more likely (p = 0.050) to experience a ≥2 point increase on one or more item, a difference that emerged early and continued throughout the 12-week trial. Compared to placebo, fluoxetine was not associated with a clinically significant increase in suicide ideation among adults with minor depressive disorder during 12 weeks of treatment. Copyright © 2013 Elsevier Ltd. All rights reserved.

  2. Impact of inhalational exposure to ethanol fuel on the pharmacokinetics of verapamil, ibuprofen and fluoxetine as in vivo probe drugs for CYP3A, CYP2C and CYP2D in rats.

    Science.gov (United States)

    Cardoso, Juciane Lauren Cavalcanti; Lanchote, Vera Lucia; Pereira, Maria Paula Marques; Capela, Jorge Manuel Vieira; de Moraes, Natália Valadares; Lepera, José Salvador

    2015-10-01

    Occupational toxicology and clinical pharmacology integration will be useful to understand potential exposure-drug interaction and to shape risk assessment strategies in order to improve occupational health. The aim of the present study was to evaluate the effect of exposure to ethanol fuel on in vivo activities of cytochrome P450 (CYP) isoenzymes CYP3A, CYP2C and CYP2D by the oral administration of the probe drugs verapamil, ibuprofen and fluoxetine. Male Wistar rats exposed to filtered air or to 2000 ppm ethanol in a nose-only inhalation chamber during (6 h/day, 5 days/week, 6 weeks) received single oral doses of 10 mg/kg verapamil or 25 mg/kg ibuprofen or 10 mg/kg fluoxetine. The enantiomers of verapamil, norverapamil, ibuprofen and fluoxetine in plasma were analyzed by LC-MS/MS. The area under the curve plasma concentration versus time extrapolated to infinity (AUC(0-∞)) was calculated using the Gauss-Laguerre quadrature. Inhalation exposure to ethanol reduces the AUC of both verapamil (approximately 2.7 fold) and norverapamil enantiomers (>2.5 fold), reduces the AUC(0-∞) of (+)-(S)-IBU (approximately 2 fold) and inhibits preferentially the metabolism of (-)-(R)-FLU. In conclusion, inhalation exposure of ethanol at a concentration of 2 TLV-STEL (6 h/day for 6 weeks) induces CYP3A and CYP2C but inhibits CYP2D in rats. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. Anti-inflammatory and ameliorative effects of gallic acid on fluoxetine-induced oxidative stress and liver damage in rats.

    Science.gov (United States)

    Karimi-Khouzani, Omid; Heidarian, Esfandiar; Amini, Sayed Asadollah

    2017-08-01

    Fluoxetine-induced liver damage is a cause of chronic liver disease. In the present study the hepatoprotective effects of gallic acid against fluoxetine-induced liver damage were examined. Forty-eight male rats were divided into six groups as follow: group 1, the control group; group 2, rats receiving fluoxetine (24mg/kg bw daily, po) without treatment; group 3, rats receiving 24mg/kg bw fluoxetine, treated with 50mg/kg bw silymarin and groups 4, 5, and 6 in which gallic acid (50, 100, and 200mg/kg bw, po, respectively) was prescribed after the consumption of fluoxetine. The histopathological changes of hepatic tissues were checked out. Fluoxetine caused a significant increase in the levels of serum glutamate oxaloacetate transaminase (GOT), serum glutamate pyruvate transaminase (GPT), lipid profiles, urea, fasting blood sugar (FBS), creatinine (Cr), protein carbonyl (PC) content, malondialdehyde (MDA), and liver TNF-α as an inflammatory element. Also, the obtained results of group 2 revealed a significant decline in ferric reducing ability of plasma (FRAP), liver catalase (CAT), superoxide dismutase (SOD), and vitamin C levels. The treatment with gallic acid showed significant ameliorations in abnormalities of fluoxetine-induced liver injury as represented by the improvement of hepatic CAT, SOD activities, vitamin C levels, serum biochemical parameters, and histopathological changes, in addition to the recovery of antioxidant defense system status. Gallic acid has inhibitory effects on fluoxetine-induced liver damage. The effect of gallic acid is derived from free radical scavenging properties and the anti-inflammatory effect related to TNF-α. Copyright © 2017. Published by Elsevier Urban & Partner Sp. z o.o.

  4. Total synthesis of fluoxetine and duloxetine through an in situ imine formation/borylation/transimination and reduction approach.

    Science.gov (United States)

    Calow, Adam D J; Fernández, Elena; Whiting, Andrew

    2014-08-28

    We report efficient, catalytic, asymmetric total syntheses of both (R)-fluoxetine and (S)-duloxetine from α,β-unsaturated aldehydes conducting five sequential one-pot steps (imine formation/copper mediated β-borylation/transimination/reduction/oxidation) followed by the specific ether group formation which deliver the desired products (R)-fluoxetine in 45% yield (96% ee) and (S)-duloxetine in 47% yield (94% ee).

  5. Predictors of Treatment Response to Fluoxetine in PTSD Following a Recent History of War Zone Stress Exposure

    Science.gov (United States)

    2013-07-01

    Purchase of the fluoxetine and gelatin capsules from VA pharmacy suppliers (purchased each 3 months throughout the first 15 months of the study...Over-encapsulation of fluoxetine and empty gelatin capsules by CTVHCS Pharmacy staff  Transfer of medications prepared by the CTVHCS Pharmacy directly...after non---progressive acquired brain injury. A systematic review. Clin Rehabil 2010;24:110---21. 222. Arciniegas DB, Silver JM. Pharmacotherapy of

  6. Sleep disturbance as detected by actigraphy in pre-pubertal juvenile monkeys receiving therapeutic doses of fluoxetine.

    Science.gov (United States)

    Golub, Mari S; Hogrefe, Casey E

    2016-01-01

    Sleep disturbance is a reported side effect of antidepressant drugs in children. Using a nonhuman primate model of childhood selective serotonin reuptake inhibitor (SSRI) therapy, sleep was studied quantitatively with actigraphy. Two 48-h sessions were recorded in the home cage environment of juvenile male rhesus monkeys at two and three years of age, after one and two years of treatment with a therapeutic dose of the SSRI fluoxetine, and compared to vehicle treated controls. A third session was conducted one year after discontinuation of treatment at four years of age. During treatment, the fluoxetine group demonstrated sleep fragmentation as indexed by a greater number of rest-activity transitions compared to controls. In addition fluoxetine led to more inactivity during the day as indexed by longer duration of rest periods and the reduced activity during these periods. The fluoxetine effect on sleep fragmentation, but not on daytime rest, was modified by the monkey's genotype for polymorphisms of monoamine oxidase A (MAOA), an enzyme that metabolizes serotonin. After treatment, the fluoxetine effect on nighttime rest-activity transitions persisted, but daytime activity was not affected. The demonstration in this nonhuman primate model of sleep disturbance in connection with fluoxetine treatment and specific genetic polymorphisms, and in the absence of diagnosed psychopathology, can help inform use of this drug in children. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. The expression of HoxB5 and SPC in neonatal rat lung after exposure to fluoxetine.

    Science.gov (United States)

    Taghizadeh, Razieh; Taghipour, Zahra; Karimi, Akbar; Shamsizadeh, Ali; Taghavi, Mohammad Mohsen; Shariati, Mahdi; Shabanizadeh, Ahmad; Jafari Naveh, Hamid Reza; Bidaki, Reza; Aminzadeh, Fariba

    2016-01-01

    Approximately 10% of pregnant women suffer from pregnancy-associated depression. Fluoxetine, as a selective serotonin reuptake inhibitor, is being employed as a therapy for depressive disorders. The present study aimed to determine the effects of fluoxetine on neonatal lung development. Thirty pregnant Wistar rats (weighing 200-250 g) were treated daily with 7 mg/kg fluoxetine from gestation day 0 to gestation day 21, via gavage. The control group received a similar volume of distilled water only. Following delivery, the newborns and their lungs were immediately weighed in both of the groups. The right lung was fixed for histological assessments while the left lung was used for evaluation of the expression of SPC and HoxB5 by the real-time polymerase chain reaction method. Results have indicated that even though the body weight and the number of neonatal rats in both groups were the same, the lung weight of neonates exposed to fluoxetine was significantly different compared to the control group ( P fluoxetine treatment group morphologically appears to be similar to the pseudoglandular phase, whereas the control group lungs experienced more development. According to the upregulated expression of HoxB5 concerning histological findings, results of the present study showed that fluoxetine can influence lung growth and may in turn lead to delay in lung development. So establishment of studies to identify the effects of antidepressant drugs during pregnancy is deserved.

  8. Effects of Fluoxetine and Visual Experience on Glutamatergic and GABAergic Synaptic Proteins in Adult Rat Visual Cortex123

    Science.gov (United States)

    Beshara, Simon; Beston, Brett R.; Pinto, Joshua G. A.

    2015-01-01

    Abstract Fluoxetine has emerged as a novel treatment for persistent amblyopia because in adult animals it reinstates critical period-like ocular dominance plasticity and promotes recovery of visual acuity. Translation of these results from animal models to the clinic, however, has been challenging because of the lack of understanding of how this selective serotonin reuptake inhibitor affects glutamatergic and GABAergic synaptic mechanisms that are essential for experience-dependent plasticity. An appealing hypothesis is that fluoxetine recreates a critical period (CP)-like state by shifting synaptic mechanisms to be more juvenile. To test this we studied the effect of fluoxetine treatment in adult rats, alone or in combination with visual deprivation [monocular deprivation (MD)], on a set of highly conserved presynaptic and postsynaptic proteins (synapsin, synaptophysin, VGLUT1, VGAT, PSD-95, gephyrin, GluN1, GluA2, GluN2B, GluN2A, GABAAα1, GABAAα3). We did not find evidence that fluoxetine shifted the protein amounts or balances to a CP-like state. Instead, it drove the balances in favor of the more mature subunits (GluN2A, GABAAα1). In addition, when fluoxetine was paired with MD it created a neuroprotective-like environment by normalizing the glutamatergic gain found in adult MDs. Together, our results suggest that fluoxetine treatment creates a novel synaptic environment dominated by GluN2A- and GABAAα1-dependent plasticity. PMID:26730408

  9. Effect of fluoxetine on the pharmacokinetics of lansoprazole: a two-treatment period study in healthy male subjects.

    Science.gov (United States)

    Vlase, Laurian; Popa, Adina; Neag, Maria; Muntean, Dana; Leucuta, Sorin E

    2011-10-01

    Fluoxetine is an inhibitor of the main metabolizing enzymes of lansoprazole and could influence the pharmacokinetics of lansoprazole. The changes in lansoprazole pharmacokinetics could have clinical significance concerning the safety of the therapy. The aim of this study was to evaluate the pharmacokinetic interaction between fluoxetine and lansoprazole in healthy subjects. A dose of lansoprazole 30 mg, alone or in combination with fluoxetine 60 mg, was administered to 18 healthy male subjects in a two-treatment study design, separated by an 8-day period in which fluoxetine alone was administered as a single oral daily dose. Plasma concentrations of lansoprazole were determined during a 12-hour period following drug administration. Lansoprazole plasma concentrations were determined by a validated liquid chromatography-mass spectrometry method. The pharmacokinetic parameters of lansoprazole were calculated using non-compartmental analysis. In the two periods of treatment, the mean maximum plasma concentration (C(max)) values were 817 ng/mL (lansoprazole alone) and 1370 ng/mL (lansoprazole in combination with fluoxetine after pre-treatment with fluoxetine for 8 days) [p lansoprazole and suggest that the observed interaction may be clinically significant, although its clinical relevance has yet to be confirmed.

  10. Duloxetine compared with fluoxetine and venlafaxine: use of meta-regression analysis for indirect comparisons

    Directory of Open Access Journals (Sweden)

    Lançon Christophe

    2006-07-01

    Full Text Available Abstract Background Data comparing duloxetine with existing antidepressant treatments is limited. A comparison of duloxetine with fluoxetine has been performed but no comparison with venlafaxine, the other antidepressant in the same therapeutic class with a significant market share, has been undertaken. In the absence of relevant data to assess the place that duloxetine should occupy in the therapeutic arsenal, indirect comparisons are the most rigorous way to go. We conducted a systematic review of the efficacy of duloxetine, fluoxetine and venlafaxine versus placebo in the treatment of Major Depressive Disorder (MDD, and performed indirect comparisons through meta-regressions. Methods The bibliography of the Agency for Health Care Policy and Research and the CENTRAL, Medline, and Embase databases were interrogated using advanced search strategies based on a combination of text and index terms. The search focused on randomized placebo-controlled clinical trials involving adult patients treated for acute phase Major Depressive Disorder. All outcomes were derived to take account for varying placebo responses throughout studies. Primary outcome was treatment efficacy as measured by Hedge's g effect size. Secondary outcomes were response and dropout rates as measured by log odds ratios. Meta-regressions were run to indirectly compare the drugs. Sensitivity analysis, assessing the influence of individual studies over the results, and the influence of patients' characteristics were run. Results 22 studies involving fluoxetine, 9 involving duloxetine and 8 involving venlafaxine were selected. Using indirect comparison methodology, estimated effect sizes for efficacy compared with duloxetine were 0.11 [-0.14;0.36] for fluoxetine and 0.22 [0.06;0.38] for venlafaxine. Response log odds ratios were -0.21 [-0.44;0.03], 0.70 [0.26;1.14]. Dropout log odds ratios were -0.02 [-0.33;0.29], 0.21 [-0.13;0.55]. Sensitivity analyses showed that results were

  11. Ecotoxicological assessments show sucralose and fluoxetine affect the aquatic plant, Lemna minor.

    Science.gov (United States)

    Amy-Sagers, Cherisse; Reinhardt, Keith; Larson, Danelle M

    2017-04-01

    Pharmaceuticals and personal care products (PPCP) are prevalent in aquatic systems, yet the fate and impacts on aquatic plants needs quantification for many compounds. We measured and detected sucralose (an artificial sweetener), fluoxetine (an antidepressant), and other PPCP in the Portneuf River in Idaho, USA, where Lemna minor (an aquatic plant in the environment and used in ecotoxicology studies) naturally occurs. Sucralose was hypothesized to negatively affect photosynthesis and growth of L. minor because sucralose is a chlorinated molecule that may be toxic or unusable for plant metabolism. A priori hypotheses were not created for fluoxetine due to lack of previous studies examining its impacts on plants. We conducted laboratory ecotoxicological assessments for a large range of concentrations of sucralose and fluoxetine on L. minor physiology and photosynthetic function. Frond green leaf area, root length, growth rate, photosynthetic capacity, and plant carbon isotopic composition (discrimination relative to a standard; δ 13 C) were measured among treatments ranging from 0 to 15000nmol/L-sucralose and 0-323nmol/L-fluoxetine. Contrary to our predictions, sucralose significantly increased green leaf area, photosynthetic capacity, and δ 13 C of L. minor at environmentally relevant concentrations. The increase of δ 13 C from sucralose amendments and an isotope-mixing model indicated substantial sucralose uptake and assimilation within the plant. Unlike humans who cannot break down and utilize sucralose, we documented that L. minor-a mixotrophic plant-can use sucralose as a sugar substitute to increase its green leaf area and photosynthetic capacity. Fluoxetine significantly decreased L. minor root growth, daily growth rate, and asexual reproduction at 323nmol/L-fluoxetine; however, ambiguity remains regarding the mechanisms responsible and the applicability of these extreme concentrations unprecedented in the natural environment. To our knowledge, this was the

  12. Postnatal development of rats exposed to fluoxetine or venlafaxine during the third week of pregnancy

    Directory of Open Access Journals (Sweden)

    V.A. da-Silva

    1999-01-01

    Full Text Available The aim of the present study was to compare the toxic effects of fluoxetine (F (8 and 16 mg/kg and venlafaxine (V (40 and 80 mg/kg administered during the third week of pregnancy on early development of rats. Both antidepressants were administered by gavage on pregnancy days 15 to 20 to groups of 10 to 12 animals each. Duration of gestation, food and water consumption, number of live pups and birth weight were recorded. Litters were culled to six pups at birth (day 1 and followed for growth until weaning (day 25. On day 60, a male and a female from each litter were injected with the 5-HT1 agonist, 5-methoxy-N,N-dimethyltryptamine (6 mg/kg, ip and the serotonergic syndrome was graded. Fluoxetine but not venlafaxine reduced the duration of pregnancy when compared to the control (C group (F = 21.1 days and C = 21.6 days, mean, P<0.02; maximum = 22 days and minimum = 21 days in both groups. The highest doses of both fluoxetine, 16 mg/kg (F16, and venlafaxine, 80 mg/kg (V80, reduced the food intake of pregnant rats, resulting in different rates of body weight gain during treatment (from pregnancy day 15 to day 20: F16 = 29.0 g, V80 = 28.7 g vs C = 39.5 g (median. Birth weight was influenced by treatment and sex (P<0.05; two-way ANOVA. Both doses of fluoxetine or venlafaxine reduced the body weight of litters; however, the body weight of litters from treated dams was equal to the weight of control litters by the time of weaning. At weaning there was no significant difference in weight between sexes. There was no difference among groups in number of live pups at birth, stillbirths, mortality during the lactation period or in the manifestation of serotonergic syndrome in adult rats. The occurrence of low birth weight among pups born to dams which did not show reduced food ingestion or reduction of body weight gain during treatment with lower doses of fluoxetine or venlafaxine suggests that these drugs may have a deleterious effect on prenatal

  13. Evaluation of the binding of the radiolabeled antidepressant drug, {sup 18}F-fluoxetine in the rodent brain: an in vitro and in vivo study

    Energy Technology Data Exchange (ETDEWEB)

    Mukherjee, Jogeshwar E-mail: jogeshwar_mukherjee@ketthealth.com; Das, Malay K.; Yang Zhiying; Lew, Robert

    1998-10-01

    We have developed {sup 18}F-fluoxetine as a radiotracer analog of the antidepressant drug fluoxetine (Prozac). In vitro saturation experiments of {sup 18}F-fluoxetine were carried out on rat midbrain tissue and citalopram was used for measuring nonspecific binding. A saturation curve for the binding of {sup 18}F-fluoxetine was not obtained. Even when fluoxetine (10 {mu}M) was used for measurements of nonspecific binding, a saturation curve was difficult to obtain. Other compounds, such as deprenyl, clorgyline, amphetamine, and reserpine were also not able to reduce the binding of {sup 18}F-fluoxetine. Ex vivo autoradiographic experiments with {sup 18}F-fluoxetine did not reveal any specific uptake in various brain regions. In vivo administration of {sup 18}F-fluoxetine in rats showed similar uptake in all the brain regions with little regional selectivity. A subcellular analysis of rat brain tissue after intravenous (IV) administration of {sup 18}F-fluoxetine indicated significant amounts of binding in mitochondria and synaptosomes. In summary, in vitro experiments with {sup 18}F-fluoxetine indicate little specific binding. Binding to the serotonin transporter was not identifiable. High nonspecific binding of the tracer resulting from its subcellular nature in the brain masks the ability to detect binding to the serotonin uptake sites in vivo. These findings indicate that a large portion of the binding of {sup 18}F-fluoxetine in rat brains is subcellular and clears slowly out of the cells. Other sites, such as monoamine oxidase, may also play a significant role in the action of fluoxetine.

  14. Evaluation of the binding of the radiolabeled antidepressant drug, 18F-fluoxetine in the rodent brain: an in vitro and in vivo study

    International Nuclear Information System (INIS)

    Mukherjee, Jogeshwar; Das, Malay K.; Yang Zhiying; Lew, Robert

    1998-01-01

    We have developed 18 F-fluoxetine as a radiotracer analog of the antidepressant drug fluoxetine (Prozac). In vitro saturation experiments of 18 F-fluoxetine were carried out on rat midbrain tissue and citalopram was used for measuring nonspecific binding. A saturation curve for the binding of 18 F-fluoxetine was not obtained. Even when fluoxetine (10 μM) was used for measurements of nonspecific binding, a saturation curve was difficult to obtain. Other compounds, such as deprenyl, clorgyline, amphetamine, and reserpine were also not able to reduce the binding of 18 F-fluoxetine. Ex vivo autoradiographic experiments with 18 F-fluoxetine did not reveal any specific uptake in various brain regions. In vivo administration of 18 F-fluoxetine in rats showed similar uptake in all the brain regions with little regional selectivity. A subcellular analysis of rat brain tissue after intravenous (IV) administration of 18 F-fluoxetine indicated significant amounts of binding in mitochondria and synaptosomes. In summary, in vitro experiments with 18 F-fluoxetine indicate little specific binding. Binding to the serotonin transporter was not identifiable. High nonspecific binding of the tracer resulting from its subcellular nature in the brain masks the ability to detect binding to the serotonin uptake sites in vivo. These findings indicate that a large portion of the binding of 18 F-fluoxetine in rat brains is subcellular and clears slowly out of the cells. Other sites, such as monoamine oxidase, may also play a significant role in the action of fluoxetine

  15. Differential weight restoration on olanzapine versus fluoxetine in identical twins with anorexia nervosa.

    Science.gov (United States)

    Duvvuri, Vikas; Cromley, Taya; Klabunde, Megan; Boutelle, Kerri; Kaye, Walter H

    2012-03-01

    No studies have compared the response to selective serotonin reuptake inhibitors and atypical antipsychotics in anorexia nervosa. This case study examines such a comparison. This report describes a case of 12-year-old identical twins with anorexia nervosa, one of whom was treated with olanzapine and the other with fluoxetine, while undergoing family therapy. Twin A treated with fluoxetine went from 75 to 84.4% ideal body weight, while Twin B treated with olanzapine went from 72 to 99.9% ideal body weight over the course of 9 months. This case supports the need for adequately powered, controlled clinical trials to test the efficacy of olanzapine in adolescents presenting with anorexia nervosa. Copyright © 2011 Wiley Periodicals, Inc.

  16. Mitochondrial energy metabolism of rat hippocampus after treatment with the antidepressants desipramine and fluoxetine.

    Science.gov (United States)

    Villa, Roberto Federico; Ferrari, Federica; Bagini, Laura; Gorini, Antonella; Brunello, Nicoletta; Tascedda, Fabio

    2017-07-15

    Alterations in mitochondrial functions have been hypothesized to participate in the pathogenesis of depression, because brain bioenergetic abnormalities have been detected in depressed patients by neuroimaging in vivo studies. However, this hypothesis is not clearly demonstrated in experimental studies: some suggest that antidepressants are inhibitors of mitochondrial metabolism, while others observe the opposite. In this study, the effects of 21-day treatment with desipramine (15 mg/kg) and fluoxetine (10 mg/kg) were examined on the energy metabolism of rat hippocampus, evaluating the catalytic activity of regulatory enzymes of mitochondrial energy-yielding metabolic pathways. Because of the micro-heterogeneity of brain mitochondria, we have distinguished between (a) non-synaptic mitochondria (FM) of neuronal perikaryon (post-synaptic compartment) and (b) intra-synaptic light (LM) and heavy (HM) mitochondria (pre-synaptic compartment). Desipramine and fluoxetine changed the catalytic activity of specific enzymes in the different types of mitochondria: (a) in FM, both drugs enhanced cytochrome oxidase and glutamate dehydrogenase, (b) in LM, the overall bioenergetics was unaffected and (c) in HM only desipramine increased malate dehydrogenase and decreased the activities of Electron Transport Chain Complexes. These results integrate the pharmacodynamic features of desipramine and fluoxetine at subcellular level, overcoming the previous conflicting data about the effects of antidepressants on brain energy metabolism, mainly referred to whole brain homogenates or to bulk of cerebral mitochondria. With the differentiation in non-synaptic and intra-synaptic mitochondria, this study demonstrates that desipramine and fluoxetine lead to adjustments in the mitochondrial bioenergetics respect to the energy requirements of pre- and post-synaptic compartments. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. The possible protective effects of Fluoxetine and Paroxetine against experimental Myocardial infarction

    International Nuclear Information System (INIS)

    Assiri, Adel M.; Layla, E.; Awad, Hisham A.

    2003-01-01

    The study tested the hypothesis of decreased risk of acute myocardial infaraction (AMI) with selective serotonin reuptake inhibitors (SSRIs),Rat groups; G1:control, G2A,MI was introducedisoprenaline;G2B, MI was induced by LACA ligation. In G3(Fluoxetine) and G4(Paroxetine) the drugs were given daily for two weeks .In G5(Fluoxetine) and G6(Paroxetine), MI by isopernaline (5A and 6A )was induced in last two days , and MI by coronary ligation (5B and 6B) was induced at the end of two weeks.In each group,ECG tracing, test for platelet aggregation in response to ADP and collagen , biomarkers for MI and histopathological examination for hearts were done. Induction of MI resulted in elevation of ST segment, significant increase in the platelet aggregation, total serum CK, CK-MB,and troponin I. Fluxoetine (G3) and paroxetine (G4) resulted in significant reduction in platelet aggregation, slight decrease in heart rate,insignificant changes in biomarks and no abnormal histopathalogical alterations .Pretreatment with fluoxetine or paroxetine before induction of MI , resulted in the reduction of the elevated S-T segment , significant reduction in the tested platelet aggregation ,biomarkers, ischemia and infaraction areas . In conclusion ,it was demonstrated that fluoxetine and paroxetine ,were able to to produce protective effects in AMI groups ,which were represented by the significant reduction in the biomarkers of myocardial injury ,reduction in S-T segment elevation , and the percentage of the infarct surface area .This effect is probably attributed to the reduction in platelet activation and aggregation,which is an important factor in the pathophysiology of AMI. (author)

  18. Effect of fluoxetine on disease progression in a mouse model of ALS

    Science.gov (United States)

    Koschnitzky, J. E.; Quinlan, K. A.; Lukas, T. J.; Kajtaz, E.; Kocevar, E. J.; Mayers, W. F.; Siddique, T.

    2014-01-01

    Selective serotonin reuptake inhibitors (SSRIs) and other antidepressants are often prescribed to amyotrophic lateral sclerosis (ALS) patients; however, the impact of these prescriptions on ALS disease progression has not been systematically tested. To determine whether SSRIs impact disease progression, fluoxetine (Prozac, 5 or 10 mg/kg) was administered to mutant superoxide dismutase 1 (SOD1) mice during one of three age ranges: neonatal [postnatal day (P)5–11], adult presymptomatic (P30 to end stage), and adult symptomatic (P70 to end stage). Long-term adult fluoxetine treatment (started at either P30 or P70 and continuing until end stage) had no significant effect on disease progression. In contrast, neonatal fluoxetine treatment (P5-11) had two effects. First, all animals (mutant SOD1G93A and control: nontransgenic and SOD1WT) receiving the highest dose (10 mg/kg) had a sustained decrease in weight from P30 onward. Second, the high-dose SOD1G93A mice reached end stage ∼8 days (∼6% decrease in life span) sooner than vehicle and low-dose animals because of an increased rate of motor impairment. Fluoxetine increases synaptic serotonin (5-HT) levels, which is known to increase spinal motoneuron excitability. We confirmed that 5-HT increases spinal motoneuron excitability during this neonatal time period and therefore hypothesized that antagonizing 5-HT receptors during the same time period would improve disease outcome. However, cyproheptadine (1 or 5 mg/kg), a 5-HT receptor antagonist, had no effect on disease progression. These results show that a brief period of antidepressant treatment during a critical time window (the transition from neonatal to juvenile states) can be detrimental in ALS mouse models. PMID:24598527

  19. Sex-Specific Effects of Chronic Fluoxetine Treatment on Neuroplasticity and Pharmacokinetics in Mice

    OpenAIRE

    Hodes, Georgia E.; Hill-Smith, Tiffany E.; Suckow, Raymond F.; Cooper, Thomas B.; Lucki, Irwin

    2010-01-01

    Neurogenesis is a mechanism through which antidepressants may produce therapeutic effects. There is a dearth of information regarding the effects of antidepressants on neurogenesis and neurotrophin mobilization in females. This study examined sex differences in the alteration of cell proliferation and survival in multiple regions of the brain. Additional experiments examined brain-derived neurotrophic factor (BDNF) levels and pharmacokinetics of fluoxetine to determine whether they mediate se...

  20. Serotonergic mediation of the effects of fluoxetine, but not desipramine, in the rat forced swimming test.

    Science.gov (United States)

    Page, M E; Detke, M J; Dalvi, A; Kirby, L G; Lucki, I

    1999-11-01

    The forced swimming test (FST) is a behavioral test in rodents that predicts the clinical efficacy of many types of antidepressant treatments. Recently, a behavior sampling technique was developed that scores individual response categories, including swimming, climbing and immobility. Although all antidepressant drugs reduce immobility in the FST, at least two distinct active behavioral patterns are produced by pharmacologically selective antidepressant drugs. Serotonin-selective reuptake inhibitors increase swimming behavior, while drugs acting primarily to increase extracellular levels of norepinephrine or dopamine increase climbing behavior. Distinct patterns of active behaviors in the FST may be mediated by distinct neurotransmitters, but this has not been shown directly. The present study examined the role of serotonin in mediating active behaviors in the forced swimming test after treatment with two antidepressant drugs, the selective serotonin reuptake inhibitor, fluoxetine and the selective norepinephrine reuptake inhibitor, desipramine. Endogenous serotonin was depleted by administering para-cholorophenylalanine (PCPA, 150 mg/kg, IP.) to rats 72 h and 48 h prior to the swim test. Fluoxetine (10 mg/kg, SC) or desipramine (10 mg/kg, SC) was given three times over a 24-h period prior to the FST. Behavioral responses, including immobility, swimming and climbing, were counted during the 5-min test. Pretreatment with PCPA blocked fluoxetine-induced reduction in immobility and increase in swimming behavior during the FST. In contrast, PCPA pretreatment did not interfere with the ability of desipramine to reduce immobility and increase climbing behavior. Depletion of serotonin prevented the behavioral effects of the selective serotonin reuptake inhibitor fluoxetine in the rat FST. Furthermore, depletion of serotonin had no impact on the behavioral effects induced by the selective norepinephrine reuptake inhibitor, desipramine. The effects of antidepressant drugs

  1. Fluoxetine Alleviates Behavioral Depression while Decreasing Acetylcholine Release in the Nucleus Accumbens Shell

    OpenAIRE

    Chau, David T; Rada, Pedro V; Kim, Kay; Kosloff, Rebecca A; Hoebel, Bartley G

    2011-01-01

    Selective serotonin reuptake inhibitors, such as fluoxetine, have demonstrated the ability to alleviate behavioral depression in the forced swim test; however, the sites and mechanisms of their actions remain to be further elucidated. Previous studies have suggested that behavioral depression in the swim test is mediated in part by acetylcholine (ACh) stimulating the cholinergic M1 receptors in the nucleus accumbens (NAc) shell. The current study tested whether acute, local, and chronic, subc...

  2. A patient with coexisting narcolepsy and morbid jealousy showing favourable response to fluoxetine.

    Science.gov (United States)

    Wing, Y. K.; Lee, S.; Chiu, H. F.; Ho, C. K.; Chen, C. N.

    1994-01-01

    A 37 year old Chinese man suffered from coexisting narcolepsy and morbid jealousy which were precipitated by head injury 5 years previously. Fluoxetine 20 mg/day reduced his narcoleptic symptoms and morbid jealousy but not his sleepiness. On defaulting treatment, the patient's symptoms and marital problem recurred. A common central serotonin disturbance might be involved in mediating the sleep disorder and associated psychopathology. PMID:8140016

  3. Chronic treatment with fluoxetine prevents the return of extinguished auditory-cued conditioned fear.

    Science.gov (United States)

    Deschaux, Olivier; Spennato, Guillaume; Moreau, Jean-Luc; Garcia, René

    2011-05-01

    We have recently shown that post-extinction exposure of rats to a sub-threshold reminder shock can reactivate extinguished context-related freezing and found that chronic treatment with fluoxetine before fear extinction prevents this phenomenon. In the present study, we examined whether these findings would be confirmed with auditory fear conditioning. Rats were initially submitted to a session of five tone-shock pairings with either a 0.7- or 0.1-mA shock and underwent, 3 days later, a session of 20 tone-alone trials. At the beginning of this latter session, we observed cue-conditioned freezing in rats that received the strong, but not the weak, shock. At the end, both groups (strong and weak shocks) displayed similar low levels of freezing, indicating fear extinction in rats exposed to the strong shock. These rats exhibited again high levels of cue-evoked freezing when exposed to three tone-shock pairings with 0.1-mA shock. This reemergence of cue-conditioned fear was completely abolished by chronic (over a 21-day period) fluoxetine treatment which spared, when administered before the initial fear conditioning, the original tone-shock association. These data extend our previous findings and suggest that chronic fluoxetine treatment favor extinction memory by dampening the reactivation of the original tone-shock association.

  4. BiteStrip analysis of the effect of fluoxetine and paroxetine on sleep bruxism.

    Science.gov (United States)

    Isa Kara, M; Ertaş, Elif Tarım; Ozen, Emrullah; Atıcı, Meral; Aksoy, Selami; Erdogan, Muharrem Serif; Kelebek, Seyfi

    2017-08-01

    The relationship between sleep bruxism (SB) and selective serotonin reuptake inhibitors (SSRIs) is still under debate because of the lack of well-designed objective studies. The current study investigates possible effects of SSRIs, fluoxetine, and paroxetine on SB in patients with anxiety and depression. Thirty users of SSRIs for treatment of depression or anxiety were enrolled in the study. After clinical and anamnestic examination, 15 fluoxetine and 15 paroxetine users were included. For an objective evaluation of SB, a single-use disposable home screening device, BiteStrip, was used prior to the first SSRI intake and was repeated on the 7th and 15th days. Patients' self-reported data also were obtained for assessment of patient awareness. BiteStrip scores were significantly higher on the 7th and 15th days than the first measurement (pfluoxetine or paroxetine. Fluoxetine and paroxetine, SSRIs used for the treatment of anxiety and depression, may initiate or aggravate SB. Clinicians should consider that SSRIs may be the cause of SB when SSRI users are referred to dental clinics for SB symptoms. As there is a shortage of researches on this subject, further studies are necessary to confirm the existence of SSRI-induced SB. Copyright © 2016. Published by Elsevier Ltd.

  5. Augmenting Cognitive Behavior Therapy for School Refusal with Fluoxetine: A Randomized Controlled Trial.

    Science.gov (United States)

    Melvin, Glenn A; Dudley, Amanda L; Gordon, Michael S; Klimkeit, Ester; Gullone, Eleonora; Taffe, John; Tonge, Bruce J

    2017-06-01

    This study investigates whether the augmentation of cognitive behavior therapy (CBT) with fluoxetine improves outcomes in anxious school refusing adolescents (11-16.5 years). Sixty-two participants were randomly allocated to CBT alone, CBT + fluoxetine or CBT + placebo. All treatments were well tolerated; with one suicide-attempt in the CBT + placebo group. All groups improved significantly on primary (school attendance) and secondary outcome measures (anxiety, depression, self-efficacy and clinician-rated global functioning); with gains largely maintained at 6-months and 1-year. Few participants were anxiety disorder free after acute treatment. During the follow-up period anxiety and depressive disorders continued to decline whilst school attendance remained stable, at around 54 %. The only significant between-group difference was greater adolescent-reported treatment satisfaction in the CBT + fluoxetine group than the CBT alone group. These results indicate the chronicity of school refusal, and the need for future research into how to best improve school attendance rates.

  6. Does selective serotonin reuptake inhibitor (SSRI) fluoxetine affects mussel Mytilus galloprovincialis?

    International Nuclear Information System (INIS)

    Gonzalez-Rey, Maria; Bebianno, Maria João

    2013-01-01

    Fluoxetine (FLX) the active pharmaceutical ingredient (API) in Prozac ® is a widely prescribed psychoactive drug which ubiquitous occurrence in the aquatic environment is associated to a poor removal rate in waste-water treatment plant (WWTP) systems. This API acts as a selective serotonin reuptake inhibitor (SSRI) frequently reported to cause disrupting effects in non-target species. The objective of this study includes a multibiomarker response evaluation on mussel Mytilus galloprovincialis during two weeks exposure to 75 ng L −1 FLX assessing antioxidant enzymes activities – superoxide dismutase (SOD), catalase (CAT) and glutathione-S-transferase (GST); lipid peroxidation (LPO), acetylcholinesterase (AChE) neurotoxic response and endocrine disruption through alkali-labile phosphates (ALP) indirect measurement of vitellogenin-like proteins. Results show transient tissue-specific enzymatic responses and damage affecting mostly mussel gills. However, the clear ALP levels inhibition throughout time in both sex-differentiated gonads gives evidence to FLX reinforced action as an endocrine disruptor rather than an oxidative or neurotoxic inducer. - Highlights: ► Short-time exposure of Mytilus galloprovincialis to antidepressant fluoxetine. ► Tissue-specific transient antioxidant enzymes activities alteration. ► Lipid peroxidation (LPO) induction in exposed-tissues. ► Acetylcholinesterase (AChE) activity upregulation in exposed gills. ► ALP levels downregulation in exposed sex-differentiated mussels. - Exposure to 75 ng L −1 antidepressant fluoxetine (FLX) induces tissue-specific multibiomarker responses alteration in mussel Mytilus galloprovincialis.

  7. Coadministration of melatonin and fluoxetine does not improve the 3-month outcome following ECT.

    Science.gov (United States)

    Grunhaus, L; Hirschman, S; Dolberg, O T; Schreiber, S; Dannon, P N

    2001-06-01

    At least 50% of patients with manic depressive disorder (MDD) treated successfully with electroconvulsive therapy (ECT) will experience a relapse within the first year of follow-up. Sleep disturbances are very common in MDD and may constitute forerunners of relapse. In this study we tested the hypothesis that melatonin, a sleep-promoting hormone, would decrease the 3-month relapse rate after successful ECT. We included in the study patients with MDD successfully treated with ECT (post-ECT Hamilton Rating Scale for Depression [HRSD] < or = 10). Patients were blindly randomized to two groups, one receiving fluoxetine + placebo and one receiving fluoxetine + melatonin. Assessments (HRSD, Brief Psychiatric Rating Scale, Global Assessment of Function Scale, Global Depression Scale, Pittsburgh Sleep Quality Index, Mini-Mental State Exam, and pill count) were performed for 12 weeks after ECT. Ten of the 35 patients (28.5%) relapsed during the follow-up period. Relapse rates were similar in both groups of patients. Sleep reports were not improved by melatonin. Patients who achieved a higher functional state post-ECT relapsed less often. We conclude that the addition of melatonin to on-going fluoxetine treatment did not have a beneficial effect either on the 3-month outcome post-ECT or on the sleep reports of these patients.

  8. Mice with ablated adult brain neurogenesis are not impaired in antidepressant response to chronic fluoxetine.

    Science.gov (United States)

    Jedynak, Paulina; Kos, Tomasz; Sandi, Carmen; Kaczmarek, Leszek; Filipkowski, Robert K

    2014-09-01

    The neurogenesis hypothesis of major depression has two main facets. One states that the illness results from decreased neurogenesis while the other claims that the very functioning of antidepressants depends on increased neurogenesis. In order to verify the latter, we have used cyclin D2 knockout mice (cD2 KO mice), known to have virtually no adult brain neurogenesis, and we demonstrate that these mice successfully respond to chronic fluoxetine. After unpredictable chronic mild stress, mutant mice showed depression-like behavior in forced swim test, which was eliminated with chronic fluoxetine treatment, despite its lack of impact on adult hippocampal neurogenesis in cD2 KO mice. Our results suggest that new neurons are not indispensable for the action of antidepressants such as fluoxetine. Using forced swim test and tail suspension test, we also did not observe depression-like behavior in control cD2 KO mice, which argues against the link between decreased adult brain neurogenesis and major depression. Copyright © 2014 Elsevier Ltd. All rights reserved.

  9. Strain-specific outcomes of repeated social defeat and chronic fluoxetine treatment in the mouse.

    Science.gov (United States)

    Razzoli, Maria; Carboni, Lucia; Andreoli, Michela; Michielin, Francesca; Ballottari, Alice; Arban, Roberto

    2011-01-01

    Social stress is a risk factor for affective disorders in vulnerable individuals. Although the biological nature of stress susceptibility/resilience remains to be elucidated, genetic variation is considered amongst the principal contributors to brain disorders. Furthermore, genetic predisposition may be determinant for the therapeutic outcome, as proposed for antidepressant treatments. In the present studies we compared the inherently diverse genetic backgrounds of 2 mouse strains by assessing the efficacy of a chronic antidepressant treatment in a repeated social stress procedure. C57BL/6J and BalbC mice underwent 10-day social defeats followed by 28-day fluoxetine treatment (10 mg/kg/mL, p.o.). In C57BL/6J, most of the social defeat-induced changes were of metabolic nature including persistently altered feed efficiency and decreased abdominal fat stores that were ameliorated by fluoxetine. BalbC mouse behavior was persistently affected by social defeat both in the social avoidance and the forced swim tests, and in either procedure it was restored by chronic fluoxetine, whereas their endocrine parameters were mostly unaffected. The highlighted strain-specific responsivity to the metabolic and behavioral consequences of social defeat and to the chronic antidepressant treatment offers a promising research tool to further explore the underlying neural mechanisms and genetic basis of stress susceptibility and treatment response. Copyright © 2010 Elsevier Inc. All rights reserved.

  10. Chronic fluoxetine inhibits sexual behavior in the male rat: reversal with oxytocin.

    Science.gov (United States)

    Cantor, J M; Binik, Y M; Pfaus, J G

    1999-06-01

    Selective serotonin reuptake inhibitors, used widely in the treatment of depression, progressively inhibit sexual orgasm in many patients and induce a transient inhibition of sexual desire. We attempted to model the effects of these drugs in sexually experienced male rats during tests of copulation in bilevel chambers. These chambers allow the study of both appetitive and consummatory sexual responses of male rats. Males were treated daily with fluoxetine hydrochloride (0, 1, 5, or 10 mg/kg) and tested for sexual behavior with receptive females at 4-day intervals. Rats were treated with oxytocin (200 ng/kg) or saline after ejaculations had decreased. Fluoxetine decreased ejaculatory responses of male rats in a dose- and time-dependent fashion, but left the copulatory efficiency of the males intact. In contrast, conditioned level changing, a measure of appetitive sexual excitement, was inhibited following acute and chronic treatment with 10 mg/kg, although tolerance may have developed to the effect of 5 mg/kg. Subsequent administration of oxytocin restored the ejaculatory response but not the measure of sexual excitement to baseline levels. The reversal by oxytocin of the fluoxetine-induced deficit in ejaculations is consistent with the hypothesis that serotonin suppresses ejaculatory mechanisms by interrupting the action of oxytocin, which normally accompanies sexual behavior. Co-administration of oxytocin may help to alleviate the predominant sexual side effect of serotonin reuptake blockers.

  11. Efficacy evaluation of fluoxetine combined with conventional drug treatment on unstable angina patients complicated with depression

    Institute of Scientific and Technical Information of China (English)

    Chun-Hua Liao

    2015-01-01

    Objective:To study the efficacy of fluoxetine combined with conventional drug treatment on unstable angina patients complicated with depression. Methods:120 cases of unstable angina patients with depression were randomly divided into two groups. The anti-depression group received fluoxetine combined with conventional drug therapy; the conventional group received conventional drug therapy. Then contents of monoamine neurotransmitters and their metabolites, antioxidants and inflammatory mediators of both groups were compared. Results:Serum monoamine neurotransmitters NE, 5-HT and HA levels of the anti-depression group were higher than those of the conventional group and metabolites 5-HIAA and HVA contents were lower than those of the conventional group; serum SOD, CAT, GSH and HSP-70 contents of the anti-depression group were higher than those of the conventional group, and hs-CRP, MMP9, MCP1 and HMGB1 contents were lower than those of the conventional group. Conclusion:Fluoxetine combined with conventional drug therapy can increase the contents of monoamine neurotransmitters and antioxidants, and reduce oxidative stress response and inflammatory response; it is an ideal method for treating unstable angina complicated with depression.

  12. An exploratory study of adolescent response to fluoxetine using psychological and biological predictors

    Directory of Open Access Journals (Sweden)

    Ada H. Zohar

    2018-01-01

    Full Text Available Background Not enough is known about predicting therapeutic response to serotonin-specific reuptake inhibitors, and specifically to fluoxetine. This exploratory study used psychological and biological markers for (retrospective prediction of treatment-response to fluoxetine in depressed and/or anxious adolescents. Methods Forty-one consecutive adolescent outpatients with a primary diagnosis of severe affective and/or anxiety disorders were assessed and treated with an open-label 8-week trial of fluoxetine. Type D personality was assessed with the 14-item questionnaire, the DS14. In addition, TNFα, IL-6, and IL-1b were measured pre- and post-treatment. Results There was an elevation of Type D personality in patients, compared to the adolescent population rate. Post-treatment, 44% of patients were classified as non-responders; the relative risk of non-response for Type D personality patients was 2.8. Binary logistic regression predicting response vs. non-response showed a contribution of initial TNFα levels as well as Type D personality to non-response. Conclusions In this exploratory study, the most significant contributor to non-response was Type D personality. However, the measurement of Type D was not prospective, and thus may be confounded with psychiatric morbidity. The measurement of personality in psychiatric settings may contribute to the understanding of treatment response and have clinical utility.

  13. Fluoxetine induces input-specific hippocampal dendritic spine remodeling along the septo-temporal axis in adulthood and middle age

    Science.gov (United States)

    McAvoy, Kathleen; Russo, Craig; Kim, Shannen; Rankin, Genelle; Sahay, Amar

    2015-01-01

    Fluoxetine, a selective serotonin-reuptake inhibitor (SSRI), is known to induce structural rearrangements and changes in synaptic transmission in hippocampal circuitry. In the adult hippocampus, structural changes include neurogenesis, dendritic and axonal plasticity of pyramidal and dentate granule neurons, and dedifferentiation of dentate granule neurons. However, much less is known about how chronic fluoxetine affects these processes along the septo-temporal axis and during the aging process. Importantly, studies documenting the effects of fluoxetine on density and distribution of spines along different dendritic segments of dentate granule neurons and CA1 pyramidal neurons along the septo-temporal axis of hippocampus in adulthood and during aging are conspicuously absent. Here, we use a transgenic mouse line in which mature dentate granule neurons and CA1 pyramidal neurons are genetically labeled with green fluorescent protein (GFP) to investigate the effects of chronic fluoxetine treatment (18mg/kg/day) on input-specific spine remodeling and mossy fiber structural plasticity in the dorsal and ventral hippocampus in adulthood and middle age. In addition, we examine levels of adult hippocampal neurogenesis, maturation state of dentate granule neurons, neuronal activity and glutamic acid decarboxylase-67 expression in response to chronic fluoxetine in adulthood and middle age. Our studies reveal that while chronic fluoxetine fails to augment adult hippocampal neurogenesis in middle age, the middle-aged hippocampus retains high sensitivity to changes in the dentate gyrus (DG) such as dematuration, hypoactivation, and increased glutamic acid decarboxylase 67 (GAD67) expression. Interestingly, the middle-aged hippocampus shows greater sensitivity to fluoxetine-induced input-specific synaptic remodeling than the hippocampus in adulthood with the stratum-oriens of CA1 exhibiting heightened structural plasticity. The input-specific changes and circuit

  14. Quantitative Cross-Species Extrapolation between Humans and Fish: The Case of the Anti-Depressant Fluoxetine

    Science.gov (United States)

    Margiotta-Casaluci, Luigi; Owen, Stewart F.; Cumming, Rob I.; de Polo, Anna; Winter, Matthew J.; Panter, Grace H.; Rand-Weaver, Mariann; Sumpter, John P.

    2014-01-01

    Fish are an important model for the pharmacological and toxicological characterization of human pharmaceuticals in drug discovery, drug safety assessment and environmental toxicology. However, do fish respond to pharmaceuticals as humans do? To address this question, we provide a novel quantitative cross-species extrapolation approach (qCSE) based on the hypothesis that similar plasma concentrations of pharmaceuticals cause comparable target-mediated effects in both humans and fish at similar level of biological organization (Read-Across Hypothesis). To validate this hypothesis, the behavioural effects of the anti-depressant drug fluoxetine on the fish model fathead minnow (Pimephales promelas) were used as test case. Fish were exposed for 28 days to a range of measured water concentrations of fluoxetine (0.1, 1.0, 8.0, 16, 32, 64 µg/L) to produce plasma concentrations below, equal and above the range of Human Therapeutic Plasma Concentrations (HTPCs). Fluoxetine and its metabolite, norfluoxetine, were quantified in the plasma of individual fish and linked to behavioural anxiety-related endpoints. The minimum drug plasma concentrations that elicited anxiolytic responses in fish were above the upper value of the HTPC range, whereas no effects were observed at plasma concentrations below the HTPCs. In vivo metabolism of fluoxetine in humans and fish was similar, and displayed bi-phasic concentration-dependent kinetics driven by the auto-inhibitory dynamics and saturation of the enzymes that convert fluoxetine into norfluoxetine. The sensitivity of fish to fluoxetine was not so dissimilar from that of patients affected by general anxiety disorders. These results represent the first direct evidence of measured internal dose response effect of a pharmaceutical in fish, hence validating the Read-Across hypothesis applied to fluoxetine. Overall, this study demonstrates that the qCSE approach, anchored to internal drug concentrations, is a powerful tool to guide the

  15. Interstitial lung disease induced by fluoxetine: Systematic review of literature and analysis of Vigiaccess, Eudravigilance and a national pharmacovigilance database.

    Science.gov (United States)

    Deidda, Arianna; Pisanu, Claudia; Micheletto, Laura; Bocchetta, Alberto; Del Zompo, Maria; Stochino, Maria Erminia

    2017-06-01

    We investigated a pulmonary adverse drug reaction possibly induced by fluoxetine, the Interstitial Lung Disease, by performing a systematic review of published case reports on this subject, a review of the World Health Organization VigiAccess database, of the European EudraVigilance database and of a national Pharmacovigilance database (Italian Pharmacovigilance Network). The research found a total of seven cases linking fluoxetine to Interstitial Lung Disease in the literature. 36 cases of interstitial lung disease related to fluoxetine were retrieved from the VigiAccess database (updated to July 2016), and 36 reports were found in EudraVigilance database (updated to June 2016). In the Italian Pharmacovigilance database (updated to August 2016), we found only one case of Interstitial Lung Disease, codified as "pulmonary disease". Our investigation shows that fluoxetine might be considered as a possible cause of Interstitial Lung Disease. In particular, although here we do not discuss the assessment of benefits and harms of fluoxetine, since this antidepressant is widely used, our review suggests that fluoxetine-induced Interstitial Lung Disease should be considered in patients with dyspnea, associated or not with dry cough, who are treated with this drug. An early withdrawn of fluoxetine could be useful to obtain a complete remission of this adverse drug reaction and special attention should be particularly devoted to long-term therapy, and to female and elderly patients. Although the spontaneous reporting system is affected by important limitations, drug post- marketing surveillance represents an important tool to evaluate the real world effectiveness and safety of drugs. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Fluoxetine induces input-specific hippocampal dendritic spine remodeling along the septotemporal axis in adulthood and middle age.

    Science.gov (United States)

    McAvoy, Kathleen; Russo, Craig; Kim, Shannen; Rankin, Genelle; Sahay, Amar

    2015-11-01

    Fluoxetine, a selective serotonin-reuptake inhibitor (SSRI), is known to induce structural rearrangements and changes in synaptic transmission in hippocampal circuitry. In the adult hippocampus, structural changes include neurogenesis, dendritic, and axonal plasticity of pyramidal and dentate granule neurons, and dedifferentiation of dentate granule neurons. However, much less is known about how chronic fluoxetine affects these processes along the septotemporal axis and during the aging process. Importantly, studies documenting the effects of fluoxetine on density and distribution of spines along different dendritic segments of dentate granule neurons and CA1 pyramidal neurons along the septotemporal axis of hippocampus in adulthood and during aging are conspicuously absent. Here, we use a transgenic mouse line in which mature dentate granule neurons and CA1 pyramidal neurons are genetically labeled with green fluorescent protein (GFP) to investigate the effects of chronic fluoxetine treatment (18 mg/kg/day) on input-specific spine remodeling and mossy fiber structural plasticity in the dorsal and ventral hippocampus in adulthood and middle age. In addition, we examine levels of adult hippocampal neurogenesis, maturation state of dentate granule neurons, neuronal activity, and glutamic acid decarboxylase-67 expression in response to chronic fluoxetine in adulthood and middle age. Our studies reveal that while chronic fluoxetine fails to augment adult hippocampal neurogenesis in middle age, the middle-aged hippocampus retains high sensitivity to changes in the dentate gyrus (DG) such as dematuration, hypoactivation, and increased glutamic acid decarboxylase 67 (GAD67) expression. Interestingly, the middle-aged hippocampus shows greater sensitivity to fluoxetine-induced input-specific synaptic remodeling than the hippocampus in adulthood with the stratum-oriens of CA1 exhibiting heightened structural plasticity. The input-specific changes and circuit

  17. Evaluation of the stability of fluoxetine in pluronic lecithin organogel and the determination of an appropriate beyond-use date.

    Science.gov (United States)

    Peacock, Gina F; Sauvageot, Jurgita

    2014-01-01

    Fluoxetine is a commonly prescribed psychotropic medication for a variety of behavioral diagnoses in veterinary practice, and fluoxetine in Pluronic lecithin organogel has been used successfully in treating inappropriate urine spraying in felines. Historically, pharmacists have assigned a variety of beyond-use dates to extemporaneously compound drugs in Pluronic lecithin organogel. The objective of this study was to evaluate the stability of fluoxetine in Pluronic lecithin organogel over a period of six months and to determine an appropriate beyond-use date. A stability-indicating high-performance liquid chromatography method for fluoxetine in Pluronic lecithin organogel was validated in our laboratory. Fluoxetine-Pluronic lecithin organogel 50 mg/mL was prepared by a local compounding pharmacy and analyzed by high-performance liquid chromatograph at 0, 7, 14, 21, 28, 45, 60, 90, and 180 days. Physical stability was also assessed by visual observation. At each time point percent of initial concentration was calculated. The beyond-use date was determined as the time period that the samples maintained at least 90 percent of the initial concentration. At 180 days, the mean percent of initial concentration was 99 +/- 1.5 and, visually, the fluoxetine-Pluronic lecithin organogel retained the original color and consistency, without detectable separation of the different phases of Pluronic lecithin organogel. Since fluoxetine was physically stable and retained greater than 90 percent of initial concentration in Pluronic lecithin organogel for 180 days when stored at room temperature and protected from light, a beyond-use date of 180 days is appropriate.

  18. Effect of co-administration of fluoxetine and amantadine on immunoendocrine parameters in rats subjected to a forced swimming test.

    Science.gov (United States)

    Rogóz, Zofia; Kubera, Marta; Rogóz, Katarzyna; Basta-Kaim, Agnieszka; Budziszewska, Bogusława

    2009-01-01

    Considerable attention has been paid to a possible role of immunological dysregulation in the pathogenesis of depression. It has been reported that combined administration of antidepressant drugs and the non-competitive NMDA receptor antagonist amantadine reduces immobility time in the forced swimming test (FST). Moreover, preliminary clinical data show that such a combination of drugs has a beneficial effect on treatment-resistant depressed patients. Since immune activation and a pro-inflammatory response are clearly evident in treatment-resistant depression, the aim of the present study was to examine the effect of a combination of the antidepressant fluoxetine and amantadine on immunoendocrine parameters in rats subjected to the forced swimming test. The obtained results revealed synergistic antidepressant effects of the combined administration of fluoxetine (10 mg/kg) and amantadine (10 mg/kg) - drugs otherwise ineffective when given separately in the above doses. Antidepressant activity was accompanied with a significant decrease in the capacity of splenocytes to proliferate in response to concanavalin A. Moerover, fluoxetine and the combination of amantadine and fluoxetine reduced relative spleen weight in rats subjected to the FST, compared to rats treated with the vehicle. The combination of amantadine and fluoxetine enhanced the production of the negative immunoregulator interleukin-10 (but not interferon-gamma) in rats subjected to the FST. The exposure to the FST produced an increase in plasma corticosterone levels, which was significantly attenuated by pretreatment with fluoxetine and amantadine. In summary, the antidepressive efficacy of a combination of fluoxetine and amantadine given in suboptimal doses may be related to the negative immunoendocrine effects of these drugs.

  19. Effects of ketamine and N-methyl-D-aspartate on fluoxetine-induced antidepressant-related behavior using the forced swimming test.

    Science.gov (United States)

    Owolabi, Rotimi Adegbenga; Akanmu, Moses Atanda; Adeyemi, Oluwole Isaac

    2014-04-30

    This study investigated the effects of ketamine on fluoxetine-induced antidepressant behavior using the forced swimming test (FST) in mice. In order to understand the possible role of N-methyl-d-aspartate (NMDA) neurotransmission in the antidepressant effect of fluoxetine, different groups of mice (n=10) were administered with acute ketamine (3mg/kg, i.p.), acute NMDA (75mg/kg and 150mg/kg, i.p.) and a 21-day chronic ketamine (15mg/kg, i.p./day) were administered prior to the administration of fluoxetine (20mg/kg, i.p.) in the mice. Antidepressant related behavior (immobility score) was measured using the forced swimming test. The results showed that the acute ketamine and fluoxetine alone treatments elicited a significant (pfluoxetine-induced decrease in immobility score. In contrast, pre-treatment with NMDA (150mg/kg) significantly (pfluoxetine-induced decrease in immobility score. On the other hand, chronic administration of ketamine significantly elicited an increase in immobility score as well as reversed the reduction induced by fluoxetine. Similarly, NMDA administration at both 75mg/kg and 150mg/kg increased immobility score in chronically administered ketamine groups. Furthermore, chronic administration of ketamine, followed by NMDA (75mg/kg) and fluoxetine significantly elevated the immobility score when compared with the group that received NMDA and fluoxetine but not chronically treated with ketamine. It can be suggested) that facilitation of NMDA transmission blocked fluoxetine-induced reduction in immobility score, while down-regulation of NMDA transmission is associated with increase in fluoxetine-induced antidepressant-related behavior in mice. Down-regulation of the NMDA transmission is proposed as an essential component of mechanism of suppression of depression related behaviors by fluoxetine. Modulation of NMDA transmission is suggested to be relevant in the mechanism of action of fluoxetine. Copyright © 2014 Elsevier Ireland Ltd. All rights

  20. Effects of fluoxetine on mast cell morphology and protease-1 expression in gastric antrum in a rat model of depression

    Institute of Scientific and Technical Information of China (English)

    Zhen-Hua Chen; Ling Xiao; Ji-Hong Chen; He-Shen Luo; Gao-Hua Wang; Yong-Lan Huang; Xiao-Ping Wang

    2008-01-01

    AIM: To investigate the effects of fluoxetine on depression-induced changes of mast cell morphology and protease-1 (rMCP-1) expression in rats.METHODS: A Sprague-Dawley rat model of chronic stress-induced depression was established. Fifty experimental rats were randomly divided into the following groups: normal control group, fluoxetine +normal control group, depressed model group, saline + depressed model group, and fluoxetine + depressed model group. Laser scanning confocal microscopy (LSCM) immunofluorecence and RT-PCR techniques were used to investigate rMCP-1 expression in gastric antrum. Mast cell morphology was observed under transmission electron microscopy. ANOVA was used for statistical analysis among groups.RESULTS: Morphologic observation indicated that depression induced mast cell proliferation, activation,and granule hyperplasia. Compared with the normal control group, the average immunofluorescence intensity of gastric antrum rMCP-1 significantly increased in depressed model group (37.4 4- 7.7 vs 24.5+ 5.6, P < 0.01) or saline + depressed model group (39.9 4- 5.0 vs 24.5 ± 5.6, P < 0.01), while there was no significant difference between fluoxetine + normal control group (23.1 4- 3.4) or fluoxetine + depressed model group (26.1 4- 3.6) and normal control group.The average level of rMCP-lmRNA of gastric antrum significantly increased in depressed model group (0.759 ± 0.357 vs 0.476 ± 0.029, P < 0.01) or saline + depressed model group (0.781 4- 0.451 vs 0.476 ±0.029, P < 0.01 ), while no significant difference was found between fluoxetine + normal control group (0.460 ± 0.027) or fluoxetine + depressed model group (0.488 ± 0.030) and normal control group. Fluoxetine showed partial inhibitive effects on mast cell ultrastructural alterations and de-regulated rMCP-1 expression in gastric antrum of the depressed rat model.CONCLUSION: Chronic stress can induce mast cell proliferation, activation, and granule hyperplasia in gastric antrum. Fluoxetine

  1. Concomitant administration of fluoxetine and amantadine modulates the activity of peritoneal macrophages of rats subjected to a forced swimming test.

    Science.gov (United States)

    Roman, Adam; Rogóz, Zofia; Kubera, Marta; Nawrat, Dominika; Nalepa, Irena

    2009-01-01

    Recent studies show that administration of a non-competitive NMDA receptor antagonist, amantadine (AMA), potentiates the action of antidepressant drugs. Since antidepressants may modulate functioning of the immune system and activation of a pro-inflammatory response in depressive disorders is frequently reported, the aim of the present study was to examine whether a combined administration of AMA and the antidepressant, fluoxetine (FLU), to rats subsequently subjected to a forced swimming test (FST) modifies the parameters of macrophage activity, directly related to their immunomodulatory functions, i.e., arginase (ARG) activity and synthesis of nitric oxide (NO). We found that 10 mg/kg AMA and 10 mg/kg FLU, ineffective in FST for antidepressant-like activity when administered alone, increased the ARG/NO ratio in macrophages when administered concomitantly. This effect was accompanied by a decrease of cellular adherence. Concurrently, the basal metabolic activity of the cells measured with reduction of resazurin, and intracellular host defense as assessed by a synthesis of superoxide anion, were not affected by such antidepressive treatment. Our data indicate that co-administration of AMA and FLU decreases the pro-inflammatory properties of macrophages and causes a redirection of immune response toward anti-inflammatory activity, as one can anticipate in the case of an effective antidepressive treatment.

  2. Fluoxetine Maintains a State of Heightened Responsiveness to Motor Training Early After Stroke in a Mouse Model.

    Science.gov (United States)

    Ng, Kwan L; Gibson, Ellen M; Hubbard, Robert; Yang, Juemin; Caffo, Brian; O'Brien, Richard J; Krakauer, John W; Zeiler, Steven R

    2015-10-01

    Data from both humans and animal models suggest that most recovery from motor impairment after stroke occurs in a sensitive period that lasts only weeks and is mediated, in part, by an increased responsiveness to training. Here, we used a mouse model of focal cortical stroke to test 2 hypotheses. First, we investigated whether responsiveness to training decreases over time after stroke. Second, we tested whether fluoxetine, which can influence synaptic plasticity and stroke recovery, can prolong the period over which large training-related gains can be elicited after stroke. Mice were trained to perform a skilled prehension task to an asymptotic level of performance after which they underwent stroke induction in the caudal forelimb area. The mice were then retrained after a 1- or 7-day delay with and without fluoxetine. Recovery of prehension after a caudal forelimb area stroke was complete if training was initiated 1 day after stroke but incomplete if it was delayed by 7 days. In contrast, if fluoxetine was administered at 24 hours after stroke, then complete recovery of prehension was observed even with the 7-day training delay. Fluoxetine seemed to mediate its beneficial effect by reducing inhibitory interneuron expression in intact premotor cortex rather than through effects on infarct volume or cell death. There is a gradient of diminishing responsiveness to motor training over the first week after stroke. Fluoxetine can overcome this gradient and maintain maximal levels of responsiveness to training even 7 days after stroke. © 2015 American Heart Association, Inc.

  3. Antidepressant-like effects of the xanthine oxidase enzyme inhibitor allopurinol in rats. A comparison with fluoxetine.

    Science.gov (United States)

    Gürbüz Özgür, Börte; Aksu, Hatice; Birincioğlu, Mustafa; Dost, Turhan

    2015-11-01

    Allopurinol is a xanthine oxidase enzyme inhibitor that is widely used for the treatment of hyperuricemia and gout. The activity of tryptophan 2,3-dioxygenase, which metabolizes tryptophan (TRP), is decreased by xanthine oxidase inhibitors, causing TRP levels in the body to be increased. Increases in TRP levels in the brain might have antidepressant effects. The purpose of this study is to evaluate the antidepressant effects of allopurinol compared to those of fluoxetine, which is a proven antidepressant. Thirty-two Wistar albino male rats were divided into four groups (control, 10mg/kg fluoxetine, 50mg/kg allopurinol, 50mg/kg allopurinol+10 mg/kg fluoxetine; n=8 per group), and forced swimming tests were performed before and after 14days of drug administration. Serotonin, 5-hydroxyindolacetic acid and uric acid levels were measured in blood samples after the final treatment. When allopurinol and fluoxetine were administered separately, a decrease in the duration of immobility and an increased duration of swimming were observed in the forced swimming test. The results showed similar antidepressant efficacies between allopurinol and fluoxetine. However, we found no statistically significant difference in the antidepressant effect of the combined therapy versus single drug therapy. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. Bi-phasic regulation of glycogen content in astrocytes via Cav-1/PTEN/PI3K/AKT/GSK-3β pathway by fluoxetine.

    Science.gov (United States)

    Bai, Qiufang; Song, Dan; Gu, Li; Verkhratsky, Alexei; Peng, Liang

    2017-04-01

    Here, we present the data indicating that chronic treatment with fluoxetine regulates Cav-1/PTEN/PI3K/AKT/GSK-3β signalling pathway and glycogen content in primary cultures of astrocytes with bi-phasic concentration dependence. At lower concentrations, fluoxetine downregulates gene expression of Cav-1, decreases membrane content of PTEN, increases activity of PI3K/AKT, and elevates GSK-3β phosphorylation thus suppressing its activity. At higher concentrations, fluoxetine acts in an inverse fashion. As expected, fluoxetine at lower concentrations increased while at higher concentrations decreased glycogen content in astrocytes. Our findings indicate that bi-phasic regulation of glycogen content via Cav-1/PTEN/PI3K/AKT/GSK-3β pathway by fluoxetine may be responsible for both therapeutic and side effects of the drug.

  5. Fluoxetine up-regulates expression of cellular FLICE-inhibitory protein and inhibits LPS-induced apoptosis in hippocampus-derived neural stem cell

    International Nuclear Information System (INIS)

    Chiou, S.-H.; Chen, S.-J.; Peng, C-H.; Chang, Y.-L.; Ku, H.-H.; Hsu, W.-M.; Ho, Larry L.-T.; Lee, C.-H.

    2006-01-01

    Fluoxetine is a widely used antidepressant compound which inhibits the reuptake of serotonin in the central nervous system. Recent studies have shown that fluoxetine can promote neurogenesis and improve the survival rate of neurons. However, whether fluoxetine modulates the proliferation or neuroprotection effects of neural stem cells (NSCs) needs to be elucidated. In this study, we demonstrated that 20 μM fluoxetine can increase the cell proliferation of NSCs derived from the hippocampus of adult rats by MTT test. The up-regulated expression of Bcl-2, Bcl-xL and the cellular FLICE-inhibitory protein (c-FLIP) in fluoxetine-treated NSCs was detected by real-time RT-PCR. Our results further showed that fluoxetine protects the lipopolysaccharide-induced apoptosis in NSCs, in part, by activating the expression of c-FLIP. Moreover, c-FLIP induction by fluoxetine requires the activation of the c-FLIP promoter region spanning nucleotides -414 to -133, including CREB and SP1 sites. This effect appeared to involve the phosphatidylinositol-3-kinase-dependent pathway. Furthermore, fluoxetine treatment significantly inhibited the induction of proinflammatory factor IL-1β, IL-6, and TNF-α in the culture medium of LPS-treated NSCs (p < 0.01). The results of high performance liquid chromatography coupled to electrochemical detection further confirmed that fluoxentine increased the functional production of serotonin in NSCs. Together, these data demonstrate the specific activation of c-FLIP by fluoxetine and indicate the novel role of fluoxetine for neuroprotection in the treatment of depression

  6. Adolescence fluoxetine increases serotonergic activity in the raphe-hippocampus axis and improves depression-like behaviors in female rats that experienced neonatal maternal separation.

    Science.gov (United States)

    Yoo, Sang Bae; Kim, Bom-Taeck; Kim, Jin Young; Ryu, Vitaly; Kang, Dong-Won; Lee, Jong-Ho; Jahng, Jeong Won

    2013-06-01

    This study was conducted to examine if fluoxetine, a selective 5-hydroxytryptamine (5-HT) reuptake inhibitor, would reverse adverse behavioral effects of neonatal maternal separation in female rats. Sprague-Dawley pups were separated from dam daily for 3h during postnatal day (PND) 1-14 (maternal separation; MS) or left undisturbed (non-handled; NH). Female NH and MS pups received intraperitoneal injection of fluoxetine (10mg/kg) or vehicle daily from PND 35 until the end of the whole experimental period. Rats were either subjected to behavioral tests during PND 44-54, or sacrificed for neurochemical analyses during PND 43-45. Daily food intake and weight gain of both NH and MS pups were suppressed by fluoxetine, with greater effects in MS pups. MS experience increased immobility and decrease swimming in forced swim test. Swimming was increased, although immobility was not significantly decreased, in MS females by adolescence fluoxetine. However, adolescence fluoxetine increased immobility during forced swim test and decreased time spent in open arms during elevated plus maze test in NH females. Fluoxetine normalized MS-induced decrease of the raphe 5-HT levels and increased 5-HT metabolism in the hippocampus in MS females, and increased the hypothalamic 5-HT both in NH and MS. Fluoxetine decreased the raphe 5-HT and increased the plasma corticosterone in NH females. Results suggest that decreased 5-HTergic activity in the raphe nucleus is implicated in the pathophysiology of depression-like behaviors, and increased 5-HTergic activities in the raphe-hippocampus axis may be a part of anti-depressant efficacy of fluoxetine, in MS females. Also, an extra-hypothalamic 5-HTergic activity may contribute to the increased anorectic efficacy of fluoxetine in MS females. Additionally, decreased 5-HT in the raphe and elevated plasma corticosterone may be related with fluoxetine-induced depression- and/or anxiety-like behaviors in NH females. Copyright © 2012 Elsevier Ltd

  7. Differential in vivo regulation of TH and DBH mRNA in rat atria by maprotiline and fluoxetine

    Directory of Open Access Journals (Sweden)

    Spasojević Nataša

    2011-01-01

    Full Text Available It is well known that antidepressants affect central monoaminergic neurotransmission and that they also modulate hormone release in peripheral tissues. Repeated maprotiline (a noradrenaline reuptake inhibitor and fluoxetine (a serotonin reuptake inhibitor treatment on gene expression of the catecholamine biosynthetic enzymes were examined in rat atria and ventricles in vivo. Maprotiline decreased the gene expression of tyrosine hydroxylase (TH and dopamineβ-hydroxylase (DBH in the rat atrium. Fluoxetine increased gene expression of TH and DBH, but not of phenylethanolamine N-methyltransferase (PNMT. Chronic application of antidepressants did not change the expression of these enzymes in the ventricles. We conclude that repeated administration of fluoxetine enhances gene transcription of TH and DBH and subsequently stimulates noradrenaline synthesis in rat atria in vivo.

  8. Chronic Fluoxetine Induces the Enlargement of Perforant Path-Granule Cell Synapses in the Mouse Dentate Gyrus

    Science.gov (United States)

    Kitahara, Yosuke; Ohta, Keisuke; Hasuo, Hiroshi; Shuto, Takahide; Kuroiwa, Mahomi; Sotogaku, Naoki; Togo, Akinobu; Nakamura, Kei-ichiro; Nishi, Akinori

    2016-01-01

    A selective serotonin reuptake inhibitor is the most commonly prescribed antidepressant for the treatment of major depression. However, the mechanisms underlying the actions of selective serotonin reuptake inhibitors are not fully understood. In the dentate gyrus, chronic fluoxetine treatment induces increased excitability of mature granule cells (GCs) as well as neurogenesis. The major input to the dentate gyrus is the perforant path axons (boutons) from the entorhinal cortex (layer II). Through voltage-sensitive dye imaging, we found that the excitatory neurotransmission of the perforant path synapse onto the GCs in the middle molecular layer of the mouse dentate gyrus (perforant path-GC synapse) is enhanced after chronic fluoxetine treatment (15 mg/kg/day, 14 days). Therefore, we further examined whether chronic fluoxetine treatment affects the morphology of the perforant path-GC synapse, using FIB/SEM (focused ion beam/scanning electron microscopy). A three-dimensional reconstruction of dendritic spines revealed the appearance of extremely large-sized spines after chronic fluoxetine treatment. The large-sized spines had a postsynaptic density with a large volume. However, chronic fluoxetine treatment did not affect spine density. The presynaptic boutons that were in contact with the large-sized spines were large in volume, and the volumes of the mitochondria and synaptic vesicles inside the boutons were correlated with the size of the boutons. Thus, the large-sized perforant path-GC synapse induced by chronic fluoxetine treatment contains synaptic components that correlate with the synapse size and that may be involved in enhanced glutamatergic neurotransmission. PMID:26788851

  9. Acute Exposure to Fluoxetine Alters Aggressive Behavior of Zebrafish and Expression of Genes Involved in Serotonergic System Regulation

    Directory of Open Access Journals (Sweden)

    Michail Pavlidis

    2017-04-01

    Full Text Available Zebrafish, Danio rerio, is an emerging model organism in stress and neurobehavioral studies. In nature, the species forms shoals, yet when kept in pairs it exhibits an agonistic and anxiety-like behavior that leads to the establishment of dominant-subordinate relationships. Fluoxetine, a selective serotonin reuptake inhibitor, is used as an anxiolytic tool to alter aggressive behavior in several vertebrates and as an antidepressant drug in humans. Pairs of male zebrafish were held overnight to develop dominant—subordinate behavior, either treated or non-treated for 2 h with fluoxetine (5 mg L−1, and allowed to interact once more for 1 h. Behavior was recorded both prior and after fluoxetine administration. At the end of the experiment, trunk and brain samples were also taken for cortisol determination and mRNA expression studies, respectively. Fluoxetine treatment significantly affected zebrafish behavior and the expression levels of several genes, by decreasing offensive aggression in dominants and by eliminating freezing in the subordinates. There was no statistically significant difference in whole-trunk cortisol concentrations between dominant and subordinate fish, while fluoxetine treatment resulted in higher (P = 0.004 cortisol concentrations in both groups. There were statistically significant differences between dominant and subordinate fish in brain mRNA expression levels of genes involved in stress axis (gr, mr, neural activity (bdnf, c-fos, and the serotonergic system (htr2b, slc6a4b. The significant decrease in the offensive and defensive aggression following fluoxetine treatment was concomitant with a reversed pattern in c-fos expression levels. Overall, an acute administration of a selective serotonin reuptake inhibitor alters aggressive behavior in male zebrafish in association with changes in the neuroendocrine mediators of coping styles.

  10. Interleukin-1β causes fluoxetine resistance in an animal model of epilepsy-associated depression.

    Science.gov (United States)

    Pineda, Eduardo A; Hensler, Julie G; Sankar, Raman; Shin, Don; Burke, Teresa F; Mazarati, Andréy M

    2012-04-01

    Depression represents a common comorbidity of epilepsy and is frequently resistant to selective serotonin reuptake inhibitors (SSRI). We tested the hypothesis that the SSRI resistance in epilepsy associated depression may be a result of a pathologically enhanced interleukin-1β (IL1-β) signaling, and consequently that the blockade of IL1-β may restore the effectiveness of SSRI. Epilepsy and concurrent depression-like impairments were induced in Wistar rats by pilocarpine status epilepticus (SE). The effects of the 2-week long treatment with fluoxetine, interleukin-1 receptor antagonist (IL-1ra), and their combination were examined using behavioral, biochemical, neuroendocrine, and autoradiographic assays. In post-SE rats, depression-like impairments included behavioral deficits indicative of hopelessness and anhedonia; the hyperactivity of the hypothalamo-pituitary-adrenocortical axis; the diminished serotonin output from raphe nucleus; and the upregulation of presynaptic serotonin 1-A (5-HT1A) receptors. Fluoxetine monotherapy exerted no antidepressant effects, whereas the treatment with IL-1ra led to the complete reversal of anhedonia and to a partial improvement of all other depressive impairments. Combined administration of fluoxetine and IL-1ra completely abolished all hallmarks of epilepsy-associated depressive abnormalities, with the exception of the hyperactivity of the hypothalamo-pituitary-adrenocortical axis, the latter remaining only partially improved. We propose that in certain forms of depression, including but not limited to depression associated with epilepsy, the resistance to SSRI may be driven by the pathologically enhanced interleukin-1β signaling and by the subsequent upregulation of presynaptic 5-HT1A receptors. In such forms of depression, the use of interleukin-1β blockers in conjunction with SSRI may represent an effective therapeutic approach.

  11. A Concise Total Synthesis of (R)-Fluoxetine, a Potent and Selective Serotonin Reuptake Inhibitor

    OpenAIRE

    de Fátima, Ângelo; Lapis, Alexandre Augusto M.; Pilli, Ronaldo A.

    2005-01-01

    (R)-Fluoxetine, potent and selective serotonin reuptake inhibitor, has been synthesized in six steps, 50% overall yield and 99% ee from benzaldehyde via catalytic asymmetric allylation with Maruoka's catalyst. (R)-Fluoxetina, um inibidor potente e seletivo da recaptação da serotonina, foi sintetizada em seis etapas, 50% de rendimento total e 99% de excesso enantiomérico a partir do benzaldeído via alilação catalítica assimétrica empregando-se o sistema catalítico desenvolvido por Maruoka e...

  12. Emerging Hyperprolactinemic Galactorrhea in Obsessive Compulsive Disorder with a Stable Dose of Fluoxetine.

    Science.gov (United States)

    Chatterjee, Seshadri Sekhar; Mitra, Sayantanava; Mallik, Nitu

    2015-12-31

    While fluoxetine (FXT) is a frequently prescribed selective serotonin reuptake inhibitor (SSRI), with few major side-effects; altered serotonergic transmissions in hypothalamic pathways might lead to a distressing, and often embarrassing, manifestation of galactorrhea by altering prolactin release in those on FXT. We report here a case of FXT-induced hyperprolactinemic galactorrhea developing late into treatment on a stable regimen, who responded well to subsequent replacement with sertraline. Based on present finding, we suggest that while SSRIs may share similar mechanisms of action, there exist individual differences in their effects on prolactin secretion pathways.

  13. Single fluoxetine treatment before but not after stress prevents stress-induced hippocampal long-term depression and spatial memory retrieval impairment in rats

    Science.gov (United States)

    Han, Huili; Dai, Chunfang; Dong, Zhifang

    2015-01-01

    A growing body of evidence has shown that chronic treatment with fluoxetine, a widely prescribed medication for treatment of depression, can affect synaptic plasticity in the adult central nervous system. However, it is not well understood whether acute fluoxetine influences synaptic plasticity, especially on hippocampal CA1 long-term depression (LTD), and if so, whether it subsequently impacts hippocampal-dependent spatial memory. Here, we reported that LTD facilitated by elevated-platform stress in hippocampal slices was completely prevented by fluoxetine administration (10 mg/kg, i.p.) 30 min before stress. The LTD was not, however, significantly inhibited by fluoxetine administration immediately after stress. Similarly, fluoxetine incubation (10 μM) during electrophysiological recordings also displayed no influence on the stress-facilitated LTD. In addition, behavioral results showed that a single fluoxetine treatment 30 min before but not after acute stress fully reversed the impairment of spatial memory retrieval in the Morris water maze paradigm. Taken together, these results suggest that acute fluoxetine treatment only before, but not after stress, can prevent hippocampal CA1 LTD and spatial memory retrieval impairment caused by behavioral stress in adult animals. PMID:26218751

  14. Microautoradiography of [{sup 123}I]ADAM in mice treated with fluoxetine and serotonin reuptake inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Ye, X.-X.; Chen, J.-C.; Liu, R.-S.; Wey, S.-P.; Lee, J.-S.; Chen, C.-C.; Fu, Y.-K.; Ting, Gann; Hwang, J.-J. E-mail: jjhwang@ym.edu.tw

    2004-07-01

    A radiopharmaceutical, {sup 123}I-labeled 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine ([{sup 123}I]ADAM), has been developed recently for evaluation of how serotonin transporters (SERT) function in the brain. However, the detailed biodistribution and specific binding in certain brain areas are not well investigated. In this study, both phosphor plate imaging and microautoradiography were applied to explore the binding characteristics of [{sup 123}I]ADAM in SERT neurons. The effect of two psychotropics and one narcotic on the binding of [{sup 123}I]ADAM to SERT was also studied. Fluoxetine and desipramine, both are psychotropics and specific SERT ligands and decreased the affinity of [{sup 123}I]ADAM, while p-chloroamphetamine (PCA), a narcotic, destroyed most of serotonergic neurons, as well as reducing the concentration of serotonin and the number of SERT in the brain as shown by the biodistribution of [{sup 123}I]ADAM. Significant and selective accumulation of [{sup 123}I]ADAM in the areas from midbrain to brain stem in normal mice with maximum target-to-background ratio was found at 90 minutes postinjection. A rapid clearance of [{sup 131}I]ADAM at 120 minutes postinjection was found in the CA1, CA3 and ThN brain areas. In addition, the inhibition effect on binding ability of [{sup 123}I]ADAM to SERT by the psychotropics and the narcotic was found to have the order of: PCA > fluoxetine > desipramine.

  15. Microautoradiography of [123I]ADAM in mice treated with fluoxetine and serotonin reuptake inhibitors

    International Nuclear Information System (INIS)

    Ye, X.-X.; Chen, J.-C.; Liu, R.-S.; Wey, S.-P.; Lee, J.-S.; Chen, C.-C.; Fu, Y.-K.; Ting, Gann; Hwang, J.-J.

    2004-01-01

    A radiopharmaceutical, 123 I-labeled 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine ([ 123 I]ADAM), has been developed recently for evaluation of how serotonin transporters (SERT) function in the brain. However, the detailed biodistribution and specific binding in certain brain areas are not well investigated. In this study, both phosphor plate imaging and microautoradiography were applied to explore the binding characteristics of [ 123 I]ADAM in SERT neurons. The effect of two psychotropics and one narcotic on the binding of [ 123 I]ADAM to SERT was also studied. Fluoxetine and desipramine, both are psychotropics and specific SERT ligands and decreased the affinity of [ 123 I]ADAM, while p-chloroamphetamine (PCA), a narcotic, destroyed most of serotonergic neurons, as well as reducing the concentration of serotonin and the number of SERT in the brain as shown by the biodistribution of [ 123 I]ADAM. Significant and selective accumulation of [ 123 I]ADAM in the areas from midbrain to brain stem in normal mice with maximum target-to-background ratio was found at 90 minutes postinjection. A rapid clearance of [ 131 I]ADAM at 120 minutes postinjection was found in the CA1, CA3 and ThN brain areas. In addition, the inhibition effect on binding ability of [ 123 I]ADAM to SERT by the psychotropics and the narcotic was found to have the order of: PCA > fluoxetine > desipramine

  16. PET study of the distribution of [{sup 11}C]fluoxetine in a monkey brain

    Energy Technology Data Exchange (ETDEWEB)

    Shiue, C.-Y.; Shiue, Grace G.; Cornish, Kurtis G.; O' Rourke, Maria F

    1995-07-01

    No-carrier-added [{sup 11}C]fluoxetine (2) was synthesized by methylation of norfluoxetine (1) with [{sup 11}C]H{sub 3}I in 20% radiochemical yield in a synthesis time of 40 min from EOB with a specific activity of 0.48 Ci/{mu}M (EOB). In vivo study in mouse indicated that the uptake of 2 in mouse tissues was high and the radioactivity remained constant throughout the study. The uptake of 2 in mouse brain was 4%/g. PET study in a Rhesus monkey also showed that the uptakes of 2 in different brain regions were similar and the retention of radioactivity in these regions remained constant throughout the study (80 min). Analysis of arterial plasma by HPLC showed that only 20% of radioactivity in the plasma remained as 2 at 30 min post-injection. These results suggest that the uptake of fluoxetine in monkey brain is probably not receptor mediated. Rather, blood flow, lipophilicity or other transport mechanisms may play a role in its uptake.

  17. Effects of fluoxetine on the reproduction of two prosobranch mollusks: Potamopyrgus antipodarum and Valvata piscinalis

    International Nuclear Information System (INIS)

    Gust, M.; Buronfosse, T.; Giamberini, L.; Ramil, M.; Mons, R.; Garric, J.

    2009-01-01

    Fluoxetine is a widely used antidepressant, frequently found in aquatic ecosystems. We investigated its effects on two freshwater prosobranch gastropods: Valvata piscinalis (European valve snail) and Potamopyrgus antipodarum (New Zealand mudsnail), which have different reproductive modes. The fecundity of V. piscinalis (cumulate number of eggs at day 42) was not affected with an NOEC of 100 μg/L nominal concentration (69 μg/L measured concentration). The mudsnail P. antipodarum responded in a biphasic dose-effect curve at low concentrations. The cumulate number of neonates at day 42 had an LOEC of 100 μg/L (69 μg/L) and an NOEC of 33.3 μg/L (13 μg/L), whereas the embryos in the brood pouch at day 42 only showed an LOEC of 3.7 μg/L (1 μg/L). We also observed histological effects in P. antipodarum (gonadal thickness). Among the sexual steroids we measured only testosterone which varied, independent of reproduction. Moreover the use of two closely related species highlights the interspecific variability. - Fluoxetine has significant effects on the reproduction and development of some freshwater snails

  18. PET study of the distribution of [11C]fluoxetine in a monkey brain

    International Nuclear Information System (INIS)

    Shiue, C.-Y.; Shiue, Grace G.; Cornish, Kurtis G.; O'Rourke, Maria F.

    1995-01-01

    No-carrier-added [ 11 C]fluoxetine (2) was synthesized by methylation of norfluoxetine (1) with [ 11 C]H 3 I in 20% radiochemical yield in a synthesis time of 40 min from EOB with a specific activity of 0.48 Ci/μM (EOB). In vivo study in mouse indicated that the uptake of 2 in mouse tissues was high and the radioactivity remained constant throughout the study. The uptake of 2 in mouse brain was 4%/g. PET study in a Rhesus monkey also showed that the uptakes of 2 in different brain regions were similar and the retention of radioactivity in these regions remained constant throughout the study (80 min). Analysis of arterial plasma by HPLC showed that only 20% of radioactivity in the plasma remained as 2 at 30 min post-injection. These results suggest that the uptake of fluoxetine in monkey brain is probably not receptor mediated. Rather, blood flow, lipophilicity or other transport mechanisms may play a role in its uptake

  19. Placebo-Controlled Study of Pimozide Augmentation of Fluoxetine in Body Dysmorphic Disorder

    Science.gov (United States)

    Phillips, Katharine A.

    2006-01-01

    Objective Although body dysmorphic disorder often responds to serotonin reuptake inhibitors (SRIs), most patients do not respond or respond only partially. However, placebo-controlled studies of augmentation of SRIs have not been done. Furthermore, although 40%–50% of patients are delusional, studies of antipsychotic medications have not been done. Method Twenty-eight patients with body dysmorphic disorder or its delusional variant participated in an 8-week, placebo-controlled, double-blind, parallel-group study of pimozide augmentation of fluoxetine. Results Pimozide was not more effective than placebo: two (18.2%) of 11 subjects responded to pimozide and three (17.6%) of 17 subjects responded to placebo. There was no significant effect of baseline delusionality on endpoint severity of body dysmorphic disorder. Delusionality did not decrease significantly more with pimozide than placebo. Conclusions Pimozide augmentation of fluoxetine treatment for body dysmorphic disorder was not more effective than placebo, even in more delusional patients. Further studies of augmentation for SRIs are needed. PMID:15677604

  20. Effects of fluoxetine on the reproduction of two prosobranch mollusks: Potamopyrgus antipodarum and Valvata piscinalis

    Energy Technology Data Exchange (ETDEWEB)

    Gust, M. [Laboratoire d' ecotoxicologie, Cemagref, 3b quai Chauveau, CP 220, 69336 Lyon Cedex 09 (France)], E-mail: marion.gust@cemagref.fr; Buronfosse, T. [Laboratoire d' endocrinologie, Ecole Nationale Veterinaire de Lyon, avenue Bourgelat, 69280 Marcy l' Etoile (France)], E-mail: thierry.buronfosse@inserm.fr; Giamberini, L. [Laboratoire des interactions Ecotoxicologie, Biodiversite, Ecosystemes, CNRS UMR 7146, campus Bridoux, 57000 Metz (France)], E-mail: giamb@sciences.univ-metz.fr; Ramil, M. [Federal Institute of Hydrology (BFG), D-56068 Koblenz, Am Mainzer Tor 1 (Germany)], E-mail: mramil@usc.es; Mons, R. [Laboratoire d' ecotoxicologie, Cemagref, 3b quai Chauveau, CP 220, 69336 Lyon Cedex 09 (France)], E-mail: raphael.mons@cemagref.fr; Garric, J. [Laboratoire d' ecotoxicologie, Cemagref, 3b quai Chauveau, CP 220, 69336 Lyon Cedex 09 (France)], E-mail: jeanne.garric@cemagref.fr

    2009-02-15

    Fluoxetine is a widely used antidepressant, frequently found in aquatic ecosystems. We investigated its effects on two freshwater prosobranch gastropods: Valvata piscinalis (European valve snail) and Potamopyrgus antipodarum (New Zealand mudsnail), which have different reproductive modes. The fecundity of V. piscinalis (cumulate number of eggs at day 42) was not affected with an NOEC of 100 {mu}g/L nominal concentration (69 {mu}g/L measured concentration). The mudsnail P. antipodarum responded in a biphasic dose-effect curve at low concentrations. The cumulate number of neonates at day 42 had an LOEC of 100 {mu}g/L (69 {mu}g/L) and an NOEC of 33.3 {mu}g/L (13 {mu}g/L), whereas the embryos in the brood pouch at day 42 only showed an LOEC of 3.7 {mu}g/L (1 {mu}g/L). We also observed histological effects in P. antipodarum (gonadal thickness). Among the sexual steroids we measured only testosterone which varied, independent of reproduction. Moreover the use of two closely related species highlights the interspecific variability. - Fluoxetine has significant effects on the reproduction and development of some freshwater snails.

  1. Morphological analysis of the enamel organ in rats treated with fluoxetine

    Directory of Open Access Journals (Sweden)

    Henrique Morais Silva

    2010-01-01

    Full Text Available PURPOSE: Previous studies have evaluated the presence of serotonin in the dental epithelia and mesenchyme during odontogenesis, suggesting its participation in tooth development. MATERIALS AND METHODS: Here, we used fluoxetine, a selective serotonin re-uptake inhibitor, at a dose of 10 mg/kg, administered for 20 days during pregnancy in 12 Wistar rats to examine the influence of this drug on the development of the enamel organ of the upper first molars of rat fetuses at 17 days of intra-uterine life (i.u.l., and at one, five and ten days postpartum. The pregnant rats were anesthetized with xylazine at 10 mg/kg and ketamine at 25 mg/kg. The fetuses were removed and beheaded; their jaws were removed, and the upper jaws were exposed. The tissues were fixed in Bouin's fixative, decalcified in 5% nitric acid for 4 - 12 h, conventionally processed for microscopy, and embedded in paraffin. Serial sections of approximately 5 mm were obtained and stained with hematoxylin and eosin, as well as periodic acid-Schiff. RESULTS AND CONCLUSION: Morphological analysis showed no structural changes in the experimental group compared to the controls, suggesting that, at the dose used, fluoxetine does not interfere with serotonin-mediated development of the enamel organ or the process of amelogenesis.

  2. Fluoxetine and diclofenac interaction on food intake in goldfish, Carassius auratus

    Directory of Open Access Journals (Sweden)

    Mohammad Navid Forsatkar

    2014-07-01

    Full Text Available This study was carried out to investigate the interaction of simultaneous use of fluoxetine (Flx, a selective serotonin reuptake inhibitor, and diclofenac (Dcf, a nonsteroidal anti-inflammatory drug, on food intake in goldfish, Carassius auratus. Treatments with different dosage of Flx including control, 0, 1, and 10  µg/g body weight (BW were injected in the fish with mean weight of 30.16 ± 8.57 g every other day in total of 5 times. Then fish were exposed to 3 different levels of Dcf including 0, 10, and 100 mg/l for 5 days. Injection of fluoxetine significantly decreased food intake and consequently body weight. After 5 days exposure to Dcf, the amount of food intake in the Dcf receiving treatments of 1 mg/l and 10 mg/l was significantly larger than that of 0 mg/l Dcf recieving treatment in both the Flx dosage groups of 1 μg/g BW and 10 μg/g BW. Our results indicated that Dcf inhibits behavioral change effects of Flx showing the complex effects of pharmaceuticals on fish.

  3. Allosteric modulation of the effect of escitalopram, paroxetine and fluoxetine: in-vitro and in-vivo studies

    DEFF Research Database (Denmark)

    Mansari, Mostafa El; Wiborg, Ove; Mnie-Filali, Ouissame

    2006-01-01

    -citalopram attenuated the association rates of escitalopram and paroxetine to the 5-HT transporter, but had no effect on the association rates of fluoxetine, venlafaxine or sertraline. In the rat dorsal raphe nucleus, R-citalopram (250 microg/kg i.v.) blocked the suppressant effect on neuronal firing activity of both...

  4. Synthesis of /sup 14/C- and /sup 3/H-labeled fluoxetine, a selective serotonin uptake inhibitor

    Energy Technology Data Exchange (ETDEWEB)

    Robertson, D.W.; Krushinski, J.H.; Wong, D.T.; Kau, D.

    1987-11-01

    Fluoxetine (N-methyl-..gamma..-(4-(trifluoromethyl)phenoxy) benzenepropanamine) is a potent, highly selective serotonin uptake inhibitor that is useful in treating a variety of major psychiatric derangements. We have synthesized this compound in /sup 14/C- and /sup 3/H-labeled forms. The tritium label was introduced in the final step by catalytic dehalogenation of the brominated fluoxetine precursor. Reaction conditions could be controlled such that catalytic hydrogenolysis of the labile C-O benzylic bond was minimized. Following HPLC purification, (/sup 3/H)-fluoxetine was obtained in a state of high radiochemical purity (98%) and specific activity (20.4 Ci/mmol). The /sup 14/C-label was introduced in the final step via a nucleophilic aromatic substitution reaction between the sodium salt of ..cap alpha..-(2-(methylamino)ethyl)benzenemethanol and uniformly ring-labeled p-chlorobenzotrifluoride. Following purification by flash chromatography, (/sup 14/C)-fluoxetine was obtained in 98.3% radiochemical purity with a specific activity of 5.52 mCi/mmol.

  5. Fluoxetine-clonazepam cotherapy for anxious depression: an exploratory, post-hoc analysis of a randomized, double blind study.

    Science.gov (United States)

    Papakostas, George I; Clain, Alisabet; Ameral, Victoria E; Baer, Lee; Brintz, Carrie; Smith, Ward T; Londborg, Peter D; Glaudin, Vincent; Painter, John R; Fava, Maurizio

    2010-01-01

    Anxious depression, defined as major depressive disorder (MDD) accompanied by high levels of anxiety, seems to be both common and difficult to treat, with antidepressant monotherapy often yielding modest results. We sought to examine the relative benefits of antidepressant-anxiolytic cotherapy versus antidepressant monotherapy for patients with anxious depression versus without anxious depression. We conducted a post-hoc analysis of an existing dataset (N=80), from a 3-week, randomized, double-blind trial which demonstrated cotherapy with fluoxetine and clonazepam to result in superior efficacy than fluoxetine monotherapy in MDD. The present analysis involved examining whether anxious depression status served as a predictor and moderator of symptom improvement. Anxious depression status was not found to predict symptom improvement, or serve as a moderator of clinical improvement to cotherapy versus monotherapy. However, the advantage in remission rates in favor of cotherapy versus monotherapy was, numerically, much larger for patients with anxious depression (32.2%) than it was for patients without anxious MDD (9.7%). The respective number needed to treat statistic for these two differences in response rates were, approximately, one in three for patients with anxious depression versus one in 10 for patients without anxious depression. The efficacy of fluoxetine-clonazepam cotherapy compared with fluoxetine monotherapy was numerically but not statistically enhanced for patients with anxious depression than those without anxious depression.

  6. Chronic treatment with fluoxetine and sertraline prevents forced swimming test-induced hypercontractility of rat detrusor muscle.

    Science.gov (United States)

    Bilge, Sirri; Bozkurt, Ayhan; Bas, Duygu B; Aksoz, Elif; Savli, Evren; Ilkaya, Fatih; Kesim, Yuksel

    2008-01-01

    Serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors represent important targets for the development of new treatments for detrusor overactivity and urinary incontinence. The present study was undertaken to investigate the effects of the forced swimming test (FST) on the contractile response of isolated rat detrusor muscle and to examine the effects of in vivo treatments of fluoxetine and sertraline on altered detrusor muscle contractility. Fluoxetine (20 mg/kg ip) and sertraline (10 mg/kg ip) were administered once a day for 14 days. Rats were exposed to the FST on the 15th day. After the test, detrusor muscles were removed and placed in organ baths, and the contraction responses induced by carbachol, potassium chloride (KCl) and electrical field stimulation (EFS) were recorded. The contractile responses of detrusor muscle strips to carbachol and electrical field stimulation were found to be increased at all carbachol doses and frequencies, respectively. FST also increased the contractile responses to KCl, which is used to test the differences in postreceptor-mediated contractions. The hypercontractile responses of detrusor strips to carbachol, EFS and KCl were abolished by treatment with both fluoxetine and sertraline. These treatments also decreased the immobility duration in the FST consistent with an antidepressant-like effect in this test. The results of this study provide the first evidence that FST increases contractility of the rat detrusor muscle, and this hypercontractility was abolished by chronic treatments of fluoxetine and sertraline at antidepressant doses by decreasing the postreceptor-mediated events.

  7. Differential regulation of the excitability of prefrontal cortical fast-spiking interneurons and pyramidal neurons by serotonin and fluoxetine.

    Directory of Open Access Journals (Sweden)

    Ping Zhong

    2011-02-01

    Full Text Available Serotonin exerts a powerful influence on neuronal excitability. In this study, we investigated the effects of serotonin on different neuronal populations in prefrontal cortex (PFC, a major area controlling emotion and cognition. Using whole-cell recordings in PFC slices, we found that bath application of 5-HT dose-dependently increased the firing of FS (fast spiking interneurons, and decreased the firing of pyramidal neurons. The enhancing effect of 5-HT in FS interneurons was mediated by 5-HT₂ receptors, while the reducing effect of 5-HT in pyramidal neurons was mediated by 5-HT₁ receptors. Fluoxetine, the selective serotonin reuptake inhibitor, also induced a concentration-dependent increase in the excitability of FS interneurons, but had little effect on pyramidal neurons. In rats with chronic fluoxetine treatment, the excitability of FS interneurons was significantly increased, while pyramidal neurons remained unchanged. Fluoxetine injection largely occluded the enhancing effect of 5-HT in FS interneurons, but did not alter the reducing effect of 5-HT in pyramidal neurons. These data suggest that the excitability of PFC interneurons and pyramidal neurons is regulated by exogenous 5-HT in an opposing manner, and FS interneurons are the major target of Fluoxetine. It provides a framework for understanding the action of 5-HT and antidepressants in altering PFC network activity.

  8. Fluoxetine treatment is effective in a rat model of childhood-induced post-traumatic stress disorder.

    Science.gov (United States)

    Ariel, Lior; Inbar, Sapir; Edut, Schachaf; Richter-Levin, Gal

    2017-11-30

    Although selective serotonin reuptake inhibitors (SSRIs) are first-line treatment for post-traumatic stress disorder (PTSD) patients, their therapeutic efficacy is limited. Childhood adversities are considered a risk factor for developing PTSD in adulthood but may trigger PTSD without additional trauma in some individuals. Nevertheless, just as childhood is considered a vulnerable period it may also be an effective period for preventive treatment. Using a rat model of childhood-induced PTSD, pre-pubertal stress (juvenile stress, JVS), we compared the therapeutic effects of fluoxetine and examined the effectiveness of 1 month of fluoxetine treatment following JVS and into adulthood compared to treatment in adulthood. Since not all individuals develop PTSD following a trauma, comparing only group means is not the adequate type of analysis. We employed a behavioral profiling approach, which analyzes individual differences compared to the normal behavior of a control group. Animals exposed to JVS exhibited a higher proportion of affected animals as measured using the elevated plus maze 8 weeks after JVS. Fluoxetine treatment following the JVS significantly decreased the proportion of affected animals as measured in adulthood. Fluoxetine treatment in adulthood was not effective. The results support the notion that childhood is not only a vulnerable period but also an effective period for preventive treatment.

  9. Quantitative cross-species extrapolation between humans and fish: the case of the anti-depressant fluoxetine.

    Directory of Open Access Journals (Sweden)

    Luigi Margiotta-Casaluci

    Full Text Available Fish are an important model for the pharmacological and toxicological characterization of human pharmaceuticals in drug discovery, drug safety assessment and environmental toxicology. However, do fish respond to pharmaceuticals as humans do? To address this question, we provide a novel quantitative cross-species extrapolation approach (qCSE based on the hypothesis that similar plasma concentrations of pharmaceuticals cause comparable target-mediated effects in both humans and fish at similar level of biological organization (Read-Across Hypothesis. To validate this hypothesis, the behavioural effects of the anti-depressant drug fluoxetine on the fish model fathead minnow (Pimephales promelas were used as test case. Fish were exposed for 28 days to a range of measured water concentrations of fluoxetine (0.1, 1.0, 8.0, 16, 32, 64 µg/L to produce plasma concentrations below, equal and above the range of Human Therapeutic Plasma Concentrations (H(TPCs. Fluoxetine and its metabolite, norfluoxetine, were quantified in the plasma of individual fish and linked to behavioural anxiety-related endpoints. The minimum drug plasma concentrations that elicited anxiolytic responses in fish were above the upper value of the H(TPC range, whereas no effects were observed at plasma concentrations below the H(TPCs. In vivo metabolism of fluoxetine in humans and fish was similar, and displayed bi-phasic concentration-dependent kinetics driven by the auto-inhibitory dynamics and saturation of the enzymes that convert fluoxetine into norfluoxetine. The sensitivity of fish to fluoxetine was not so dissimilar from that of patients affected by general anxiety disorders. These results represent the first direct evidence of measured internal dose response effect of a pharmaceutical in fish, hence validating the Read-Across hypothesis applied to fluoxetine. Overall, this study demonstrates that the qCSE approach, anchored to internal drug concentrations, is a powerful tool

  10. Evaluation of the antidepressant, anxiolytic and memory-improving efficacy of aripiprazole and fluoxetine in ethanol-treated rats.

    Science.gov (United States)

    Burda-Malarz, Kinga; Kus, Krzysztof; Ratajczak, Piotr; Czubak, Anna; Hardyk, Szymon; Nowakowska, Elżbieta

    2014-07-01

    Some study results indicate a positive effect of aripiprazole (ARI) on impaired cognitive functions caused by brain damage resulting from chronic EtOH abuse. However, other research shows that to manifest itself, an ARI antidepressant effect requires a combined therapy with another selective serotonin reuptake inhibitor antidepressant, namely, fluoxetine (FLX). The aim of this article was to assess antidepressant and anxiolytic effects of ARI as well as its effect on spatial memory in ethanol-treated (alcoholized) rats. On the basis of alcohol consumption pattern, groups of (1) ethanol-preferring rats, with mean ethanol intake above 50%, and (2) ethanol-nonpreferring rats (EtNPRs), with mean ethanol intake below 50% of total daily fluid intake, were formed. The group of EtNPRs was used for this study, subdivided further into three groups administered ARI, FLX and a combination of both, respectively. Behavioral tests such as Porsolt's forced swimming test, the Morris water maze test and the two-compartment exploratory test were employed. Behavioral test results demonstrated (1) no antidepressant effect of ARI in EtNPRs in subchronic treatment and (2) no procognitive effect of ARI and FLX in EtNPRs in combined single administration. Combined administration of both drugs led to an anxiogenic effect and spatial memory deterioration in study animals. ARI had no antidepressant effect and failed to improve spatial memory in rats. However, potential antidepressant, anxiolytic and procognitive properties of the drug resulting from its mechanism of action encourage further research aimed at developing a dose of both ARI and FLX that will prove such effects in alcoholized EtNPRs.

  11. Sonochemical degradation of the pharmaceutical fluoxetine: Effect of parameters, organic and inorganic additives and combination with a biological system

    Energy Technology Data Exchange (ETDEWEB)

    Serna-Galvis, Efraím A.; Silva-Agredo, Javier [Grupo de Investigación en Remediación Ambiental y Biocatálisis, Instituto de Química, Facultad de Ciencias Exactas y Naturales, Universidad de Antioquia UdeA, Calle 70 No. 52-21, Medellín (Colombia); Giraldo-Aguirre, Ana L. [Grupo de Diseño y Formulación de Medicamentos, Cosméticos y Afines (DYFOMECO), Facultad de Química Farmacéutica, Universidad de Antioquia UdeA, Calle 70 No. 52-21, Medellín (Colombia); Torres-Palma, Ricardo A., E-mail: ricardo.torres@udea.edu.co [Grupo de Investigación en Remediación Ambiental y Biocatálisis, Instituto de Química, Facultad de Ciencias Exactas y Naturales, Universidad de Antioquia UdeA, Calle 70 No. 52-21, Medellín (Colombia)

    2015-08-15

    Fluoxetine (FLX), one of the most widely used antidepressants in the world, is an emergent pollutant found in natural waters that causes disrupting effects on the endocrine systems of some aquatic species. This work explores the total elimination of FLX by sonochemical treatment coupled to a biological system. The biological process acting alone was shown to be unable to remove the pollutant, even under favourable conditions of pH and temperature. However, sonochemical treatment (600 kHz) was shown to be able to remove the pharmaceutical. Several parameters were evaluated for the ultrasound application: the applied power (20–60 W), dissolved gas (air, Ar and He), pH (3–11) and initial concentration of fluoxetine (2.9–162.0 μmol L{sup −1}). Additionally, the presence of organic (1-hexanol and 2-propanol) and inorganic (Fe{sup 2+}) compounds in the water matrix and the degradation of FLX in a natural mineral water were evaluated. The sonochemical treatment readily eliminates FLX following a kinetic Langmuir. After 360 min of ultrasonic irradiation, 15% mineralization was achieved. Analysis of the biodegradability provided evidence that the sonochemical process transforms the pollutant into biodegradable substances, which can then be mineralized in a subsequent biological treatment. - Highlights: • The pharmaceutical fluoxetine was effectively eliminated upon ultrasonic action. • Ultrasonic power, dissolved gas, pH and concentration of fluoxetine were evaluated. • Fe{sup 2+}, sodium nitrate or nitric acid had a positive effect on the FLX degradation. • More hydrophobic or volatile compounds than fluoxetine diminished the efficiency. • A sonochemical-biological combined process led to the total mineralization of FLX.

  12. Developmental fluoxetine exposure increases behavioral despair and alters epigenetic regulation of the hippocampal BDNF gene in adult female offspring.

    Science.gov (United States)

    Boulle, Fabien; Pawluski, Jodi L; Homberg, Judith R; Machiels, Barbie; Kroeze, Yvet; Kumar, Neha; Steinbusch, Harry W M; Kenis, Gunter; van den Hove, Daniel L A

    2016-04-01

    A growing number of infants are exposed to selective serotonin reuptake inhibitor (SSRI) medications during the perinatal period. Perinatal exposure to SSRI medications alter neuroplasticity and increase depressive- and anxiety-related behaviors, particularly in male offspring as little work has been done in female offspring to date. The long-term effects of SSRI on development can also differ with previous exposure to prenatal stress, a model of maternal depression. Because of the limited work done on the role of developmental SSRI exposure on neurobehavioral outcomes in female offspring, the aim of the present study was to investigate how developmental fluoxetine exposure affects anxiety and depression-like behavior, as well as the regulation of hippocampal brain-derived neurotrophic factor (BDNF) signaling in the hippocampus of adult female offspring. To do this female Sprague-Dawley rat offspring were exposed to prenatal stress and fluoxetine via the dam, for a total of four groups of female offspring: 1) No Stress+Vehicle, 2) No Stress+Fluoxetine, 3) Prenatal Stress+Vehicle, and 4) Prenatal Stress+Fluoxetine. Primary results show that, in adult female offspring, developmental SSRI exposure significantly increases behavioral despair measures on the forced swim test, decreases hippocampal BDNF exon IV mRNA levels, and increases levels of the repressive histone 3 lysine 27 tri-methylated mark at the corresponding promoter. There was also a significant negative correlation between hippocampal BDNF exon IV mRNA levels and immobility in the forced swim test. No effects of prenatal stress or developmental fluoxetine exposure were seen on tests of anxiety-like behavior. This research provides important evidence for the long-term programming effects of early-life exposure to SSRIs on female offspring, particularily with regard to affect-related behaviors and their underlying molecular mechanisms. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Evaluation of antidepressant like activity of curcumin and its combination with fluoxetine and imipramine: an acute and chronic study.

    Science.gov (United States)

    Sanmukhani, Jayesh; Anovadiya, Ashish; Tripathi, Chandrabhanu B

    2011-01-01

    Curcumin is the active ingredient of commonly used spice Curuma longa Linn. In the present study, the antidepressant like activity of curcumin and its combination with fluoxetine and imipramine was studied in acute model (three doses 24, 5 and 1 h before test) of forced swimming test (FST) in glass jar and tail suspension test (TST) in mice and in chronic model (14 day study) of FST with water wheel in rats. All the tests were carried out in the following seven groups (n = 6 in each group), drugs being given orally (doses for mice): Group 1 (vehicle), group 2 (curcumin 50 mg/kg), group 3 (curcumin 100 mg/kg), group 4 (fluoxetine 20 mg/kg), group 5 (imipramine 15 mg/kg), group 6 (curcumin 100 mg/kg plus fluoxetine 20 mg/kg) and group 7 (curcumin 100 mg/kg plus imipramine 15 mg/kg). Equivalent doses for rats were used. Both the acute model of FST and TST, and the chronic model of FST with water wheel showed significant antidepressant like activity of curcumin in 100 mg/kg dose as compared to vehicle control (p fluoxetine and imipramine (p > 0.05) but its addition to fluoxetine and imipramine did not improve their antidepressant activity (p > 0.05). Curcumin increased both the swimming and climbing behavior in FST, thus its antidepressant like activity could be due to an increase in serotonin, norepinephrine and dopamine levels in the brain. Curcumin can be a useful antidepressant especially in cases which respond to drugs having mixed effects on serotonin and catecholamines levels in the brain.

  14. Changes of cytosolic calcium and contractility of young rat vas deferens by acute treatment with amphetamine, fluoxetine or sibutramine.

    Science.gov (United States)

    Jurkiewicz, Neide Hyppolito; da Silva Júnior, Edilson Dantas; de Souza, Bruno Palmieri; Ferreira Verde, Luciana; Drawanz Pereira, Janaina; Mendes Sobrinho, Cairo; Soubhi Smaili, Soraya; Caricati-Neto, Afonso; Miranda-Ferreira, Regiane; Jurkiewicz, Aron

    2012-09-15

    Previous studies conducted in our laboratory indicated that administration of amphetamine, fluoxetine or sibutramine affects the sympathetic nervous system of the rat vas deferens. Therefore, our goal was to verify the role of calcium in vasa deferentia from young rats pretreated with a single dose of these drugs. Young 40-day-old male Wistar rats were pretreated with amphetamine 3 mg/kg, fluoxetine 10 mg/kg or sibutramine 6 mg/kg for 4 h before the experiments. CaCl(2) (10 mM) was used to induce contraction through time-effect curves in calcium-free solution to measure phasic and tonic components. We also evaluated the calcium-induced fluorescence of vas deferens cut into thin slices. In rats pretreated with amphetamine, we found an increase of the tonic contraction component which was reduced by verapamil. The phasic and tonic responses were increased in the group treated with fluoxetine, but only the tonic response was more sensitive to the antagonism by verapamil. The group treated with sibutramine showed an increase of phasic response whereas the tonic component was decreased. In this group an increase of the affinity for verapamil antagonism was found. In the calcium fluorescence study it was observed that the group treated with amphetamine, fluoxetine or sibutramine showed higher basal Ca(2+) fluorescence after stimulus with KCl (70 mM), noradrenaline (10(-4)M) or acetylcholine (10(-4)M). In all pretreated groups the calcium fluorescence was diminished by nifedipine 10(-7)M. Therefore, the pretreatment with amphetamine, fluoxetine or sibutramine seems to affect the calcium contractility and homeostasis in young rat vas deferens. Copyright © 2012 Elsevier B.V. All rights reserved.

  15. Sonochemical degradation of the pharmaceutical fluoxetine: Effect of parameters, organic and inorganic additives and combination with a biological system

    International Nuclear Information System (INIS)

    Serna-Galvis, Efraím A.; Silva-Agredo, Javier; Giraldo-Aguirre, Ana L.; Torres-Palma, Ricardo A.

    2015-01-01

    Fluoxetine (FLX), one of the most widely used antidepressants in the world, is an emergent pollutant found in natural waters that causes disrupting effects on the endocrine systems of some aquatic species. This work explores the total elimination of FLX by sonochemical treatment coupled to a biological system. The biological process acting alone was shown to be unable to remove the pollutant, even under favourable conditions of pH and temperature. However, sonochemical treatment (600 kHz) was shown to be able to remove the pharmaceutical. Several parameters were evaluated for the ultrasound application: the applied power (20–60 W), dissolved gas (air, Ar and He), pH (3–11) and initial concentration of fluoxetine (2.9–162.0 μmol L −1 ). Additionally, the presence of organic (1-hexanol and 2-propanol) and inorganic (Fe 2+ ) compounds in the water matrix and the degradation of FLX in a natural mineral water were evaluated. The sonochemical treatment readily eliminates FLX following a kinetic Langmuir. After 360 min of ultrasonic irradiation, 15% mineralization was achieved. Analysis of the biodegradability provided evidence that the sonochemical process transforms the pollutant into biodegradable substances, which can then be mineralized in a subsequent biological treatment. - Highlights: • The pharmaceutical fluoxetine was effectively eliminated upon ultrasonic action. • Ultrasonic power, dissolved gas, pH and concentration of fluoxetine were evaluated. • Fe 2+ , sodium nitrate or nitric acid had a positive effect on the FLX degradation. • More hydrophobic or volatile compounds than fluoxetine diminished the efficiency. • A sonochemical-biological combined process led to the total mineralization of FLX

  16. Comparing the effects of fluoxetine and imipramine on total cholesterol, triglyceride, and weight in patients with major depression

    Directory of Open Access Journals (Sweden)

    Shahsavand Ananloo Esmaeil

    2013-01-01

    Full Text Available Abstract Background There are some reports on the effects of antidepressants on metabolic syndrome. However, our search in the previously published literature showed a lack of information on the comparison of the effects of different classes of antidepressants on lipid profile. Therefore, this study was aimed to compare the effects of fluoxetine and imipramine on serum total cholesterol (TC and triglyceride (TG as well as body weight (BW in patients with major depressive disorder. Methods Fifty one patients, 18 to 70 years of age, with major depressive disorder complied with the criteria of this preliminary, open-label clinical trial. Subjects received either imipramine (75–200 mg/day or fluoxetine (20–40 mg/day for 8 weeks. Total cholesterol and TG levels, as well as BW were compared at baseline with those at weeks 4 and 8. Data was analyzed by SPSS software version 16.0. Results In the fluoxetine group, TC levels decreased from 165.71 mg/dL to 156.71 mg/dL at week 4 (P = 0.07, and to 143.94 mg/dL at week 8 (P = 0.16; TG levels decreased from 129.35 mg/dL to 115.88 mg/dL at week 4 (P Repeated measures ANOVA showed significant effects on both TC and TG levels as well as on BW in all patients receiving imipramine. However, in patients on fluoxetine, repeated measures ANOVA showed significant effects of this medication only on TC levels in males. Conclusions Monitoring TC and TG and BW is recommended before starting imipramine in depressed patients with increased risk for cardiovascular disease. Fluoxetine may be the preferred agent in those with high or borderline high lipid levels.

  17. Proteomic characterization of hippocampus of chronically socially isolated rats treated with fluoxetine: Depression-like behaviour and fluoxetine mechanism of action.

    Science.gov (United States)

    Perić, Ivana; Costina, Victor; Stanisavljević, Andrijana; Findeisen, Peter; Filipović, Dragana

    2018-06-01

    Due to the severity of depressive symptoms, there remains a necessity in defining the underlying mechanisms of depression and the precise actions of antidepressants in alleviating these symptoms. Proteomics is a powerful and promising tool for discovering novel pathways of cellular responses to disease and treatment. As chronic social isolation (CSIS) is a valuable animal model for studying depression, we performed a comparative subproteomic study of rat hippocampus to explore the effect of six weeks of CSIS and the therapeutic effect of chronic fluoxetine (Flx) treatment (last three weeks of CSIS; 15 mg/kg/day). Behaviorally, Flx treatment normalized the decreased sucrose preference and increased marble burying results resulting from CSIS, indicative of a FLX-induced attenuation of both anhedonia and anxiety. An analysis of cytosolic and nonsynaptic mitochondrial subproteome patterns revealed that CSIS resulted in down-regulation of proteins involved in mitochondrial transport and energy processes, primarily tricarboxylic acid (TCA) cycle and oxidative phosphorylation. Chronic Flx treatment resulted in an up-regulation of CSIS-altered proteins and additional expression of other transporter and energy-involved proteins. Immunohistochemical analysis revealed hippocampal subregion-specific effects of CSIS and/or Flx treatment on selective protein expressions. Copyright © 2018 Elsevier Ltd. All rights reserved.

  18. Maternal postpartum corticosterone and fluoxetine differentially affect adult male and female offspring on anxiety-like behavior, stress reactivity, and hippocampal neurogenesis.

    Science.gov (United States)

    Gobinath, Aarthi R; Workman, Joanna L; Chow, Carmen; Lieblich, Stephanie E; Galea, Liisa A M

    2016-02-01

    Postpartum depression (PPD) affects approximately 15% of mothers, disrupts maternal care, and can represent a form of early life adversity for the developing offspring. Intriguingly, male and female offspring are differentially vulnerable to the effects of PPD. Antidepressants, such as fluoxetine, are commonly prescribed for treating PPD. However, fluoxetine can reach offspring via breast milk, raising serious concerns regarding the long-term consequences of infant exposure to fluoxetine. The goal of this study was to examine the long-term effects of maternal postpartum corticosterone (CORT, a model of postpartum stress/depression) and concurrent maternal postpartum fluoxetine on behavioral, endocrine, and neural measures in adult male and female offspring. Female Sprague-Dawley dams were treated daily with either CORT or oil and fluoxetine or saline from postnatal days 2-23, and offspring were weaned and left undisturbed until adulthood. Here we show that maternal postpartum fluoxetine increased anxiety-like behavior and impaired hypothalamic-pituitary-adrenal (HPA) axis negative feedback in adult male, but not female, offspring. Furthermore, maternal postpartum fluoxetine increased the density of immature neurons (doublecortin-expressing) in the hippocampus of adult male offspring but decreased the density of immature neurons in adult female offspring. Maternal postpartum CORT blunted HPA axis negative feedback in males and tended to increase density of immature neurons in males but decreased it in females. These results indicate that maternal postpartum CORT and fluoxetine can have long-lasting effects on anxiety-like behavior, HPA axis negative feedback, and adult hippocampal neurogenesis and that adult male and female offspring are differentially affected by these maternal manipulations. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. Effects of periadolescent fluoxetine and paroxetine on elevated plus-maze, acoustic startle, and swimming immobility in rats while on and off-drug

    OpenAIRE

    Williams Michael T; Skelton Matthew R; Morford LaRonda R; Graham Devon L; Vorhees Charles V

    2011-01-01

    Abstract Rationale Whether selective serotonin reuptake inhibitors (SSRIs) exposure during adolescent brain development causes lasting effects remains unresolved. Objective Assess the effects of fluoxetine and paroxetine 60 days after adolescent exposure compared with when on-drug. Methods Male Sprague-Dawley littermates (41 litters) were gavaged on postnatal days 33-53 with fluoxetine (3 or 10 mg/kg/day), paroxetine (3, 10 or, 17 mg/kg/day), or water; half were tested while on-drug (21 litte...

  20. Data-mining for detecting signals of adverse drug reactions of fluoxetine using the Korea Adverse Event Reporting System (KAERS) database.

    Science.gov (United States)

    Kim, Seonji; Park, Kyounghoon; Kim, Mi-Sook; Yang, Bo Ram; Choi, Hyun Jin; Park, Byung-Joo

    2017-10-01

    Selective serotonin reuptake inhibitors (SSRIs) have become one of the most broadly used medications in psychiatry. Fluoxetine is the first representative antidepressant SSRI drug approved by the Food and Drug Administration (FDA) in 1987. Safety information on fluoxetine use alone was less reported than its combined use with other drugs. There were no published papers on adverse drug reactions (ADRs) of fluoxetine analyzing spontaneous adverse events reports. We detected signals of the adverse drug reactions of fluoxetine by data mining using the Korea Adverse Events Reporting System (KAERS) database. We defined signals in this study by the reporting odds ratios (ROR), proportional reporting ratios (PRR), and information components (IC) indices. The KAERS database included 860,224 AE reports, among which 866 reports contained fluoxetine. We compared the labels of fluoxetine among the United States, UK, Germany, France, China, and Korea. Some of the signals, including emotional lability, myositis, spinal stenosis, paradoxical drug reaction, drug dependence, extrapyramidal disorder, adrenal insufficiency, and intracranial hemorrhage, were not labeled in the six countries. In conclusion, we identified new signals that were not known at the time of market approval. However, certain factors should be required for signal evaluation, such as clinical significance, preventability, and causality of the detected signals. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Antidepressant-like effect of fluoxetine may depend on translocator protein activity and pretest session duration in forced swimming test in mice.

    Science.gov (United States)

    Kudryashov, Nikita V; Kalinina, Tatiana S; Shimshirt, Alexander A; Korolev, Anton O; Volkova, Anna V; Voronina, Tatiana A

    2018-06-01

    The antidepressant-like effect of fluoxetine (20 mg/kg i.p.) has been assessed using the forced swimming test (FST) in IRC (CD-1) mice exposed or not to a pretest session of different duration (5 or 20 min). The influence of the mitochondrial translocator protein (TSPO) activity on the antidepressant-like effect of fluoxetine (20 mg/kg i.p.) in the FST was also studied. The antidepressant-like effect of fluoxetine was observed only in mice subjected to a 5-min pretest session 24 h before the FST. The TSPO antagonist PK11195 [1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide; 1 or 3 mg/kg i.p.] inhibited the antidepressant activity of fluoxetine in the FST. In the present study, fluoxetine or PK11195 was administered for a short duration. We suppose that the functional activity of TSPO may depend on a pretest session and that using this procedure is necessary to detect antidepressant activity of fluoxetine-like drugs.

  2. A multibiomarker approach to explore interactive effects of propranolol and fluoxetine in marine mussels

    International Nuclear Information System (INIS)

    Franzellitti, Silvia; Buratti, Sara; Du, Bowen; Haddad, Samuel P.; Chambliss, C. Kevin; Brooks, Bryan W.; Fabbri, Elena

    2015-01-01

    A multi-biomarker approach, including several lysosomal parameters, activity and mRNA expression of antioxidant enzymes, and DNA damage, was employed to investigate the nominal effects of 0.3 ng/L fluoxetine (FX) and 0.3 ng/L propranolol (PROP) alone or in combination (0.3 ng/L FX + 0.3 ng/L PROP) on Mediterranean mussels after a 7 day treatment. FX co-exposure appears to facilitate PROP bioaccumulation because PROP only accumulated in digestive gland of FX + PROP treated mussels. Lysosomal parameters were significantly impaired by FX + PROP treatment, while no clear antioxidant responses at the catalytic and transcriptional levels were observed. Biomarker responses led to a “medium stress level” diagnosis in FX + PROP treated mussels, according to the Expert System, whereas 0.3 ng/L PROP or FX alone did not induce consistent stress conditions. These findings suggest vulnerability of coastal marine mussels to FX and PROP contamination at environmentally relevant levels. - Highlights: • FX and PROP combined effects were assessed in marine mussels using biomarkers. • PROP bioaccumulation was observed in digestive gland of FX + PROP treated mussels. • Lysosomal parameters were significantly impaired by FX + PROP treatment. • No clear antioxidant responses at the catalytic and mRNA levels were observed. • FX + PROP treatment increased stress levels of mussels compared with the single chemicals. - Fluoxetine and propranolol induce interactive effects on marine mussels biomarker responses and pharmaceutical bioaccumulation

  3. Sequential treatment with fluoxetine and relapse--prevention CBT to improve outcomes in pediatric depression.

    Science.gov (United States)

    Kennard, Betsy D; Emslie, Graham J; Mayes, Taryn L; Nakonezny, Paul A; Jones, Jessica M; Foxwell, Aleksandra A; King, Jessica

    2014-10-01

    The authors evaluated a sequential treatment strategy of fluoxetine and relapse-prevention cognitive-behavioral therapy (CBT) to determine effects on remission and relapse in youths with major depressive disorder. Youths 8-17 years of age with major depression were treated openly with fluoxetine for 6 weeks. Those with an adequate response (defined as a reduction of 50% or more on the Children's Depression Rating Scale-Revised [CDRS-R]) were randomly assigned to receive continued medication management alone or continued medication management plus CBT for an additional 6 months. The CBT was modified to address residual symptoms and was supplemented by well-being therapy. Primary outcome measures were time to remission (with remission defined as a CDRS-R score of 28 or less) and rate of relapse (with relapse defined as either a CDRS-R score of 40 or more with a history of 2 weeks of symptom worsening, or clinical deterioration). Of the 200 participants enrolled in acute-phase treatment, 144 were assigned to continuation treatment with medication management alone (N=69) or medication management plus CBT (N=75). During the 30-week continuation treatment period, time to remission did not differ significantly between treatment groups (hazard ratio=1.26, 95% CI=0.87, 1.82). However, the medication management plus CBT group had a significantly lower risk of relapse than the medication management only group (hazard ratio=0.31, 95% CI=0.13, 0.75). The estimated probability of relapse by week 30 was lower with medication management plus CBT than with medication management only (9% compared with 26.5%). Continuation-phase relapse-prevention CBT was effective in reducing the risk of relapse but not in accelerating time to remission in children and adolescents with major depressive disorder.

  4. Chronic Fluoxetine Induces Activity Changes in Recovery From Poststroke Anxiety, Depression, and Cognitive Impairment.

    Science.gov (United States)

    Vahid-Ansari, Faranak; Albert, Paul R

    2018-01-01

    Poststroke depression (PSD) is a common outcome of stroke that limits recovery and is only partially responsive to chronic antidepressant treatment. In order to elucidate changes in the cortical-limbic circuitry associated with PSD and its treatment, we examined a novel mouse model of persistent PSD. Focal endothelin-1-induced ischemia of the left medial prefrontal cortex (mPFC) in male C57BL6 mice resulted in a chronic anxiety and depression phenotype. Here, we show severe cognitive impairment in spatial learning and memory in the stroke mice. The behavioral and cognitive phenotypes were reversed by chronic (4-week) treatment with fluoxetine, alone or with voluntary exercise (free-running wheel), but not by exercise alone. To assess chronic cellular activation, FosB + cells were co-labeled for markers of glutamate/pyramidal (VGluT1-3/CaMKIIα), γ-aminobutyric acid (GAD67), and serotonin (TPH). At 6 weeks poststroke versus sham (or 4 days poststroke), left mPFC stroke induced widespread FosB activation, more on the right (contralesional) than on the left side. Stroke activated glutamate cells of the mPFC, nucleus accumbens, amygdala, hippocampus, and raphe serotonin neurons. Chronic fluoxetine balanced bilateral neuronal activity, reducing total FosB and FosB/CamKII + cells (mPFC, nucleus accumbens), and unlike exercise, increasing FosB/GAD67 + cells (septum, amygdala) or both (hippocampus, raphe). In summary, chronic antidepressant but not exercise mediates recovery in this unilateral ischemic PSD model that is associated with region-specific reversal of stroke-induced pyramidal cell hyperactivity and increase in γ-aminobutyric acidergic activity. Targeted brain stimulation to restore brain activity could provide a rational approach for treating clinical PSD.

  5. Homeopathic Individualized Q-Potencies versus Fluoxetine for Moderate to Severe Depression: Double-Blind, Randomized Non-Inferiority Trial

    Directory of Open Access Journals (Sweden)

    U. C. Adler

    2011-01-01

    Full Text Available Homeopathy is a complementary and integrative medicine used in depression, The aim of this study is to investigate the non-inferiority and tolerability of individualized homeopathic medicines [Quinquagintamillesmial (Q-potencies] in acute depression, using fluoxetine as active control. Ninety-one outpatients with moderate to severe depression were assigned to receive an individualized homeopathic medicine or fluoxetine 20 mg day−1 (up to 40 mg day−1 in a prospective, randomized, double-blind double-dummy 8-week, single-center trial. Primary efficacy measure was the analysis of the mean change in the Montgomery & Åsberg Depression Rating Scale (MADRS depression scores, using a non-inferiority test with margin of 1.45. Secondary efficacy outcomes were response and remission rates. Tolerability was assessed with the side effect rating scale of the Scandinavian Society of Psychopharmacology. Mean MADRS scores differences were not significant at the 4th (P = .654 and 8th weeks (P = .965 of treatment. Non-inferiority of homeopathy was indicated because the upper limit of the confidence interval (CI for mean difference in MADRS change was less than the non-inferiority margin: mean differences (homeopathy-fluoxetine were −3.04 (95% CI −6.95, 0.86 and −2.4 (95% CI −6.05, 0.77 at 4th and 8th week, respectively. There were no significant differences between the percentages of response or remission rates in both groups. Tolerability: there were no significant differences between the side effects rates, although a higher percentage of patients treated with fluoxetine reported troublesome side effects and there was a trend toward greater treatment interruption for adverse effects in the fluoxetine group. This study illustrates the feasibility of randomized controlled double-blind trials of homeopathy in depression and indicates the non-inferiority of individualized homeopathic Q-potencies as compared to fluoxetine in acute treatment of

  6. Homeopathic Individualized Q-Potencies versus Fluoxetine for Moderate to Severe Depression: Double-Blind, Randomized Non-Inferiority Trial

    Science.gov (United States)

    Adler, U. C.; Paiva, N. M. P.; Cesar, A. T.; Adler, M. S.; Molina, A.; Padula, A. E.; Calil, H. M.

    2011-01-01

    Homeopathy is a complementary and integrative medicine used in depression, The aim of this study is to investigate the non-inferiority and tolerability of individualized homeopathic medicines [Quinquagintamillesmial (Q-potencies)] in acute depression, using fluoxetine as active control. Ninety-one outpatients with moderate to severe depression were assigned to receive an individualized homeopathic medicine or fluoxetine 20 mg day−1 (up to 40 mg day−1) in a prospective, randomized, double-blind double-dummy 8-week, single-center trial. Primary efficacy measure was the analysis of the mean change in the Montgomery & Åsberg Depression Rating Scale (MADRS) depression scores, using a non-inferiority test with margin of 1.45. Secondary efficacy outcomes were response and remission rates. Tolerability was assessed with the side effect rating scale of the Scandinavian Society of Psychopharmacology. Mean MADRS scores differences were not significant at the 4th (P = .654) and 8th weeks (P = .965) of treatment. Non-inferiority of homeopathy was indicated because the upper limit of the confidence interval (CI) for mean difference in MADRS change was less than the non-inferiority margin: mean differences (homeopathy-fluoxetine) were −3.04 (95% CI −6.95, 0.86) and −2.4 (95% CI −6.05, 0.77) at 4th and 8th week, respectively. There were no significant differences between the percentages of response or remission rates in both groups. Tolerability: there were no significant differences between the side effects rates, although a higher percentage of patients treated with fluoxetine reported troublesome side effects and there was a trend toward greater treatment interruption for adverse effects in the fluoxetine group. This study illustrates the feasibility of randomized controlled double-blind trials of homeopathy in depression and indicates the non-inferiority of individualized homeopathic Q-potencies as compared to fluoxetine in acute treatment of outpatients

  7. The role of fluoxetine on macrophage function in chronic pain (Experimental study in Balb/c mice

    Directory of Open Access Journals (Sweden)

    Dwi Pudjonarko

    2015-11-01

    Full Text Available Chronic pain raises stress conditions such as depression that can lower the cellular immunity. Fluoxetine is an antidepressant  used as an adjuvant in pain management but no one has been linked it with the body immune system. The objectives of this research were to proof the benefits of fluoxetine in  preventing degradation of macrophage function in chronic pain by measuring the macrophage phagocytic index , macrophage NO levels and the liver bacterial count in BALB/c mice infected with Listeria Monocytogenes.A Post Test - Only Control Group Design was conducted using 28 male mice strain BALB /c, age 8-10 weeks. The control group (C, mice got the same standard feed as the other groups. Chronic pain group (P, mice were injected with 20μL intraplantar CFA on day-1. Pain + fluoxetine early group (PFE were treated with P + fluoxetine 5 mg / kg ip day-1, the 4th, the 7th and the 10th, while the Pain + fluoxetine late group (PFL were treated with P + fluoxetine 5 mg / kg ip on day 7th and 10th. All mice were injected with 104 live Listeria monocytogenes iv on day 8th. Termination was performed on day 13th. Differences within groups  were analyzed using  One-way ANOVA and Kruskall Wallis, whereas the correlation of variables were analyzed using  Pearson's product moment. The experimental results showed that The macrophage phagocytic index and NO macrophage level (pg/mL in PFE group(2,24±1,013; 0,24±0,239 was higher than than P group (1,68±0,920; 0,21±0,263 and there was no different in the macrophage phagocytic index of PFE group compared to C group (p=0,583; p=0,805. In PFL group (4,32±1,459; 0,54±0,294 the macrophage phagocytic index as well as NO macrophage level (pg/mL was higher than P group (1,68±0,920; 0,21±0,263 with p=0,002; p=0,017. P group Bacterial count (log cfu/gram (2,30±0,849 was significantly higher than C group(1,15±0,223 (p=0,007, while PFE group bacterial count (1,96±0,653 and PFL group bacterial count (1,84±0

  8. Reduced vasopressin receptors activation mediates the anti-depressant effects of fluoxetine and venlafaxine in bulbectomy model of depression.

    Science.gov (United States)

    Poretti, María Belén; Sawant, Rahul S; Rask-Andersen, Mathias; de Cuneo, Marta Fiol; Schiöth, Helgi B; Perez, Mariela F; Carlini, Valeria Paola

    2016-03-01

    In response to stress, corticotropin releasing hormone (CRH) and vasopressin (AVP) are released from the hypothalamus, activate their receptors (CRHR1, CRHR2 or AVPr1b), and synergistically act to induce adrenocorticotropic hormone (ACTH) release from the anterior pituitary. Overstimulation of this system has been frequently associated with major depression states. The objective of the study is to assess the role of AVP and CRH receptors in fluoxetine and venlafaxine effects on the expression of depression-related behavior. In an animal model of depression (olfactory bulbectomy in mice, OB), we evaluated the effects of fluoxetine or venlafaxine (both 10 mg/kg/day) chronic administration on depression-related behavior in the tail suspension test. Plasma levels of AVP, CRH, and ACTH were determined as well as participation of their receptors in the expression of depression related-behavior and gene expression of AVP and CRH receptors (AVPr1b, CRHR1, and CRHR2) in the pituitary gland. The expression of depressive-like behavior in OB animals was reversed by treatment with both antidepressants. Surprisingly, OB-saline mice exhibited increased AVP and ACTH plasma levels, with no alterations in CRH levels when compared to sham mice. Chronic fluoxetine or venlafaxine reversed these effects. In addition, a significant increase only in AVPr1b gene expression was found in OB-saline. The antidepressant therapy used seems to be more likely related to a reduced activation of AVP rather than CRH receptors, since a positive correlation between AVP levels and depressive-like behavior was observed in OB animals. Furthermore, a full restoration of depressive behavior was observed in OB-fluoxetine- or venlafaxine-treated mice only when AVP was centrally administered but not CRH.

  9. Association of regulatory TPH2 polymorphisms with higher reduction in depressive symptoms in children and adolescents treated with fluoxetine.

    Science.gov (United States)

    Gassó, Patricia; Rodríguez, Natalia; Boloc, Daniel; Blázquez, Ana; Torres, Teresa; Gortat, Ana; Plana, Maria Teresa; Lafuente, Amalia; Mas, Sergi; Arnaiz, Joan Albert; Lázaro, Luisa

    2017-07-03

    Genetic variability related to the brain serotonergic system has a significant impact on both the susceptibility to psychiatric disorders, such as major depressive disorder (MDD), and the response to antidepressant drugs, such as fluoxetine. TPH2 is one of the most important serotonergic candidate genes in selective serotonin reuptake inhibitors (SSRIs) pharmacogenetic studies. The aim of the present study was to evaluate the influence of regulatory polymorphisms that are specifically located in human TPH2 transcription factor binding sites (TFBSs), and therefore could be functional by altering gene expression, on clinical improvement in children and adolescents treated with fluoxetine. The selection of SNPs was also based on their linkage disequilibrium with TPH2 rs4570625, a genetic variant with questionable functionality, which was previously associated with clinical response in our pediatric population. A total of 83 children and adolescents were clinically evaluated 12weeks after initiating antidepressant treatment with fluoxetine for the first time. Clinical improvement was assessed by reductions in depressive symptoms measured using the Children's Depression Inventory (CDI) scale. The polymorphisms rs11179002, rs60032326 and rs34517220 were, for the first time in the literature, significantly associated with higher clinical improvement. The strongest association was found for rs34517220. In particular, minor allele homozygotes showed higher score reductions on the CDI scale compared with the major allele carriers. Interestingly, this polymorphism is located in a human TPH2 TFBS for two relevant transcription factors in the serotoninergic neurons, Foxa1 and Foxa2, which together with the high level of significance found for this SNP, could indicate that rs34517220 is in fact the crucial functional genetic variant related to the fluoxetine response. These results provide new evidence for the role of regulatory genetic variants that could modulate human TPH2

  10. Differential interaction with the serotonin system by S-ketamine, vortioxetine, and fluoxetine in a genetic rat model of depression.

    Science.gov (United States)

    du Jardin, Kristian Gaarn; Liebenberg, Nico; Müller, Heidi Kaastrup; Elfving, Betina; Sanchez, Connie; Wegener, Gregers

    2016-07-01

    The mechanisms mediating ketamine's antidepressant effect have only been partly resolved. Recent preclinical reports implicate serotonin (5-hydroxytryptamine; 5-HT) in the antidepressant-like action of ketamine. Vortioxetine is a multimodal-acting antidepressant that is hypothesized to exert its therapeutic activity through 5-HT reuptake inhibition and modulation of several 5-HT receptors. The objective of this study was to evaluate the therapeutic-like profiles of S-ketamine, vortioxetine, and the serotonin reuptake inhibitor fluoxetine in response to manipulation of 5-HT tone. Flinders Sensitive Line (FSL) rats, a genetic model of depression, were depleted of 5-HT by repeated administration of 4-chloro-DL-phenylalanine methyl ester HCl (pCPA). Using pCPA-pretreated and control FSL rats, we investigated the acute and sustained effects of S-ketamine (15 mg/kg), fluoxetine (10 mg/kg), or vortioxetine (10 mg/kg) on recognition memory and depression-like behavior in the object recognition task (ORT) and forced swim test (FST), respectively. The behavioral phenotype of FSL rats was unaffected by 5-HT depletion. Vortioxetine, but not fluoxetine or S-ketamine, acutely ameliorated the memory deficits of FSL rats in the ORT irrespective of 5-HT tone. No sustained effects were observed in the ORT. In the FST, all three drugs demonstrated acute antidepressant-like activity but only S-ketamine had sustained effects. Unlike vortioxetine, the antidepressant-like responses of fluoxetine and S-ketamine were abolished by 5-HT depletion. These observations suggest that the acute and sustained antidepressant-like effects of S-ketamine depend on endogenous stimulation of 5-HT receptors. In contrast, the acute therapeutic-like effects of vortioxetine on memory and depression-like behavior may be mediated by direct activity at 5-HT receptors.

  11. Removal of fluoxetine and its effects in the performance of an aerobic granular sludge sequential batch reactor

    Energy Technology Data Exchange (ETDEWEB)

    Moreira, Irina S.; Amorim, Catarina L. [CBQF – Centro de Biotecnologia e Química Fina – Laboratório Associado, Escola Superior de Biotecnologia, Universidade Católica Portuguesa/Porto, Rua Dr. António Bernardino Almeida, 4200-072 Porto (Portugal); Ribeiro, Ana R. [CBQF – Centro de Biotecnologia e Química Fina – Laboratório Associado, Escola Superior de Biotecnologia, Universidade Católica Portuguesa/Porto, Rua Dr. António Bernardino Almeida, 4200-072 Porto (Portugal); Centro de Química Medicinal da Universidade do Porto (CEQUIMED-UP), Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto (Portugal); CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Rua Central de Gandra 1317, 4585-116 Gandra PRD (Portugal); Mesquita, Raquel B.R. [CBQF – Centro de Biotecnologia e Química Fina – Laboratório Associado, Escola Superior de Biotecnologia, Universidade Católica Portuguesa/Porto, Rua Dr. António Bernardino Almeida, 4200-072 Porto (Portugal); Laboratory of Hydrobiology, Institute of Biomedical Sciences Abel Salazar (ICBAS) and Institute of Marine Research (CIIMAR), Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto (Portugal); and others

    2015-04-28

    Highlights: • Enantioselective removal of fluoxetine by aerobic granular sludge was evaluated. • Sorption of fluoxetine to aerobic granules occurred. • Bacterial community gradually changed during operation of sequential batch reactor. • Main biological processes occurring within the granules were preserved. • Overall performance of the reactor was recovered after initial fluoxetine shock loads. - Abstract: Fluoxetine (FLX) is a chiral fluorinated pharmaceutical mainly indicated for treatment of depression and is one of the most distributed drugs. There is a clear evidence of environmental contamination with this drug. Aerobic granular sludge sequencing batch reactors constitute a promising technology for wastewater treatment; however the removal of carbon and nutrients can be affected by micropollutants. In this study, the fate and effect of FLX on reactor performance and on microbial population were investigated. FLX adsorption/desorption to the aerobic granules was observed. FLX shock loads (≤4 μM) did not show a significant effect on the COD removal. Ammonium removal efficiency decreased in the beginning of first shock load, but after 20 days, ammonia oxidizing bacteria became adapted. The nitrite concentration in the effluent was practically null indicating that nitrite oxidizing bacteria was not inhibited, whereas, nitrate was accumulated in the effluent, indicating that denitrification was affected. Phosphate removal was affected at the beginning showing a gradual adaptation, and the effluent concentration was <0.04 mM after 70 days. A shift in microbial community occurred probably due to FLX exposure, which induced adaptation/restructuration of the microbial population. This contributed to the robustness of the reactor, which was able to adapt to the FLX load.

  12. Removal of fluoxetine and its effects in the performance of an aerobic granular sludge sequential batch reactor

    International Nuclear Information System (INIS)

    Moreira, Irina S.; Amorim, Catarina L.; Ribeiro, Ana R.; Mesquita, Raquel B.R.

    2015-01-01

    Highlights: • Enantioselective removal of fluoxetine by aerobic granular sludge was evaluated. • Sorption of fluoxetine to aerobic granules occurred. • Bacterial community gradually changed during operation of sequential batch reactor. • Main biological processes occurring within the granules were preserved. • Overall performance of the reactor was recovered after initial fluoxetine shock loads. - Abstract: Fluoxetine (FLX) is a chiral fluorinated pharmaceutical mainly indicated for treatment of depression and is one of the most distributed drugs. There is a clear evidence of environmental contamination with this drug. Aerobic granular sludge sequencing batch reactors constitute a promising technology for wastewater treatment; however the removal of carbon and nutrients can be affected by micropollutants. In this study, the fate and effect of FLX on reactor performance and on microbial population were investigated. FLX adsorption/desorption to the aerobic granules was observed. FLX shock loads (≤4 μM) did not show a significant effect on the COD removal. Ammonium removal efficiency decreased in the beginning of first shock load, but after 20 days, ammonia oxidizing bacteria became adapted. The nitrite concentration in the effluent was practically null indicating that nitrite oxidizing bacteria was not inhibited, whereas, nitrate was accumulated in the effluent, indicating that denitrification was affected. Phosphate removal was affected at the beginning showing a gradual adaptation, and the effluent concentration was <0.04 mM after 70 days. A shift in microbial community occurred probably due to FLX exposure, which induced adaptation/restructuration of the microbial population. This contributed to the robustness of the reactor, which was able to adapt to the FLX load

  13. Fluoxetine prevents the development of depressive-like behavior in a mouse model of cancer related fatigue.

    Science.gov (United States)

    Norden, Diana M; Devine, Raymond; Bicer, Sabahattin; Jing, Runfeng; Reiser, Peter J; Wold, Loren E; Godbout, Jonathan P; McCarthy, Donna O

    2015-03-01

    Cancer patients frequently suffer from fatigue, a complex syndrome associated with tiredness and depressed mood. Cancer-related fatigue (CRF) can be present at the time of diagnosis, escalates during treatment, and can persist for years after treatment. CRF negatively influences quality of life, limits functional independence, and is associated with decreased survival in patients with incurable disease. We have previously shown that increased pro-inflammatory cytokine expression in the brain contributes to depressive- and fatigue-like behaviors in a mouse model of CRF. Inflammatory cytokines increase the activity of indoleamine 2,3-dioxygenase (IDO) and kynurenine 3-monooxygenase (KMO), which competitively reduce serotonin synthesis. Reduced serotonin availability in the brain and increased production of alternative neuroactive metabolites of tryptophan are thought to contribute to the development of depression and fatigue. The purpose of this study was to determine the effects of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), on brain cytokines and behavioral measures of fatigue and depression in tumor-bearing mice. Here we show that tumor growth increased brain expression of pro-inflammatory cytokines and KMO. Treatment with fluoxetine had no effect on tumor growth, muscle wasting, fatigue behavior, or cytokine expression in the brain. Fluoxetine, however, reduced depressive-like behaviors in tumor bearing mice. In conclusion, our data confirm that increased brain expression of pro-inflammatory cytokines is associated with tumor-induced fatigue- and depressive-like behaviors. However, it is possible to separate the effects of tumor growth on mood and fatigue-like behaviors using SSRIs such as fluoxetine. Copyright © 2014 Elsevier Inc. All rights reserved.

  14. Synergy effects of fluoxetine and variability in temperature lead to proportionally greater fitness costs in Daphnia: A multigenerational test.

    Science.gov (United States)

    Barbosa, Miguel; Inocentes, Núrya; Soares, Amadeu M V M; Oliveira, Miguel

    2017-12-01

    Increased variability in water temperature is predicted to impose disproportionally greater fitness costs than mean increase in temperature. Additionally, water contaminants are currently a major source of human-induced stress likely to produce fitness costs. Global change models forecast an increase in these two human-induced stressors. Yet, in spite the growing interest in understanding how organisms respond to global change, the joint fitness effects of water pollution and increased variability in temperature remain unclear. Here, using a multigenerational design, we test the hypothesis that exposure to high concentrations of fluoxetine, a human medicine commonly found in freshwater systems, causes increased lifetime fitness costs, when associated with increased variability in temperature. Although fluoxetine and variability in temperature elicited some fitness cost when tested alone, when both stressors acted together the costs were disproportionally greater. The combined effect of fluoxetine and variability in temperature led to a reduction of 37% in lifetime reproductive success and a 17.9% decrease in population growth rate. Interestingly, fluoxetine and variability in temperature had no effect on the probability of survival. Freshwater systems are among the most imperilled ecosystems, often exposed to multiple human-induced stressors. Our results indicate that organisms face greater fitness risk when exposed to multiple stressors at the same time than when each stress acts alone. Our study highlights the importance of using a multi-generational approach to fully understand individual environmental tolerance and its responses to a global change scenario in aquatic systems. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Acute administration of fluoxetine normalizes rapid eye movement sleep abnormality, but not depressive behaviors in olfactory bulbectomized rats.

    Science.gov (United States)

    Wang, Yi-Qun; Tu, Zhi-Cai; Xu, Xing-Yuan; Li, Rui; Qu, Wei-Min; Urade, Yoshihiro; Huang, Zhi-Li

    2012-01-01

    In humans, depression is associated with altered rapid eye movement (REM) sleep. However, the exact nature of the relationship between depressive behaviors and sleep abnormalities is debated. In this study, bilateral olfactory bulbectomy (OBX) was carried out to create a model of depression in rats. The sleep-wake profiles were assayed using a cutting-edge sleep bioassay system, and depressive behaviors were evaluated by open field and forced swimming tests. The monoamine content and monoamine metabolite levels in the brain were determined by a HPLC-electrochemical detection system. OBX rats exhibited a significant increase in REM sleep, especially between 15:00 and 18:00 hours during the light period. Acute treatment with fluoxetine (10 mg/kg, i.p.) immediately abolished the OBX-induced increase in REM sleep, but hyperactivity in the open field test and the time spent immobile in the forced swimming test remained unchanged. Neurochemistry studies revealed that acute administration of fluoxetine increased serotonin (5-HT) levels in the hippocampus, thalamus, and midbrain and decreased levels of the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA). The ratio of 5-HIAA to 5-HT decreased in almost all regions of the brain. These results indicate that acute administration of fluoxetine can reduce the increase in REM sleep but does not change the depressive behaviors in OBX rats, suggesting that there was no causality between REM sleep abnormalities and depressive behaviors in OBX rats. © 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.

  16. [Effects of chronic fluoxetine treatment on manifestation of sexual motivation and social behavior in mice of ASC line].

    Science.gov (United States)

    Tikhonova, M A; Otroshchenko, E A; Kulikov, A V

    2010-02-01

    Sexual dysfunctions are the typical symptoms accompanying depressive disorders. However antidepressants which improve general state of the patients have no effect on sexual disorders. Mice of ASC (Antidepressant Sensitive Catalepsy) line with high hereditary predisposition to catalepsy were proposed as a model of genetically associated depressive-like condition. The work was aimed at comparison of behavioral indices of sexual motivation and social interest of ASC mice with those of mice of parental inbred AKR and CBA strains, and at the study of the effects of chronic fluoxetine treatment in doses of 10 and 20 mg/kg on these parameters in ASC mice. ASC males demonstrated reduced sexual motivation which was not corrected by fluoxetine. ASC mice did not differ in the expression of social interest and aggression towards juvenile intruder from mice of parental strains. Fluoxetine failed to alter social behavior of ASC mice in social interaction test but its higher dose decreased percentage of aggressors. ASC mouse line seems to be a perspective model to study genetic mechanisms of sexual dysfunctions associated with depressive conditions.

  17. From selective to highly selective SSRIs: a comparison of the antinociceptive properties of fluoxetine, fluvoxamine, citalopram and escitalopram.

    Science.gov (United States)

    Schreiber, Shaul; Pick, Chaim G

    2006-08-01

    Most Serotonin Selective Reuptake Inhibitors (SSRIs) have been found to possess secondary binding properties, while citalopram and its S-enantiomer (escitalopram) have been reconfirmed "purest SSRIs". Using the mouse model of acute pain hotplate analgesia meter, we evaluated the antinociceptive properties of fluoxetine, fluvoxamine, citalopram and escitalopram, injected i.p. Fluvoxamine induced a dose-dependent clear antinociceptive effect (with an ED(50) value of 6.4 mg/kg). Both fluoxetine and citalopram induced (separately) only a weak antinociceptive effect with an inverse "U" shape curve. All three drug's effects were not abolished by naloxone. Escitalopram did not elicit any effect at quasi-equipotent doses. These findings show that fluoxetine, fluvoxamine and citalopram given i.p. are weak antinociceptors, (not mediated through opioid mechanisms), while escitalopram possesses no antinociceptive properties when injected i.p. This difference between citalopram and escitalopram calls for further studies in order to assess the various differences between the two enantiomers of citalopram, and between each enantiomer and the racemic mixture.

  18. Effects of fluoxetine on the amygdala and the hippocampus after administration of a single prolonged stress to male Wistar rates: In vivo proton magnetic resonance spectroscopy findings.

    Science.gov (United States)

    Han, Fang; Xiao, Bing; Wen, Lili; Shi, Yuxiu

    2015-05-30

    Posttraumatic stress disorder (PTSD) is an anxiety- and memory-based disorder. The hippocampus and amygdala are key areas in mood regulation. Fluoxetine was found to improve the anxiety-related symptoms of PTSD patients. However, little work has directly examined the effects of fluoxetine on the hippocampus and the amygdala. In the present study, male Wistar rats received fluoxetine or vehicle after exposure to a single prolonged stress (SPS), an animal model of PTSD. In vivo proton magnetic resonance spectroscopy ((1)H-MRS) was performed -1, 1, 4, 7 and 14 days after SPS to examine the effects of fluoxetine on neurometabolite changes in amygdala, hippocampus and thalamus. SPS increased the N-acetylaspartate (NAA)/creatine (Cr) and choline moieties (Cho)/Cr ratios in the bilateral amygdala on day 4, decreased the NAA/Cr ratio in the left hippocampus on day 1, and increased both ratios in the right hippocampus on day 14. But no significant change was found in the thalamus. Fluoxetine treatment corrected the SPS increases in the NAA/Cr and Cho/Cr levels in the amygdala on day 4 and in the hippocampus on day 14, but it failed to normalise SPS-associated decreases in NAA/Cr levels in the left hippocampus on day 1. These results suggested that metabolic abnormalities in the amygdala and the hippocampus were involved in SPS, and different effects of fluoxetine in correcting SPS-induced neurometabolite changes among the three areas. These findings have implications for fluoxetine treatment in PTSD. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  19. Neuroendocrine disruption in the shore crab Carcinus maenas: Effects of serotonin and fluoxetine on chh- and mih-gene expression, glycaemia and ecdysteroid levels.

    Science.gov (United States)

    Robert, Alexandrine; Monsinjon, Tiphaine; Delbecque, Jean-Paul; Olivier, Stéphanie; Poret, Agnès; Foll, Frank Le; Durand, Fabrice; Knigge, Thomas

    2016-06-01

    Serotonin, a highly conserved neurotransmitter, controls many biological functions in vertebrates, but also in invertebrates. Selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, are commonly used in human medication to ease depression by affecting serotonin levels. Their residues and metabolites can be detected in the aquatic environment and its biota. They may also alter serotonin levels in aquatic invertebrates, thereby perturbing physiological functions. To investigate whether such perturbations can indeed be expected, shore crabs (Carcinus maenas) were injected either with serotonin, fluoxetine or a combination of both. Dose-dependent effects of fluoxetine ranging from 250 to 750nM were investigated. Gene expression of crustacean hyperglycemic hormone (chh) as well as moult inhibiting hormone (mih) was assessed by RT-qPCR at 2h and 12h after injection. Glucose and ecdysteroid levels in the haemolymph were monitored in regular intervals until 12h. Serotonin led to a rapid increase of chh and mih expression. On the contrary, fluoxetine only affected chh and mih expression after several hours, but kept expression levels significantly elevated. Correspondingly, serotonin rapidly increased glycaemia, which returned to normal or below normal levels after 12h. Fluoxetine, however, resulted in a persistent low-level increase of glycaemia, notably during the period when negative feedback regulation reduced glycaemia in the serotonin treated animals. Ecdysteroid levels were significantly decreased by serotonin and fluoxetine, with the latter showing less pronounced and less rapid, but longer lasting effects. Impacts of fluoxetine on glycaemia and ecdysteroids were mostly observed at higher doses (500 and 750nM) and affected principally the response dynamics, but not the amplitude of glycaemia and ecdysteroid-levels. These results suggest that psychoactive drugs are able to disrupt neuroendocrine control in decapod crustaceans, as they interfere with the

  20. Effect of co-treatment with fluoxetine or mirtazapine and risperidone on the active behaviors and plasma corticosterone concentration in rats subjected to the forced swim test.

    Science.gov (United States)

    Rogóż, Zofia; Kabziński, Marcin; Sadaj, Witold; Rachwalska, Paulina; Gądek-Michalska, Anna

    2012-01-01

    Several clinical reports have postulated a beneficial effect of the addition of a low dose of risperidone to the ongoing treatment with antidepressants in treatment-resistant depression. The present study aimed to examine the effect of treatment with fluoxetine or mirtazapine, given separately or jointly with risperidone, on active behavior and plasma corticosterone level in male Wistar rats subjected to the forced swim test (FST). The obtained results showed that fluoxetine (5 mg/kg), mirtazapine (5 and 10 mg/kg) or risperidone (0.05 and 0.1 mg/kg) did not change the active behavior of rats in the FST. However, co-treatment with fluoxetine (10 mg/kg) and risperidone (0.1 mg/kg) induced an antidepressant-like effect in that test because it significantly increased the swimming time and decreased the immobility time, while combined treatment with mirtazapine at 5 and 10 mg/kg and risperidone at 0.05 and 0.1 mg/kg evoked a significant increase in the swimming time and also climbing, and decreased the immobility time. WAY 100635 (a 5-HT(1A) receptor antagonist) at a dose of 0.1 mg/kg inhibited the antidepressant-like effect induced by co-administration of fluoxetine or mirtazapine and risperidone. Active behavior in that test did not reflect an increase in general activity, since combined treatment with fluoxetine or mirtazapine and risperidone failed to enhance the exploratory activity of rats. Co-treatment with fluoxetine or mirtazapine and risperidone did not reduce the stress-induced increase in plasma corticosterone concentration in animals subjected to the FST. The obtained results indicate that risperidone applied in a low dose enhances the antidepressant-like activity of fluoxetine and mirtazapine in the FST (but does not normalize the stress-induced increase in corticosterone level in these rats), and that 5-HT(1A) receptors may play some role in these effects.

  1. Fluoxetine for Autistic Behaviors (FAB trial): study protocol for a randomized controlled trial in children and adolescents with autism.

    Science.gov (United States)

    Mouti, Anissa; Reddihough, Dinah; Marraffa, Catherine; Hazell, Philip; Wray, John; Lee, Katherine; Kohn, Michael

    2014-06-16

    Serotonin reuptake inhibitors (SSRIs) are commonly prescribed off-label for children with autism. To date, clinical trials examining the use of SSRIs in autism have been limited by small sample sizes and inconclusive results. The efficacy and safety of SSRIs for moderating autistic behaviors is yet to be adequately examined to provide evidence to support current clinical practice. The aim of the Fluoxetine for Autistic Behaviors (FAB) study is to determine the efficacy and safety of low dose fluoxetine compared with placebo, for reducing the frequency and severity of repetitive stereotypic behaviors in children and adolescents with an autism spectrum disorder (ASD). The relationship between the effectiveness of fluoxetine treatment and serotonin transporter genotype will also be explored. The FAB study is a multicenter, double-blinded, randomized controlled trial, funded by the Australian Government's National Health and Medical Research Council (NHMRC) grant. Participants will be aged between 7.5 and 17 years with a confirmed diagnosis of ASD. Eligible participants will be randomized to either placebo or fluoxetine for a 16-week period. Medication will be titrated over the first four weeks. Reponses to medication will be monitored fortnightly using the Clinical Global Impressions Scale (CGI). The primary outcome measure is the Children's Yale-Brown Obsessive Compulsive Scale-Modified for Pervasive Developmental Disorders (CYBOCS-PDD), administered at baseline and 16 weeks. Secondary outcome measures include the Aberrant Behaviour Scale (ABC), the Spence Children's Anxiety Scale Parent Report (SCAS-P), and the Repetitive Behaviors Scale (RBS-R), measured at baseline and 16 weeks. Participants will be invited to undergo genetic testing for SLC6A4 allele variants using a cheek swab. Continuous outcomes, including the primary outcome will be compared between the active and placebo groups using unadjusted linear regression. Binary outcomes will be compared using

  2. Transient postnatal fluoxetine decreases brain concentrations of 20-HETE and 15-epi-LXA4, arachidonic acid metabolites in adult mice.

    Science.gov (United States)

    Yuan, Zhi-Xin; Rapoport, Stanley I

    2015-10-01

    Transient postnatal exposure of rodents to the selective serotonin (5-HT) reuptake inhibitor (SSRI) fluoxetine alters behavior and brain 5-HT neurotransmission during adulthood, and also reduces brain arachidonic (ARA) metabolic consumption and protein level of the ARA metabolizing enzyme, cytochrome P4504A (CYP4A). Brain 20-hydroxyeicosatetraenoic acid (20-HETE), converted by CYP4A from ARA, will be reduced in adult mice treated transiently and postnatally with fluoxetine. Male mice pups were injected i.p. daily with fluoxetine (10mg/kg) or saline during P4-P21. At P90 their brain was high-energy microwaved and analyzed for 20-HETE and six other ARA metabolites by enzyme immunoassay. Postnatal fluoxetine vs. saline significantly decreased brain concentrations of 20-HETE (-70.3%) and 15-epi-lipoxin A4 (-60%) in adult mice, but did not change other eicosanoid concentrations. Behavioral changes in adult mice treated postnatally with fluoxetine may be related to reduced brain ARA metabolism involving CYP4A and 20-HETE formation. Published by Elsevier Ltd.

  3. Adult-Onset Fluoxetine Treatment Does Not Improve Behavioral Impairments and May Have Adverse Effects on the Ts65Dn Mouse Model of Down Syndrome

    Directory of Open Access Journals (Sweden)

    Markus Heinen

    2012-01-01

    Full Text Available Down syndrome is caused by triplication of chromosome 21 and is associated with neurocognitive phenotypes ranging from severe intellectual disability to various patterns of more selective neuropsychological deficits, including memory impairments. In the Ts65Dn mouse model of Down syndrome, excessive GABAergic neurotransmission results in local over-inhibition of hippocampal circuits, which dampens hippocampal synaptic plasticity and contributes to cognitive impairments. Treatments with several GABAA receptor antagonists result in increased plasticity and improved memory deficits in Ts65Dn mice. These GABAA receptor antagonists are, however, not suitable for clinical applications. The selective serotonin reuptake inhibitor fluoxetine, in contrast, is a widely prescribed antidepressant that can also enhance plasticity in the adult rodent brain by lowering GABAergic inhibition. For these reasons, we wondered if an adult-onset 4-week oral fluoxetine treatment restores spatial learning and memory impairments in Ts65Dn mice. Fluoxetine did not measurably improve behavioral impairments of Ts65Dn mice. On the contrary, we observed seizures and mortality in fluoxetine-treated Ts65Dn mice, raising the possibility of a drug × genotype interaction with respect to these adverse treatment outcomes. Future studies should re-address this in larger animal cohorts and determine if fluoxetine treatment is associated with adverse treatment effects in individuals with Down syndrome.

  4. Effects of fluoxetine on the rat brain in the forced swimming test: a [F-18]FDG micro-PET imaging study.

    Science.gov (United States)

    Jang, Dong-Pyo; Lee, So-Hee; Park, Chan-Woong; Lee, Sang-Yoon; Kim, Young-Bo; Cho, Zang-Hee

    2009-02-13

    We used the [F-18]FDG micro-PET neuroimaging to examine the effects of fluoxetine on brain activity in rats and on their behavioral response in the forced swimming test (FST). In the first experiment, the rats were administered doses of fluoxetine (10 or 20mg/kg) 24, 19 and 1h before the rat brains were scanned. Fluoxetine induced strong activation of the dorsal hippocampus and the deactivation of the inferior colliculus, medulla oblongata, and prelimbic cortex in a dose-dependent manner. These results seemed to be related with the changes in 5-HT (5-hydroxytryptamine, serotonin) levels after selective serotonin reuptake-inhibitor treatments. In the second experiment, the changes in glucose metabolism in the test session were measured after fluoxetine was given between pre-test and test sessions of the FST. Fluoxetine administration significantly decreased immobility behavior compared with saline administration. At the same time, the activity of the insular/piriform cortex decreased significantly. In contrast, the extent of cerebellar activation increased. The glucose metabolism of the dorsal hippocampus also increased, which suggests that post-stress changes in the facilitation of hippocampal serotonergic neurotransmission lead to decreased immobilization in the FST.

  5. Fluoxetine increases the activity of the ERK-CREB signal system and alleviates the depressive-like behavior in rats exposed to chronic forced swim stress.

    Science.gov (United States)

    Qi, Xiaoli; Lin, Wenjuan; Li, Junfa; Li, Huanhuan; Wang, Weiwen; Wang, Donglin; Sun, Meng

    2008-08-01

    Our previous research indicates that the extracellular signal-regulated kinase (ERK)-cyclic AMP-responsive-element-binding protein (CREB) signal system may be involved in the molecular mechanism of depression. The present study further investigated the effect of antidepressant fluoxetine on the ERK-CREB signal system and the depressive-like behaviors in rats. Fluoxetine was administrated to either naive rats or stressed rats for 21 days. The results showed that chronic forced swim stress induced depressive-like behaviors and decreased the levels of P-ERK2, P-CREB, ERK1/2 and CREB in hippocampus and prefrontal cortex. Fluoxetine alleviated the depressive-like behaviors and reversed the disruptions of the P-ERK2 and P-CREB in stressed rats. Fluoxetine also exerted mood-elevating effect and increased the levels of the P-ERK2 and P-CREB in naive rats. These results suggest that the ERK-CREB signal system may be the targets of the antidepressant action of fluoxetine and participate in the neuronal mechanism of depression.

  6. Testis evaluation of adult Wistar rats after neonatal treatment with fluoxetine - doi: 10.4025/actascibiolsci.v35i1.10946

    Directory of Open Access Journals (Sweden)

    Bruno Mendes Tenorio

    2012-12-01

    Full Text Available In current assay the serotoninergic system in newly-born Wistar rats underwent pharmacological modification by fluoxetine, a selective serotonin reuptake inhibitor (SSRI, to investigate its repercussion on testicular parameters in adult animals. Thirty animals were distributed according to treatment: control animals (n = 6, animals treated with 1 mg kg-1 (n = 6, 5 mg kg-1 (n = 6, 10 mg kg-1 (n = 6 and 20 mg kg-1 (n = 6 of fluoxetine (IP. When 150 days old, the animals were anesthetized and perfused intra-cardiacally with fixative solution. Testes were routinely processed for inclusion in plastic resin (methacrylate glycol. Further, 4 µm-thick histological sections were stained with toluidine blue/sodium borate 1% and analyzed histometrically. Pharmacological intervention on the serotoninergic system during the postnatal period of the testes development in Wistar rats with fluoxetine chlorohydrate reduced parameters, such as testicular weight, testis liquid weight and seminiferous tubules diameter. However, testicular parameters, such as daily sperm production (DSP, spermatogenesis efficiency (DSP/g/testis and cell population in stage VII of adult animals, were not influenced by fluoxetine chlorohydrate usage during neonatal period. Results show that administration of fluoxetine during 21 days after birth may induce adverse changes in the spermatogenesis of adult rats.  

  7. Fluoxetine treatment abolishes the in vitro respiratory response to acidosis in neonatal mice.

    Science.gov (United States)

    Voituron, Nicolas; Shvarev, Yuri; Menuet, Clément; Bevengut, Michelle; Fasano, Caroline; Vigneault, Erika; El Mestikawy, Salah; Hilaire, Gérard

    2010-10-26

    To secure pH homeostasis, the central respiratory network must permanently adapt its rhythmic motor drive to environment and behaviour. In neonates, it is commonly admitted that the retrotrapezoid/parafacial respiratory group of neurons of the ventral medulla plays the primary role in the respiratory response to acidosis, although the serotonergic system may also contribute to this response. Using en bloc medullary preparations from neonatal mice, we have shown for the first time that the respiratory response to acidosis is abolished after pre-treatment with the serotonin-transporter blocker fluoxetine (25-50 µM, 20 min), a commonly used antidepressant. Using mRNA in situ hybridization and immunohistology, we have also shown the expression of the serotonin transporter mRNA and serotonin-containing neurons in the vicinity of the RTN/pFRG of neonatal mice. These results reveal that the serotonergic system plays a pivotal role in pH homeostasis. Although obtained in vitro in neonatal mice, they suggest that drugs targeting the serotonergic system should be used with caution in infants, pregnant women and breastfeeding mothers.

  8. The antidepressant fluoxetine normalizes the nuclear glucocorticoid receptor evoked by psychosocial stress

    Science.gov (United States)

    Mitić, M.; Simić, I.; Djordjević, J.; Radojčić, M. B.; Adžić, M.

    2011-12-01

    Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the pathophysiology of depression and stress disorders. Glucocorticoids, key regulators of the stress response, exert diverse effects on cellular processes in the hippocampus. Beside non-genomic pathways, glucocorticoid effects are mediated through activation of the glucocorticoid receptor (GR), a ligand activated transcriptional factor that belongs to the nuclear hormone receptor superfamily. We analysed the GR protein levels both in the cytoplasmic and nuclear compartments of the hippocampus of Wistar rats exposed to chronic psychosocial isolation stress upon chronic fluoxetine (FLU) treatment. Under chronic stress, corticosterone levels (CORT) were decreased compared to the control, and treatment with FLU did not change its level in the stressed rats. At the molecular level, FLU normalized the level of nuclear GR protein in the hippocampus of the stressed rats. Discrepancy between normalization of nuclear GR in the hippocampus and lack of normalization of HPA axis activity judged by CORT, suggests that other brain structures such as the amygdale and prefrontal cortex that also regulate HPA axis activity, seem not to be normalized by the FLU treatment used in our study.

  9. Probing the binding of fluoxetine hydrochloride to human serum albumin by multispectroscopic techniques

    Science.gov (United States)

    Katrahalli, Umesha; Jaldappagari, Seetharamappa; Kalanur, Shankara S.

    2010-01-01

    The interaction between human serum albumin (HSA) and fluoxetine hydrochloride (FLX) have been studied by using different spectroscopic techniques viz., fluorescence, UV-vis absorption, circular dichroism and FTIR under simulated physiological conditions. Fluorescence results revealed the presence of static type of quenching mechanism in the binding of FLX to HSA. The values of binding constant, K of FLX-HSA were evaluated at 289, 300 and 310 K and were found to be 1.90 × 10 3, 1.68 × 10 3 and 1.45 × 10 3 M -1, respectively. The number of binding sites, n was noticed to be almost equal to unity thereby indicating the presence of a single class of binding site for FLX on HSA. Based on the thermodynamic parameters, Δ H0 and Δ S0 nature of binding forces operating between HSA and FLX were proposed. Spectral results revealed the conformational changes in protein upon interaction. Displacement studies indicated the site I as the main binding site for FLX on HSA. The effect of common ions on the binding of FLX to HSA was also investigated.

  10. Reduction of acute toxicity of the pharmaceutical fluoxetine (Prozac) submitted to ionizing radiation to Vibrio fischeri

    Energy Technology Data Exchange (ETDEWEB)

    Santos, Dymes R.A.; Garcia, Vanessa S.G.; Vilarrubia, Anna C.S.; Borrely, Sueli I., E-mail: vanessagarcia@usp.br, E-mail: sborrely@ipen.br [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil)

    2011-07-01

    The constant use of pharmaceutical drugs by great part of the population and its continuous input into the environment creates a growing need of investigating its presence, behavior and the effects on aquatic biota, as well as new ways to treat wastewater containing such substances. The fluoxetine hydrochloride (FH) present in the drug Prozac is an active ingredient used in the treatment of depressive and anxiety disorders. Generally, these compounds enter the aquatic environment by sewage collectors systems after undergoing prior treatment in sewage treatment plants (STPs) or without any treatment. This study focused on evaluating the reduction of acute toxicity of the pharmaceutical FH, under its manipulated formula, for the marine bacterium Vibrio fischeri. It was also evaluated the acute toxicity of the aqueous solution containing the FH after its exposition to ionizing radiation from industrial electron accelerator. It was performed acute toxicity tests lasting 15 minutes, where the average EC (50) of the non-irradiated CF water solution was approximately 0.68 mg L-1. While the CF water solution irradiated with 1 kGy, 2.5 kGy, 7.5 kGy and 10 kGy, presented an average EC(50) 1.63 mg.L{sup -1}, 2.34 mg.L{sup -1}, 2.35 mg.L{sup -1} and 1.80 mg.L{sup -1}, respectively, showing a notable reduction of the acute toxicity for this organism. (author)

  11. Synthesis of NMP, a Fluoxetine (Prozac) Precursor, in the Introductory Organic Laboratory

    Science.gov (United States)

    Perrine, Daniel M.; Sabanayagam, Nathan R.; Reynolds, Kristy J.

    1998-10-01

    A synthesis of the immediate precursor of the widely used antidepressant fluoxetine (Prozac) is described. The procedure is short, safe, and simple enough to serve as a laboratory exercise for undergraduate students in the second semester of introductory organic chemistry and is one which will be particularly interesting to those planning a career in the health sciences. The compound synthesized is (°)-N,N-dimethyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine, or "N-methyl Prozac" (NMP). The synthesis of NMP requires one two-hour period and a second three-hour period. In the first period, a common Mannich base, 3-dimethylaminopropiophenone, is reduced with sodium borohydride to form (°)-3-dimethylamino-1-phenylpropanol. In the second period, potassium t-butoxide is used to couple (°)-3-dimethylamino-1-phenylpropanol with p-chlorotrifluoromethylbenzene to form NMP, which is isolated as its oxalate salt. All processes use equipment and materials that are inexpensive and readily available in most undergraduate laboratories. Detailed physical data are given on NMP, including high-field DEPT 13C NMR.

  12. Bupropion for the treatment of fluoxetine non-responsive trichotillomania: a case report

    Directory of Open Access Journals (Sweden)

    Bipeta Rajshekhar

    2011-11-01

    Full Text Available Abstract Introduction Trichotillomania, classified as an impulse control disorder in the Diagnostic and Statistical Manual of Mental Disorders, is characterized by the recurrent pulling out of one's hair, resulting in noticeable hair loss. The condition has a varied etiology. Specific serotonin reuptake inhibitors are considered the treatment of choice; however some patients fail to respond to this class of drugs. A few older reports suggest possible benefit from treatment with bupropion. Case presentation A 23-year-old Asian woman with fluoxetine non- responsive trichotillomania was treated with sustained release bupropion (up to 450 mg/day and cognitive behavior therapy. She demonstrated clinically significant improvement on the Clinical Global Impression - Improvement scale by week 13. The improvement persisted throughout the 12-month follow-up period. Conclusions The present case report may be of interest to psychiatrists and dermatologists. Apart from the serotonergic pathway, others, such as the mesolimbic pathway, also appear to be involved in the causation of trichotillomania. Bupropion may be considered as an alternative pharmacological treatment for patients who do not respond to specific serotonin reuptake inhibitors. However, this initial finding needs to be confirmed by well designed double-blind placebo controlled trials.

  13. Fluoxetine pretreatment promotes neuronal survival and maturation after auditory fear conditioning in the rat amygdala.

    Directory of Open Access Journals (Sweden)

    Lizhu Jiang

    Full Text Available The amygdala is a critical brain region for auditory fear conditioning, which is a stressful condition for experimental rats. Adult neurogenesis in the dentate gyrus (DG of the hippocampus, known to be sensitive to behavioral stress and treatment of the antidepressant fluoxetine (FLX, is involved in the formation of hippocampus-dependent memories. Here, we investigated whether neurogenesis also occurs in the amygdala and contributes to auditory fear memory. In rats showing persistent auditory fear memory following fear conditioning, we found that the survival of new-born cells and the number of new-born cells that differentiated into mature neurons labeled by BrdU and NeuN decreased in the amygdala, but the number of cells that developed into astrocytes labeled by BrdU and GFAP increased. Chronic pretreatment with FLX partially rescued the reduction in neurogenesis in the amygdala and slightly suppressed the maintenance of the long-lasting auditory fear memory 30 days after the fear conditioning. The present results suggest that adult neurogenesis in the amygdala is sensitive to antidepressant treatment and may weaken long-lasting auditory fear memory.

  14. Radiation effects on the fluoxetine hydrochloride toxicity in the presence of domestic sewage

    Energy Technology Data Exchange (ETDEWEB)

    Silva, Vanessa H. Ogihara; Borrely, Sueli I., E-mail: vanessa.ogihara@usp.br [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil); Campos, Fabio; Piveli, Roque P. [Universidade de Sao Paulo (USP), Sao Paulo, SP (Brazil). Escola Politecnica. Centro Tecnologico de Hidraulica

    2013-07-01

    The sanitation field is directly related to environmental quality and health. The improvements in wastewater treatment systems provide benefits to the environment and their population. It is clearly understood that the conventional wastewater treatment does not remove many micropollutants, including some medicinal products, and that these products can be toxic to living organisms. The goal of this research was the assessment of toxicity of fluoxetine hydrochloride (FH) as well as the irradiation application to remove FH from waters. The FH was irradiated in water solutions and also contained in domestic sewage. Both types of samples were irradiated at a Dynamitron® Electron Beam Accelerator (EBA). The Vibrio fischeri bacteria was applied as biological assay to the samples (water solution of FH; untreated sewage and the mixture of untreated sewage + FH). The efficiency was 1.44% to 26.21% less toxic after treatments. UV-Vis Spectrometry showed the degradation of FH by radiation. 2.5 kGy was a suitable dose that could be suggested for environmental application of Electron Beam Technology. (author)

  15. Radiation effects on the fluoxetine hydrochloride toxicity in the presence of domestic sewage

    International Nuclear Information System (INIS)

    Silva, Vanessa H. Ogihara; Borrely, Sueli I.; Campos, Fabio; Piveli, Roque P.

    2013-01-01

    The sanitation field is directly related to environmental quality and health. The improvements in wastewater treatment systems provide benefits to the environment and their population. It is clearly understood that the conventional wastewater treatment does not remove many micropollutants, including some medicinal products, and that these products can be toxic to living organisms. The goal of this research was the assessment of toxicity of fluoxetine hydrochloride (FH) as well as the irradiation application to remove FH from waters. The FH was irradiated in water solutions and also contained in domestic sewage. Both types of samples were irradiated at a Dynamitron® Electron Beam Accelerator (EBA). The Vibrio fischeri bacteria was applied as biological assay to the samples (water solution of FH; untreated sewage and the mixture of untreated sewage + FH). The efficiency was 1.44% to 26.21% less toxic after treatments. UV-Vis Spectrometry showed the degradation of FH by radiation. 2.5 kGy was a suitable dose that could be suggested for environmental application of Electron Beam Technology. (author)

  16. Reduction of acute toxicity of the pharmaceutical fluoxetine (Prozac) submitted to ionizing radiation to Vibrio fischeri

    International Nuclear Information System (INIS)

    Santos, Dymes R.A.; Garcia, Vanessa S.G.; Vilarrubia, Anna C.S.; Borrely, Sueli I.

    2011-01-01

    The constant use of pharmaceutical drugs by great part of the population and its continuous input into the environment creates a growing need of investigating its presence, behavior and the effects on aquatic biota, as well as new ways to treat wastewater containing such substances. The fluoxetine hydrochloride (FH) present in the drug Prozac is an active ingredient used in the treatment of depressive and anxiety disorders. Generally, these compounds enter the aquatic environment by sewage collectors systems after undergoing prior treatment in sewage treatment plants (STPs) or without any treatment. This study focused on evaluating the reduction of acute toxicity of the pharmaceutical FH, under its manipulated formula, for the marine bacterium Vibrio fischeri. It was also evaluated the acute toxicity of the aqueous solution containing the FH after its exposition to ionizing radiation from industrial electron accelerator. It was performed acute toxicity tests lasting 15 minutes, where the average EC (50) of the non-irradiated CF water solution was approximately 0.68 mg L-1. While the CF water solution irradiated with 1 kGy, 2.5 kGy, 7.5 kGy and 10 kGy, presented an average EC(50) 1.63 mg.L -1 , 2.34 mg.L -1 , 2.35 mg.L -1 and 1.80 mg.L -1 , respectively, showing a notable reduction of the acute toxicity for this organism. (author)

  17. Nutritional management of anorexic patients with and without fluoxetine: 1-year follow-up.

    Science.gov (United States)

    Ruggiero, Giovanni M; Mauri, Massimo C; Omboni, Anna C; Volonteri, Lucia S; Dipasquale, Savina; Malvini, Lara; Redaelli, Gabriella; Pasqualinotto, Lucia; Cavagnini, Francesco

    2003-05-01

    This study evaluated the efficacy of nutritional management with and without fluoxetine (FLX) in anorexia nervosa diagnosed according to Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria. Twenty-one patients, with a mean body mass index (BMI) of 15.21+/-2.33 kg/m(2), were treated with nutritional management and FLX at a mean dosage of 30.00+/-9.35 mg (pharmacological group); seventy-four patients, with a mean BMI of 14.24+/-2.16 kg/m(2), were treated only with nutritional management (nutritional group). Clinical evaluation was carried out under single-blind conditions at basal time and after 3, 6, and 12 months by a structured clinical interview, the Eating Disorder Interview based on Longitudinal Interval Follow-Up Evaluation (EDI-LIFE) and using a self-reported questionnaire, the Eating Disorder Inventory (EDI). BMI significantly increased in both the two treatment groups. In addition, the increase shown by the pharmacological group appeared near the beginning of treatment (i.e., at T1) and it was significantly higher than the increase shown by the nutritional group. Physical exercise showed a significant decrease in the pharmacological treatment group. On the other hand, fear of fatness and the scores of the subscales of the EDI significantly decreased in the nutritional treatment group. In terms of weight, the pharmacological group presented the higher amount of therapeutic success.

  18. Differential effects of chronic fluoxetine on the behavior of dominant and subordinate naked mole-rats.

    Science.gov (United States)

    Mongillo, Daniel L; Kosyachkova, Ekaterina A; Nguyen, Tam M; Holmes, Melissa M

    2014-01-01

    Naked mole-rats are eusocial rodents that live in large subterranean colonies with a strict reproductive and social hierarchy. The breeding female (referred to as the queen) and 1 to 3 breeding males are the only reproductive members of the colony. Breeders are socially dominant and all other colony members are non-reproductive subordinates. The effects of manipulating the serotonergic neurotransmitter system on aggression and dominance behaviors are well studied in many species, but not in eusocial rodents like the naked mole-rat. The current study investigated how the serotonergic system influences aggressive/dominant behaviors in this species. To do this, two separate but related experiments were conducted: the effects of fluoxetine hydrochloride (FLX) on status-specific behaviors of subordinates (Experiment 1) and dominant queens (Experiment 2) were evaluated both in-colony and in a social-pairing paradigm. In accordance with our main hypothesis, chronic treatment of FLX attenuated the frequency and duration of aggression in queens, but not subordinates, when paired with an unfamiliar conspecific. Further exploration of pharmacological manipulation on status-specific behaviors of this eusocial species may elucidate the neurobiological mechanisms underlying their unique and rigid social hierarchy. Copyright © 2013 Elsevier B.V. All rights reserved.

  19. Oral and transdermal DL-methylphenidate-ethanol interactions in C57BL/6J mice: potentiation of locomotor activity with oral delivery.

    Science.gov (United States)

    Bell, Guinevere H; Griffin, William C; Patrick, Kennerly S

    2011-12-01

    Many abusers of dl-methylphenidate co-abuse ethanol. The present animal study examined behavioral effects of oral or transdermal DL-methylphenidate in combination with a high, depressive dose of ethanol to model co-abuse. Locomotor activity of C57BL/6J mice was recorded for 3 h following dosing with either oral DL-methylphenidate (7.5 mg/kg) or transdermal DL-methylphenidate (Daytrana®;1/4 of a 12.5 cm(2) patch; mean dose 7.5 mg/kg), with or without oral ethanol (3 g/kg). Brains were enantiospecifically analyzed for the isomers of methylphenidate and the transesterification metabolite ethylphenidate. An otherwise depressive dose of ethanol significantly potentiated oral DL-methylphenidate induced increases in total distance traveled for the first 100 min (pbrain D-methylphenidate concentrations were significantly elevated by ethanol in both the oral (65% increase) and transdermal (88% increase) groups. The corresponding L-ethylphenidate concentrations were 10 ng/g and 130 ng/g. Stimulant induced motor activity in rodents may correlate with abuse liability. Potentiation of DL-methylphenidate motor effects by concomitant ethanol carries implications regarding increased abuse potential of DL-methylphenidate when combined with ethanol. Copyright © 2011 Elsevier Inc. All rights reserved.

  20. The Aqueous Crude Extracts of Montanoa frutescens and Montanoa grandiflora Reduce Immobility Faster Than Fluoxetine Through GABAA Receptors in Rats Forced to Swim.

    Science.gov (United States)

    Rodríguez-Landa, Juan Francisco; Cueto-Escobedo, Jonathan; Flores-Aguilar, Luis Ángel; Rosas-Sánchez, Gilberto Uriel; Rovirosa-Hernández, María de Jesús; García-Orduña, Francisco; Carro-Juárez, Miguel

    2018-01-01

    Montanoa frutescens and Montanoa grandiflora have been indistinctly used for centuries in traditional Mexican medicine for reproductive impairments, anxiety, and mood disorders. Preclinical studies support their aphrodisiac and anxiolytic properties, but their effects on mood are still unexplored. The effects of 25 and 50 mg/kg of M frutescens and M grandiflora extracts were evaluated on days 1, 7, 14, 21, and 28 of treatment, and compared with fluoxetine (1 mg/kg) and Remotiv (7.14 mg/kg) in Wistar rats. The participation of GABA A receptor in the effects produced by the treatments was explored. Montanoa extracts reduced immobility since day 1 of treatment, while fluoxetine and Remotiv required 14 days. The GABA A antagonism blocked the effects of Montanoa extracts, but not of fluoxetine or Remotiv. Montanoa extracts prevented quickly the stress-induced behaviors in the swimming test through action at the GABA A receptor, exerting a protective effect different to the typical antidepressants drugs.

  1. Assessing the effects of fluoxetine on Physa acuta (Gastropoda, Pulmonata) and Chironomus riparius (Insecta, Diptera) using a two-species water-sediment test

    Energy Technology Data Exchange (ETDEWEB)

    Sanchez-Argueello, Paloma [Laboratory for Ecotoxicology, Department of the Environment, INIA, Crta, A Coruna km 7, 28040 Madrid (Spain)], E-mail: arguello@inia.es; Fernandez, Carlos; Tarazona, Jose V. [Laboratory for Ecotoxicology, Department of the Environment, INIA, Crta, A Coruna km 7, 28040 Madrid (Spain)

    2009-03-01

    Fluoxetine has been tested in a two-species water-sediment system, which allowed a two-generation study with Chironomus riparius and a partial life-cycle with the freshwater snail Physa acuta to be performed at the same time. The design considered the continuous application of fluoxetine to overlaying water for nominal concentrations of 31.25, 62.5, 125 and 250 {mu}g/L. A fifth treatment (87.5 {mu}g/L) level consisted of pulse applications once a week. Measures of water and sediment concentrations were determined once a week and at the end of experiment (day 44), respectively. The fate study demonstrated that water dissipation can be explained by partitioning of fluoxetine to sediment. At the end of experiment, the percentage of detected fluoxetine was up to 10-fold higher in sediment than in overlaying water. The employed two-species test allowed distinguishing, in the same exposure conditions, effects due to waterborne exposure together ingestion at the sediment surface (freshwater grazing snail P. acuta) and exposure by burrowing activities (sediment-dwelling insect larvae C. riparius). The effect assessment showed a stimulation of P. acuta reproduction at lower concentrations (31.25 and 62.5 {mu}g/L), while the opposite effect was observed at the highest treatment (250 {mu}g/L). Additional studies should be conducted to establish if the statistically significant differences observed in F0 sex ratio at the 62.5 {mu}g/L and F1 adult emergence at 31.25 {mu}g/L of C. riparius have a toxicological significance. This study showed that fluoxetine can affect reproduction of freshwater molluscs. The results of the present study may contribute to knowledge on ecotoxicology of pharmaceuticals, about which little data is available. The possible consequences and implications for targeting the environmental risk assessment of fluoxetine are discussed.

  2. Fluoxetine for Maintenance of Remission and to Improve Quality of Life in Patients with Crohn's Disease: a Pilot Randomized Placebo-Controlled Trial.

    Science.gov (United States)

    Mikocka-Walus, Antonina; Hughes, Patrick A; Bampton, Peter; Gordon, Andrea; Campaniello, Melissa A; Mavrangelos, Chris; Stewart, Benjamin J; Esterman, Adrian; Andrews, Jane M

    2017-04-01

    Previous studies have shown that antidepressants reduce inflammation in animal models of colitis. The present trial aimed to examine whether fluoxetine added to standard therapy for Crohn's disease [CD] maintained remission, improved quality of life [QoL] and/or mental health in people with CD as compared to placebo. A parallel randomized double-blind placebo controlled trial was conducted. Participants with clinically established CD, with quiescent or only mild disease, were randomly assigned to receive either fluoxetine 20 mg daily or placebo, and followed for 12 months. Participants provided blood and stool samples and completed mental health and QoL questionnaires. Immune functions were assessed by stimulated cytokine secretion [CD3/CD28 stimulation] and flow cytometry for cell type. Linear mixed-effects models were used to compare groups. Of the 26 participants, 14 were randomized to receive fluoxetine and 12 to placebo. Overall, 14 [54%] participants were male. The mean age was 37.4 [SD=13.2] years. Fluoxetine had no effect on inflammatory bowel disease activity measured using either the Crohn's Disease Activity Index [F(3, 27.5)=0.064, p=0.978] or faecal calprotectin [F(3, 32.5)=1.08, p=0.371], but did have modest effects on immune function. There was no effect of fluoxetine on physical, psychological, social or environmental QoL, anxiety or depressive symptoms as compared to placebo [all p>0.05]. In this small pilot clinical trial, fluoxetine was not superior to placebo in maintaining remission or improving QoL. [ID: ACTRN12612001067864.]. © European Crohn’s and Colitis Organistion (ECCO) 2016.

  3. Assessing the effects of fluoxetine on Physa acuta (Gastropoda, Pulmonata) and Chironomus riparius (Insecta, Diptera) using a two-species water-sediment test

    International Nuclear Information System (INIS)

    Sanchez-Argueello, Paloma; Fernandez, Carlos; Tarazona, Jose V.

    2009-01-01

    Fluoxetine has been tested in a two-species water-sediment system, which allowed a two-generation study with Chironomus riparius and a partial life-cycle with the freshwater snail Physa acuta to be performed at the same time. The design considered the continuous application of fluoxetine to overlaying water for nominal concentrations of 31.25, 62.5, 125 and 250 μg/L. A fifth treatment (87.5 μg/L) level consisted of pulse applications once a week. Measures of water and sediment concentrations were determined once a week and at the end of experiment (day 44), respectively. The fate study demonstrated that water dissipation can be explained by partitioning of fluoxetine to sediment. At the end of experiment, the percentage of detected fluoxetine was up to 10-fold higher in sediment than in overlaying water. The employed two-species test allowed distinguishing, in the same exposure conditions, effects due to waterborne exposure together ingestion at the sediment surface (freshwater grazing snail P. acuta) and exposure by burrowing activities (sediment-dwelling insect larvae C. riparius). The effect assessment showed a stimulation of P. acuta reproduction at lower concentrations (31.25 and 62.5 μg/L), while the opposite effect was observed at the highest treatment (250 μg/L). Additional studies should be conducted to establish if the statistically significant differences observed in F0 sex ratio at the 62.5 μg/L and F1 adult emergence at 31.25 μg/L of C. riparius have a toxicological significance. This study showed that fluoxetine can affect reproduction of freshwater molluscs. The results of the present study may contribute to knowledge on ecotoxicology of pharmaceuticals, about which little data is available. The possible consequences and implications for targeting the environmental risk assessment of fluoxetine are discussed

  4. The roles of BDNF, pCREB and Wnt3a in the latent period preceding activation of progenitor cell mitosis in the adult dentate gyrus by fluoxetine.

    Directory of Open Access Journals (Sweden)

    Scarlett B Pinnock

    2010-10-01

    Full Text Available The formation of new neurons continues into adult life in the dentate gyrus of the rat hippocampus, as in many other species. Neurogenesis itself turns out to be highly labile, and is regulated by a number of factors. One of these is the serotoninergic system: treatment with drugs (such as the SSRI fluoxetine markedly stimulates mitosis in the progenitor cells of the dentate gyrus. But this process has one remarkable feature: it takes at least 14 days of continuous treatment to be effective. This is despite the fact that the pharmacological action of fluoxetine occurs within an hour or so of first administration. This paper explores the role of BDNF in this process, using the effect of a Trk antagonist (K252a on the labelling of progenitor cells with the mitosis marker Ki67 and the associated expression of pCREB and Wnt3a. These experiments show that (i Fluoxetine increased Ki67 counts, as well as pCREB and Wnt3a expression in the dentate gyrus. The action of fluoxetine on the progenitor cells and on pCREB (but not Wnt3a depends upon Trk receptor activation, since it was prevented by icv infusion of K252a. (ii These receptors are required for both the first 7 days of fluoxetine action, during which no apparent change in progenitor mitosis occurs, as well as the second 7 days. Increased pCREB was always associated with progenitor cell mitosis, but Wnt3a expression may be necessary but not sufficient for increased progenitor cell proliferation. These results shed new light on the action of fluoxetine on neurogenesis in the adult dentate gyrus, and have both clinical and experimental interest.

  5. Effects of swim stress and fluoxetine on 5-HT1A receptor gene expression and monoamine metabolism in the rat brain regions.

    Science.gov (United States)

    Shishkina, G T; Kalinina, T S; Dygalo, N N

    2012-07-01

    Changes in gene expression of the brain serotonin (5-HT) 1A receptors may be important for the development and ameliorating depression, however identification of specific stimuli that activate or reduce the receptor transcriptional activity is far from complete. In the present study, the forced swim test (FST) exposure, the first stress session of which is already sufficient to induce behavioral despair in rats, significantly increased 5-HT1A receptor mRNA levels in the brainstem, frontal cortex, and hippocampus at 24 h. In the brainstem and frontal cortex, the elevation in the receptor gene expression after the second forced swim session was not affected following chronic administration of fluoxetine, while in the cortex, both control and FST values were significantly reduced in fluoxetine-treated rats. In contrast to untreated rats, no increase in hippocampal 5-HT1A receptor mRNA was observed in response to FST in rats chronically treated with fluoxetine. Metabolism of 5-HT (5-HIAA/5-HT) in the brainstem was significantly decreased by fluoxetine and further reduced by swim stress, showing a certain degree of independence of these changes on 5-HT1A receptor gene expression that was increased in this brain region only after the FST, but not after fluoxetine. FST exposure also decreased the brainstem dopamine metabolism, which was unexpectedly positively correlated with 5-HT1A receptor mRNA levels in the frontal cortex. Together, these data suggest that the effects of the forced swim stress as well as fluoxetine involve brain region-dependent alterations in 5-HT1A receptor gene transcription, some of which may be interrelated with concomitant changes in catecholamine metabolism.

  6. Stress-induced activation of the brainstem Bcl-xL gene expression in rats treated with fluoxetine: correlations with serotonin metabolism and depressive-like behavior.

    Science.gov (United States)

    Shishkina, Galina T; Kalinina, Tatyana S; Berezova, Inna V; Dygalo, Nikolay N

    2012-01-01

    Mechanisms underlying stress-induced depression and antidepressant drug action were shown to involve alterations in serotonergic (5-HT) neurotransmission and expression of genes coding for proteins associated with neurotrophic signaling pathways and cell-survival in the hippocampus and cortex. Expression of these genes in the brainstem containing 5-HT neurons may also be related to vulnerability or resilience to stress-related psychopathology. Here we investigated 5-HT markers and expression of genes for Brain-Derived Neurotrophic Factor (BDNF) and apoptotic proteins in the brainstem in relation to swim stress-induced behavioral despair. We found that anti-apoptotic Bcl-xL gene is sensitive to stress during the course of fluoxetine administration. Responsiveness of this gene to stress appeared concomitantly with an antidepressant-like effect of fluoxetine in the forced swim test. Bcl-xL transcript levels showed negative correlations with duration of immobility in the test and 5-HT turnover in the brainstem. In contrast, BDNF and pro-apoptotic protein Bax mRNA levels were unchanged by either fluoxetine or stress, suggesting specificity of Bcl-xL gene responses to these treatments. We also found that the levels of mRNAs for tryptophan hydroxylase-2 (TPH2) and 5-HT transporter (5-HTT) were significantly down-regulated following prolonged treatment with fluoxetine, but were not affected by stress. Unlike TPH2 and 5-HTT, 5-HT1A receptor mRNA levels were not altered by fluoxetine but significantly increased in response to swim stress. These data show that long-term fluoxetine treatment leads to changes in 5-HT and Bcl-xL responses to stress associated with antidepressant-like effects of the drug. This article is part of a Special Issue entitled 'Anxiety and Depression'. Copyright © 2011 Elsevier Ltd. All rights reserved.

  7. The effect of chronic fluoxetine on social isolation-induced changes on sucrose consumption, immobility behavior, and on serotonin and dopamine function in hippocampus and ventral striatum.

    Science.gov (United States)

    Brenes, Juan C; Fornaguera, Jaime

    2009-03-02

    This study examined the effect of fluoxetine, a selective serotonin (5-HT) reuptake inhibitor, on isolation-induced changes on sucrose consumption and preference, spontaneous open-field activity, forced swimming behavior, and on tissue levels of 5-HT and dopamine (DA) in hippocampus and ventral striatum (VS). Male Sprague-Dawley rats were reared in social isolation or group housing from postnatal day 28. Thirty-two days later, half of the isolated animals were orally treated with fluoxetine (10mg/kg/day) during the following 34 days. At the end of this period, behavior was assessed and afterward ex-vivo tissue samples were obtained. It was found that fluoxetine restored isolation-increased sucrose consumption and immobility behavior, without affecting locomotor activity, which appeared slightly increased in isolated groups both treated and untreated. In the hippocampus, isolation rearing depleted 5-HT contents and increased 3,4-dihydroxyphenylacetic acid (DOPAC) levels, as well as 5-HT and DA turnover. These neurochemical alterations were reversed by fluoxetine. In VS, treated and untreated isolated rats showed higher 5-HT levels than grouped congeners. Although fluoxetine did not affect 5-HT and DA contents in this region, it slightly reversed the alterations in the 5-HT and DA turnover observed in isolated rats. Overall, social isolation impaired incentive and escape motivated behaviors. At the neurochemical level, isolation rearing affected 5-HT rather than DA activity, and this differential effect was more noticeable in hippocampus than in VS. The chronic treatment with fluoxetine during the last month of rearing somewhat prevented these behavioral and neurochemical alterations. Our data suggest that isolation rearing is an appropriate procedure to model some developmental-related alterations underlying depression disorders.

  8. Systemic effects of fluoxetine on the amount of tooth movement, root resorption, and alveolar bone remodeling during orthodontic force application in rat

    Directory of Open Access Journals (Sweden)

    Mehdi Rafiei

    2015-01-01

    Full Text Available Background: Antidepressant drugs such as fluoxetine are of the most commonly used drugs among the public. These drugs may impact the regulation of bone cell functioning, and thus affect orthodontic tooth movement. The aim of this study was to determine the effect of fluoxetine on tooth movements during orthodontic treatment in rats. Materials and Methods: In this study, 30 male rats were randomly assigned into two groups and injected with fluoxetine 10 mg/kg (experimental group and normal saline (control group for a period of 1-month intraperitoneally 5 times/week. Then, the rats were anesthetized and a nickel-titanium closed-coil spring was placed between the left maxillary first molar and left maxillary central incisors of all samples, and then fluoxetine (experimental group and normal saline (control group were injected for another 3 weeks by the same method. After measuring tooth movements, rats were sacrificed, and histomorphometric analyses were conducted and the obtained data were statistically analyzed using independent t-test and the significance was set at 0.05. Results: Following the fluoxetine injection, the mean amount of tooth movements in the experimental group was reduced compared to the control group, which was not statistically significant (P = 0.14. There was no significant difference between the two groups regarding bone apposition rate (P = 0.83, external root resorption rate (P = 0.1, and mean number of root resorption lacunae (P = 0.16. Conclusion: Within the limitations of this study, systemic use of fluoxetine may cause insignificant reduction of tooth movement rate in rats; however, this subject needs more evaluations.

  9. Fluoxetine coupled with zinc in a chronic mild stress model of depression: Providing a reservoir for optimum zinc signaling and neuronal remodeling.

    Science.gov (United States)

    Omar, Nesreen Nabil; Tash, Reham Fathy

    2017-09-01

    Recently, depression has been envisioned as more than an alteration in neurotransmitters centered around receptor signaling pathways. Consequently, the precise mechanisms of selective serotonin reuptake inhibitor (SSRI) antidepressant drugs such as fluoxetine are being revisited. Zinc is a trace element that has been long implicated in the psychopathology and therapy of depression. Zinc has been found to be sequestered and dispensed during stress and inflammation through a family of proteins called metallothioneins (MTs). In addition, MTs are well known for their antioxidant and therefore cytoprotective action. Changes in MTs, their upstream regulators and downstream effectors in response to fluoxetine have not been yet studied. The aim of the present study is to examine whether depression-induced changes in protein levels and mRNA levels of nuclear factor-erythroid 2-related factor 2 (Nrf2), MTs, antioxidant defensive enzyme heme oxygenase (HO-1), zinc-specific receptor GPR39 and brain derived neurotrophic factor (BDNF) in the hippocampus can be reversed by fluoxetine treatment, zinc supplementation or a combination of the two. The present study investigated the effect of chronic (4weeks) combined treatment with zinc hydroaspartate (15mg/kg) and fluoxetine (10mg/kg) on a chronic mild stress model (CMS) in male Sprague-Dawley rats. Hippocampal mRNA and protein levels of Nrf2, HO-1, MTs, GPR39 (protein level only) and BDNF were significantly higher in response to a combined therapy of fluoxetine and zinc than to either monotherapy. Additionally, HO-1 and MTs gene expression was correlated with that of Nrf2 in the FLX-only group. Fluoxetine therapy activated the expression of MTs and HO-1 through an Nrf2-dependent pathway. When FLX was escorted by zinc, activated MTs had a positive impact on BDNF through the zinc signaling receptor GPR39, resulting in general improvement in neuronal plasticity as well as reduction of neuronal atrophy and neuronal cell loss. Copyright

  10. Mechanism of synergistic action following co-treatment with pramipexole and fluoxetine or sertraline in the forced swimming test in rats.

    Science.gov (United States)

    Rogóz, Zofia; Skuza, Grazyna

    2006-01-01

    The aim of the present study was to examine the effect of combined treatment of male Wistar rats with pramipexole and fluoxetine or sertraline in the forced swimming test. The obtained results showed that co-treatment with pramipexole (0.1 mg/kg) and fluoxetine (10 mg/kg) or sertraline (5 mg/kg) (in doses inactive per se) exhibited antidepressant-like activity in the forced swimming test. Sulpiride (a dopamine D(2/3) receptor antagonist) and WAY 100635 (a 5-HT(1A) receptor antagonist), either being ineffective in the forced swimming test, inhibited the antidepressant-like effect induced by co-administration of pramipexole and fluoxetine or sertraline. However, SCH 23390 (a dopamine D(1) receptor antagonist) only partly did not alter the effect of pramipexole given jointly with antidepressant drugs; on the other hand, S 33084 (a dopamine D(3) receptor antagonist) only partly decreased (in a statistically insignificant manner) that effect. Moreover, progesterone and BD 1047 (a sigma(1) receptor antagonist) counteracted the antidepressant-like effect induced by co-administration of pramipexole and sertraline (but not pramipexole and fluoxetine). In that test, active behavior did not reflect the increases in general activity, since combined administration of pramipexole and fluoxetine or sertraline failed to enhance the locomotor activity of rats. None of the tested drugs (SCH 23390, sulpiride, S 33084, WAY 100635, BD 1047 and progesterone) - alone or in combination with pramipexole and fluoxetine or sertraline - changed locomotor activity. The results described in the present paper indicate that co-administration of pramipexole and fluoxetine or sertraline may induce a more pronounced antidepressive activity than does treatment with pramipexole alone, and that in addition to other mechanisms, dopamine D(2/3) and 5-HT(1A) receptors may contribute to the antidepressant-like activity of pramipexole and fluoxetine or sertraline in the forced swimming test in rats

  11. Effects of fluoxetine on CRF and CRF1 expression in rats exposed to the learned helplessness paradigm.

    Science.gov (United States)

    Fernández Macedo, Georgina Valeria; Cladouchos, María Laura; Sifonios, Laura; Cassanelli, Pablo Martín; Wikinski, Silvia

    2013-02-01

    Stress is a common antecedent reported by people suffering major depression. In these patients, extrahypothalamic brain areas, like the hippocampus and basolateral amygdala (BLA), have been found to be affected. The BLA synthesizes CRF, a mediator of the stress response, and projects to hippocampus. The main hippocampal target for this peptide is the CRF subtype 1 receptor (CRF1). Evidence points to a relationship between dysregulation of CRF/CRF1 extrahypothalamic signaling and depression. Because selective serotonin reuptake inhibitors (SSRIs) are the first-line pharmacological treatment for depression, we investigated the effect of chronic treatment with the SSRI fluoxetine on long-term changes in CRF/CRF1 signaling in animals showing a depressive-like behavior. Male Wistar rats were exposed to the learned helplessness paradigm (LH). After evaluation of behavioral impairment, the animals were treated with fluoxetine (10 mg/kg i.p.) or saline for 21 days. We measured BLA CRF expression with RT-PCR and CRF1 expression in CA3 and the dentate gyrus of the hippocampus with in situ hybridization. We also studied the activation of one of CRF1's major intracellular signaling targets, the extracellular signal-related kinases 1 and 2 (ERK1/2) in CA3. In saline-treated LH animals, CRF expression in the BLA increased, while hippocampal CRF1 expression and ERK1/2 activation decreased. Treatment with fluoxetine reversed the changes in CRF and CRF1 expressions, but not in ERK1/2 activation. In animals exposed to the learned helplessness paradigm, there are long-term changes in CRF and CRF1 expression that are restored with a behaviorally effective antidepressant treatment.

  12. Fluoxetine treatment affects the inflammatory response and microglial function according to the quality of the living environment.

    Science.gov (United States)

    Alboni, Silvia; Poggini, Silvia; Garofalo, Stefano; Milior, Giampaolo; El Hajj, Hassan; Lecours, Cynthia; Girard, Isabelle; Gagnon, Steven; Boisjoly-Villeneuve, Samuel; Brunello, Nicoletta; Wolfer, David P; Limatola, Cristina; Tremblay, Marie-Ève; Maggi, Laura; Branchi, Igor

    2016-11-01

    It has been hypothesized that selective serotonin reuptake inhibitors (SSRIs), the most common treatment for major depression, affect mood through changes in immune function. However, the effects of SSRIs on inflammatory response are contradictory since these act either as anti- or pro-inflammatory drugs. Previous experimental and clinical studies showed that the quality of the living environment moderates the outcome of antidepressant treatment. Therefore, we hypothesized that the interplay between SSRIs and the environment may, at least partially, explain the apparent incongruence regarding the effects of SSRI treatment on the inflammatory response. In order to investigate such interplay, we exposed C57BL/6 mice to chronic stress to induce a depression-like phenotype and, subsequently, to fluoxetine treatment or vehicle (21days) while being exposed to either an enriched or a stressful condition. At the end of treatment, we measured the expression levels of several anti- and pro-inflammatory cytokines and inflammatory mediators in the whole hippocampus and in isolated microglia. We also determined microglial density, distribution, and morphology to investigate their surveillance state. Results show that the effects of fluoxetine treatment on inflammation and microglial function, as compared to vehicle, were dependent on the quality of the living environment. In particular, fluoxetine administered in the enriched condition increased the expression of pro-inflammatory markers compared to vehicle, while treatment in a stressful condition produced anti-inflammatory effects. These findings provide new insights regarding the effects of SSRIs on inflammation, which may be crucial to devise pharmacological strategies aimed at enhancing antidepressant efficacy by means of controlling environmental conditions. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Effect of Early-Life Fluoxetine on Anxiety-Like Behaviors in BDNF Val66Met Mice.

    Science.gov (United States)

    Dincheva, Iva; Yang, Jianmin; Li, Anfei; Marinic, Tina; Freilingsdorf, Helena; Huang, Chienchun; Casey, B J; Hempstead, Barbara; Glatt, Charles E; Lee, Francis S; Bath, Kevin G; Jing, Deqiang

    2017-12-01

    Adolescence is a developmental stage in which the incidence of psychiatric disorders, such as anxiety disorders, peaks. Selective serotonin reuptake inhibitors (SSRIs) are the main class of agents used to treat anxiety disorders. However, the impact of SSRIs on the developing brain during adolescence remains unknown. The authors assessed the impact of developmentally timed SSRI administration in a genetic mouse model displaying elevated anxiety-like behaviors. Knock-in mice containing a common human single-nucleotide polymorphism (Val66Met; rs6265) in brain-derived neurotrophic factor (BDNF), a growth factor implicated in the mechanism of action of SSRIs, were studied based on their established phenotype of increased anxiety-like behavior. Timed administration of fluoxetine was delivered during one of three developmental periods (postnatal days 21-42, 40-61, or 60-81), spanning the transition from childhood to adulthood. Neurochemical and anxiety-like behavioral analyses were performed. We identified a "sensitive period" during periadolescence (postnatal days 21-42) in which developmentally timed fluoxetine administration rescued anxiety-like phenotypes in BDNF Val66Met mice in adulthood. Compared with littermate controls, BDNF Met/Met mice exhibited diminished maturation of serotonergic fibers projecting particularly to the prefrontal cortex, as well as decreased expression of the serotonergic trophic factor S100B in the dorsal raphe. Interestingly, deficient serotonergic innervation, as well as S100B levels, were rescued with fluoxetine administration during periadolescence. These findings suggest that SSRI administration during a "sensitive period" during periadolescence leads to long-lasting anxiolytic effects in a genetic mouse model of elevated anxiety-like behaviors. These persistent effects highlight the role of BDNF in the maturation of the serotonin system and the capacity to enhance its development through a pharmacological intervention.

  14. Ecotoxicological assessment of the pharmaceutical fluoxetine hydrochloride and the surfactant dodecyl sodium sulfate after their submission to ionizing radiation treatment

    International Nuclear Information System (INIS)

    Santos, Dymes Rafael Alves dos

    2011-01-01

    The use of pharmaceuticals and personal care products and the consequent and continuous input of this substances in the environment generates an increasing need to investigate the presence, behavior and the effects on aquatic biota, as well as new ways to treat effluents containing such substances. Fluoxetine hydrochloride is an active ingredient used in the treatment of depressive disorders and anxiety. As the surfactant sodium dodecyl sulfate is present in many cleaning and personal care products. The present study aimed on assessing the acute toxicity of fluoxetine hydrochloride, sodium dodecyl sulfate and the mixture of both to the aquatic organisms Hyalella azteca, Daphnia similis and Vibrio ficheri. Reducing the toxicity of fluoxetine and the mixture after treatment with ionizing radiation from industrial electron beam accelerator has also been the focus of this study. For Daphnia similis the average values of CE50-4 8h found for the non-irradiated drug, surfactant and mixture were 14.4 %, 9.62 % and 13.8 %, respectively. After irradiation of the substances, the dose 5 kGy proved itself to be the most effective dose for the treatment of the drug and the mixture as it was obtained the mean values for CE50 48h 84.60 % and > 90 %, respectively. For Hyalella azteca the acute toxicity tests were performed for water column with duration of 96 hours, the mean values for CE50 96h found for the drug, the surfactant and the mixture non-irradiated were 5.63 %, 19.29 %, 6.27 %, respectively. For the drug fluoxetine and the mixture irradiated with 5 kGy, it was obtained 69.57 % and 77.7 %, respectively. For Vibrio ficheri the acute toxicity tests for the untreated drug and the drug irradiated with 5 kGy it was obtained CE50 15min of 6.9 % and 32.88 % respectively. These results presented a reduction of the acute toxicity of the test-substances after irradiation. (author)

  15. Linking embryo toxicity with genotoxic responses in the freshwater snail Physa acuta: single exposure to benzo(a)pyrene, fluoxetine, bisphenol A, vinclozolin and exposure to binary mixtures with benzo(a)pyrene.

    Science.gov (United States)

    Sánchez-Argüello, Paloma; Aparicio, Natalia; Fernández, Carlos

    2012-06-01

    Genotoxic effects on fauna after waterborne pollutant exposure have been demonstrated by numerous research programmes. Less effort has been focused on establishing relationship between genotoxicity and long-term responses at higher levels of biological organization. Taking into account that embryos may be more sensitive indicators of reproductive impairment than alterations in fertility, we have developed two assays in multiwell plates to address correlations between embryo toxicity and genotoxicity. The potential teratogenicity was assessed by analyzing abnormal development and mortality of Physa acuta at embryonic stage. Genotoxicity was measured by the micronucleus (MN) test using embryonic cells. Our results showed that linkage between genotoxicity and embryo toxicity depends on mechanisms of action of compounds under study. Embryo toxic responses showed a clear dose-related tendency whereas no clear dose-dependent effect was observed in micronucleus induction. The higher embryo toxicity was produced by benzo(a)pyrene exposure followed by fluoxetine and bisphenol A. Vinclozolin was the lower embryo toxic compound. Binary mixtures with BaP always resulted in higher embryo toxicity than single exposures but antagonistic effects were observed for MN induction. Benzo(a)pyrene produced the higher MN induction at 0.04 mg/L, which also produced clear embryo toxic effects. Fluoxetine did not induce cytogenetic effects but 0.25mg/L altered embryonic development. Bisphenol A significantly reduced hatchability at 0.5mg/L while MN induction appeared with higher treatments than those that start causing teratogenicity. Much higher concentration of vinclozolin (5mg/L) reduced hatchability and induced maximum MN formation. In conclusion, while validating one biomarker of genotoxicity and employing one ecologically relevant effect, we have evaluated the relative sensitivity of a freshwater mollusc for a range of chemicals. The embryo toxicity test is a starting point for the

  16. Fluoxetine combined with clorazepate dipotassium and behaviour modification for treatment of anxiety-related disorders in dogs.

    Science.gov (United States)

    Pineda, S; Anzola, B; Olivares, A; Ibáñez, M

    2014-03-01

    The effectiveness of clorazepate dipotassium combined with fluoxetine and a behaviour modification programme for the treatment of anxiety disorders in dogs was investigated. Forty dogs with anxiety disorders were initially enrolled and 36 dogs completed the trial. Dogs were classified into two behavioural categories (anxious dogs with aggression and anxious dogs without aggression) according to their presenting complaints, and were also subdivided into males, females, juveniles and adults. The dog owners were provided with a behaviour modification plan for their dogs to be commenced in the first week of therapy. Clorazepate dipotassium was administered PO at 1.0 mg/kg every 24 h for 4 weeks, and fluoxetine was administered PO at 1.0 mg/kg every 24 h for 10 weeks. Therapy with both drugs was initiated simultaneously. Improvement was reported in 25/36 dogs. Significant differences in treatment effects were observed between anxious dogs with aggression and anxious dogs without aggression (P<0.05). Positive correlations between owner compliance with the treatment plan and reported improvement achieved during three periods of study were also noted. Copyright © 2013 Elsevier Ltd. All rights reserved.

  17. Fluoxetine induces lean phenotype in rat by increasing the brown/white adipose tissue ratio and UCP1 expression.

    Science.gov (United States)

    da Silva, A I; Braz, G R F; Pedroza, A A; Nascimento, L; Freitas, C M; Ferreira, D J S; Manhães de Castro, R; Lagranha, C J

    2015-08-01

    The serotonergic system plays a crucial role in the energy balance regulation. Energy balance is mediated by food intake and caloric expenditure. Thus, the present study investigated the mechanisms that might be associated with fluoxetine treatment-induced weight reduction. Wistar male rat pups received daily injections with subcutaneous fluoxetine (Fx-group) or vehicle solution (Ct-group) from day 1 until 21 days of age. Several analyses were conducted to verify the involvement of mitochondria in weight reduction. We found that body weight in the Fx-group was lower compared to control. In association to lower fat mass in the Fx-group (25%). Neither neonatal caloric intake nor food intake reveals significant differences. Evaluating caloric expenditure (locomotor activity and temperature after stimulus), we did not observe differences in locomotor activity. However, we observed that the Fx group had a higher capacity to maintain body temperature in a cold environment compared with the Ct-group. Since brown adipose tissue-(BAT) is specialized for heat production and the rate of heat production is related to mitochondrial function, we found that Fx-treatment increases respiration by 36%, although after addition of GDP respiration returned to Ct-levels. Examining ROS production we observe that Fx-group produced less ROS than control group. Evaluating uncoupling protein (UCP) expression we found that Fx-treatment increases the expression by 23%. Taken together, our results suggest that modulation of serotonin system results in positive modulation of UCP and mitochondrial bioenergetics in brown fat tissue.

  18. Neurogenesis and Increase in Differentiated Neural Cell Survival via Phosphorylation of Akt1 after Fluoxetine Treatment of Stem Cells

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    Anahita Rahmani

    2013-01-01

    Full Text Available Fluoxetine (FLX is a selective serotonin reuptake inhibitor (SSRI. Its action is possibly through an increase in neural cell survival. The mechanism of improved survival rate of neurons by FLX may relate to the overexpression of some kinases such as Akt protein. Akt1 (a serine/threonine kinase plays a key role in the modulation of cell proliferation and survival. Our study evaluated the effects of FLX on mesenchymal stem cell (MSC fate and Akt1 phosphorylation levels in MSCs. Evaluation tests included reverse transcriptase polymerase chain reaction, western blot, and immunocytochemistry assays. Nestin, MAP-2, and β-tubulin were detected after neurogenesis as neural markers. Ten μM of FLX upregulated phosphorylation of Akt1 protein in induced hEnSC significantly. Also FLX did increase viability of these MSCs. Continuous FLX treatment after neurogenesis elevated the survival rate of differentiated neural cells probably by enhanced induction of Akt1 phosphorylation. This study addresses a novel role of FLX in neurogenesis and differentiated neural cell survival that may contribute to explaining the therapeutic action of fluoxetine in regenerative pharmacology.

  19. Anxiogenic-like effect of acute and chronic fluoxetine on rats tested on the elevated plus-maze

    Directory of Open Access Journals (Sweden)

    M.T.A. Silva

    1999-03-01

    Full Text Available The selective serotonin reuptake inhibitor fluoxetine (FLX is widely prescribed for depression and anxiety-related disorders. On the other hand, enhanced serotonergic transmission is known to be classically related to anxiety. In this study, the effects of acute (5.0 mg/kg and chronic (5.0 mg/kg, 22 days FLX were investigated in both food-deprived and non-deprived rats tested in the elevated plus-maze. Significant main effects of the three factors (drug, food condition and administration regimen were observed, but no interaction between them. The administration of either acute or chronic FLX resulted in an anxiogenic effect, as detected by a significant reduction in the percentage of time spent in the open arms and in the percentage of open arm entries. Food deprivation yielded an anxiolytic-like profile, probably related to changes in locomotor activity. The administration regimen resulted in an anxiolytic profile in chronically treated rats, as would be expected after 22 days of regular handling. The anxiogenic action of acute FLX is consistent with both its neurochemical and clinical profile. The discrepancy between the anxiogenic profile of chronic FLX and its therapeutic uses is discussed in terms of possible differences between the type of anxiety that is measured in the plus-maze and the types of human anxiety that are alleviated by fluoxetine.

  20. Evaluation of antidepressant like property of amisulpride per se and its comparison with fluoxetine and olanzapine using forced swimming test in albino mice.

    Science.gov (United States)

    Pawar, Ganesh R; Agrawal, Rajendra P; Phadnis, Pradeep; Paliwal, Abhay; Vyas, Savita; Solanki, Pooja

    2009-01-01

    Amisulpride, an atypical antipsychotic was evaluated for antidepressant like activity in forced swimming test in Swiss albino mice. The effect of amisulpride was compared with that of fluoxetine, the standard antidepressant and olanzapine, another atypical antipsychotic claimed to have antidepressant like activity. Both acute and chronic studies were carried out. In both the studies, animals were divided into four groups (n = 8 each) and subjected to oral drug interventions as follows -- Group 1- control (distilled water, 1 mL/kg); Group 2- fluoxetine in a dose of 10 mg/kg 23.5, 5 and 1 h before the test; Group 3-amisulpride in a dose of 70 mg/kg 23.5, 5 and 1 h before the test; Group 4- olanzapine in a dose of 2 mg/kg 23.5, 5 and 1 h before the study. In the chronic study, the treatment was given daily for 28 days with last dose being given 2 h prior to the test. A time sampling method was used to score the behavioral activity in each group. Results of both the studies indicated that animals given amisulpride displayed significant improvement in swimming behavior (p Fluoxetine also showed significant difference in activity as compared to amisulpride and olanzapine (p swimming phases in albino mice (p > 0.05). We conclude that amisulpride per se has an antidepressant like activity comparable to that of olanzapine though the activity was significantly less than that of fluoxetine.

  1. Comparing omeprazole with fluoxetine for treatment of patients with heartburn and normal endoscopy who failed once daily proton pump inhibitors: double-blind placebo-controlled trial.

    Science.gov (United States)

    Ostovaneh, M R; Saeidi, B; Hajifathalian, K; Farrokhi-Khajeh-Pasha, Y; Fotouhi, A; Mirbagheri, S S; Emami, H; Barzin, G; Mirbagheri, S A

    2014-05-01

    Patients with heartburn but without esophageal erosion respond less well to proton pump inhibitors (PPIs). There is a growing body of evidence implicating the role of psychological comorbidities in producing reflux symptoms. Pain modulators improve symptoms in patients with other functional gastrointestinal disorders. We aimed to compare the efficacy of fluoxetine with omeprazole and placebo to achieve symptomatic relief in patients with heartburn and normal endoscopy who failed once daily PPIs. Endoscopy-negative patients with heartburn who failed once daily PPIs were randomly allocated to receive 6 weeks treatment of fluoxetine, omeprazole, or placebo. Random allocation was stratified according to ambulatory pH monitoring study. Percentage of heartburn-free days and symptom severity was assessed. Sixty patients with abnormal and 84 patients with normal pH test were randomized. Subjects receiving fluoxetine experienced more improvement in percentage of heartburn-free days (median 35.7, IQR 21.4-57.1) than those on omeprazole (median 7.14, IQR 0-50, p heartburn-free days (median improvement, 57.1, IQR 35.7-57.1 vs 13.9, IQR, 0-45.6 and 7.14, 0-23.8, respectively, p heartburn and normal endoscopy who failed once daily PPIs. The superiority of fluoxetine was mostly attributed to those with normal esophageal pH rather than those with abnormal pH (ClinicalTrials.gov, number NCT01269788). © 2014 John Wiley & Sons Ltd.

  2. The selective serotonin reuptake inhibitor fluoxetine does not change rectal sensitivity and symptoms in patients with irritable bowel syndrome: a double blind, randomized, placebo-controlled study

    NARCIS (Netherlands)

    Kuiken, Sjoerd D.; Tytgat, Guido N. J.; Boeckxstaens, Guy E. E.

    2003-01-01

    BACKGROUND & AIMS: Although widely prescribed, the evidence for the use of antidepressants for the treatment of irritable bowel syndrome (IBS) is limited. In this study, we hypothesized that fluoxetine (Prozac), a selective serotonin reuptake inhibitor, has visceral analgesic properties, leading to

  3. In vivo and in vitro effect of imipramine and fluoxetine on Na+,K+-ATPase activity in synaptic plasma membranes from the cerebral cortex of rats

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    L.M. Zanatta

    2001-10-01

    Full Text Available The effects of in vivo chronic treatment and in vitro addition of imipramine, a tricyclic antidepressant, or fluoxetine, a selective serotonin reuptake inhibitor, on the cortical membrane-bound Na+,K+-ATPase activity were studied. Adult Wistar rats received daily intraperitoneal injections of 10 mg/kg of imipramine or fluoxetine for 14 days. Twelve hours after the last injection rats were decapitated and synaptic plasma membranes (SPM from cerebral cortex were prepared to determine Na+,K+-ATPase activity. There was a significant decrease (10% in enzyme activity after imipramine but fluoxetine treatment caused a significant increase (27% in Na+,K+-ATPase activity compared to control (P<0.05, ANOVA; N = 7 for each group. When assayed in vitro, the addition of both drugs to SPM of naive rats caused a dose-dependent decrease in enzyme activity, with the maximal inhibition (60-80% occurring at 0.5 mM. We suggest that a imipramine might decrease Na+,K+-ATPase activity by altering membrane fluidity, as previously proposed, and b stimulation of this enzyme might contribute to the therapeutic efficacy of fluoxetine, since brain Na+,K+-ATPase activity is decreased in bipolar patients.

  4. Dose-dependent inhibition of CYP1A2, CYP2C19 and CYP2D6 by citalopram, fluoxetine, fluvoxamine and paroxetine

    DEFF Research Database (Denmark)

    Jeppesen, U; Gram, L F; Vistisen, K

    1996-01-01

    OBJECTIVE: The purpose of this pharmacokinetic study was to investigate the dose-dependent inhibition of model substrates for CYP2D6, CYP2C19 and CYP1A2 by four marketed selective serotonin reuptake inhibitors (SSRIs): citalopram, fluoxetine, fluvoxamine and paroxetine. METHODS: The study...

  5. The antidepressant effect of melatonin and fluoxetine in diabetic rats is associated with a reduction of the oxidative stress in the prefrontal and hippocampal cortices.

    Science.gov (United States)

    Rebai, Redouane; Jasmin, Luc; Boudah, Abdennacer

    2017-09-01

    In the past few years possible mechanisms that link diabetes and depression have been found. One of these mechanisms is the increase in lipid peroxidation and decrease in antioxidant activity in the hippocampal and prefrontal cortices, which are brain areas involved in mood. The goal of the present study was to evaluate the effect of an antidepressant and of an antioxidant on behavior and oxidative activity in brains of diabetic rats. Rats rendered diabetic after a treatment with streptozotocin (STZ) (60mg/kg) were treated with fluoxetine (15mg/kg), melatonin (10mg/kg), or vehicle for 4 weeks. All animals were tested for signs of depression and anxiety using the elevated plus maze (EPM), open field test (OFT) and the forced swim test (FST). Four groups were compared: (1) normoglycemic, (2) hyperglycemic vehicle treated, and hyperglycemic (3) fluoxetine or (4) melatonin treated rats. On the last day of the study, blood samples were obtained to determine the levels of hemoglobin A1c (HbA1c). Also, brain samples were collected to measure the oxidative stress in the hippocampal and prefrontal cortices using the thiobarbituric acid reactive substances (TBARS) assay. The activity of the antioxidant enzymes catalase (CAT), glutathione peroxidase (GPx), and glutathione S-transferase (GST) were also measured on the brain samples. The results show that both fluoxetine and melatonin decrease the signs of depression and anxiety in all tests. Concomitantly, the levels of HbA1c were reduced in drug treated rats, and to a greater degree in the fluoxetine group. In the cerebral cortex of diabetic rats, TBARS was increased, while the activity of CAT, GPx and GST were decreased. Fluoxetine and melatonin treatments decreased TBARS in both cortices. In the prefrontal cortex, fluoxetine and melatonin restored the activity of CAT, while only melatonin improved the activity of GPx and GST. In the hippocampus, the activity of GPx alone was restored by melatonin, while fluoxetine had no

  6. The short-term safety and efficacy of fluoxetine in depressed adolescents with alcohol and cannabis use disorders: a pilot randomized placebo-controlled trial

    Directory of Open Access Journals (Sweden)

    Lingler Jacqui

    2009-03-01

    Full Text Available Abstract Background The objective of this study was to examine whether fluoxetine was superior to placebo in the acute amelioration of depressive symptomatology in adolescents with depressive illness and a comorbid substance use disorder. Methods Eligible subjects ages 12–17 years with either a current major depressive disorder (MDD or a depressive disorder that were also suffering from a comorbid substance-related disorder were randomized to receive either fluoxetine or placebo in this single site, 8-week double-blind, placebo-controlled study. The primary outcome analysis was a random effects mixed model for repeated measurements of Children's Depression Rating Scale-Revised (CDRS-R scores compared between treatment groups across time. Results An interim analysis was performed after 34 patients were randomized. Based on the results of a futility analysis, study enrollment was halted. Twenty-nine males and 5 females were randomized to receive fluoxetine (n = 18 or placebo (n = 16. Their mean age was 16.5 (1.1 years. Overall, patients who received fluoxetine and placebo had a reduction in CDRS-R scores. However, there was no significant difference in mean change in CDRS-R total score in those subjects treated with fluoxetine and those who received placebo (treatment difference = 0.19, S.E. = 0.58, F = 0.14, p = .74. Furthermore, there was not a significant difference in rates of positive urine drug toxicology results between treatment groups at any post-randomization visit (F = 0.22, df = 1, p = 0.65. The main limitation of this study is its modest sample size and resulting low statistical power. Other significant limitations to this study include, but are not limited to, the brevity of the trial, high placebo response rate, limited dose range of fluoxetine, and the inclusion of youth who met criteria for depressive disorders other than MDD. Conclusion Fluoxetine was not superior to placebo in alleviating depressive symptoms or in decreasing

  7. 'You've got m@il: fluoxetine coming soon!': accessibility and quality of a prescription drug sold on the web.

    Science.gov (United States)

    Gelatti, U; Pedrazzani, R; Marcantoni, C; Mascaretti, S; Repice, C; Filippucci, L; Zerbini, I; Dal Grande, M; Orizio, G; Feretti, D

    2013-09-01

    The increasing phenomenon of online pharmacies has potential for serious public health problems. This study aimed to evaluate the possibility of accessing a prescription drug in the absence of a prescription for an Italian purchaser. Fluoxetine pills were ordered from several online pharmacies. The study included website analysis, and the quality of the received product including packaging, chemical and microbiological analyses. Orders could be placed correctly on 61 of the 98 selected websites, and a sales transaction was concluded successfully on 17 websites. Thirteen drug samples were eventually received. In one case it was necessary to fill in a questionnaire before ordering the drugs. All websites displayed aggressive marketing strategies. There was wide variation in terms of domain registration, company base (when declared) and manufacturer's location (mostly India). All pills were delivered in sealed blister packs showing the lot number and manufacturer's details. A leaflet was enclosed in one case only. In three cases we received more pills than ordered, and in one case Viagra pills as a free gift. Pharmacopoeia microbiological requirements were satisfied. Chemical analysis revealed that the active principle was always present, although many samples did not meet the Pharmacopoeia "other impurities" or "total impurities" criteria. Heavy metals and solvents regulated by the Pharmacopoeia did not exceed the set limits; some of the non-regulated ones were also assessed, in some cases with a positive result (e.g. styrene). About 20% of purchase attempts resulted in delivery of the drugs, even in the absence of a medical prescription. Traceability was poor and drug quality was generally worse compared to conventional pharmacy-purchased products. Based on all these broad-spectrum results, user safety appears not to be globally guaranteed. Copyright © 2013 Elsevier B.V. All rights reserved.

  8. Alterations in amino acid levels in mouse brain regions after adjunctive treatment of brexpiprazole with fluoxetine: comparison with (R)-ketamine.

    Science.gov (United States)

    Ma, Min; Ren, Qian; Fujita, Yuko; Yang, Chun; Dong, Chao; Ohgi, Yuta; Futamura, Takashi; Hashimoto, Kenji

    2017-11-01

    Brexpiprazole, a serotonin-dopamine activity modulator, is approved in the USA as an adjunctive therapy to antidepressants for treating major depressive disorders. Similar to the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine, the combination of brexpiprazole and fluoxetine has demonstrated antidepressant-like effects in animal models of depression. The present study was conducted to examine whether the combination of brexpiprazole and fluoxetine could affect the tissue levels of amino acids [glutamate, glutamine, γ-aminobutyric acid (GABA), D-serine, L-serine, and glycine] that are associated with NMDAR neurotransmission. The tissue levels of amino acids in the frontal cortex, striatum, hippocampus, and cerebellum were measured after a single [or repeated (14 days)] oral administration of vehicle, fluoxetine (10 mg/kg), brexpiprazole (0.1 mg/kg), or a combination of the two drugs. Furthermore, we measured the tissue levels of amino acids after a single administration of the NMDAR antagonist (R)-ketamine. A single injection of the combination of fluoxetine and brexpiprazole significantly increased GABA levels in the striatum, the D-serine/L-serine ratio in the frontal cortex, and the glycine/L-serine ratio in the hippocampus. A repeated administration of the combination significantly altered the tissue levels of amino acids in all regions. Interestingly, a repeated administration of the combination significantly decreased the D-serine/L-serine ratio in the frontal cortex, striatum, and hippocampus. In contrast, a single administration of (R)-ketamine significantly increased the D-serine/L-serine ratio in the frontal cortex. These results suggested that alterations in the tissue levels of these amino acids may be involved in the antidepressant-like effects of the combination of brexpiprazole and fluoxetine.

  9. Metabolic effects of fluoxetine in adults with type 2 diabetes mellitus: a meta-analysis of randomized placebo-controlled trials.

    Directory of Open Access Journals (Sweden)

    Zi Ye

    Full Text Available BACKGROUND: The prevalence of obesity and diabetes is increasing dramatically throughout the world. Studies have shown that excess adiposity is a critical predictor of new onset T2DM. This meta-analysis is aimed to assess the metabolic effects of fluoxetine in T2DM. METHODS AND FINDINGS: Electronic search was conducted in the database Medline, PubMed, EMBASE, and the Cochrane library, from inception through to March 2011. A systematic review of the studies on the metabolic effects of fluoxetine in T2DM was performed. The weighted mean difference (WMD and its 95% CI were calculated from the raw data extracted from the original literature. The software Review Manager (version 4.3.1 and Stata (version 11.0 were applied for meta-analysis. Five randomized, placebo-controlled trials were included in the meta-analysis. According to WMD calculation, fluoxetine therapy led to 4.27 Kg of weight loss (95%CI 2.58-5.97, P<0.000 01, 1.41 mmol/L of fasting plasma glucose (FPG decrement (95%CI 0.19-2.64, P = 0.02 and 0.54 mmol/L of triglyceride (TG reduction (95%CI 0.35-0.73, P<0.000 01 compared with placebo. Moreover, fluoxetine therapy produced 0.78% of HbA1c decrement (95%CI -0.23-1.78. However, this effect was not statistically significant (P = 0.13. CONCLUSIONS: Short period of fluoxetine therapy can lead to weight loss as well as reduction of FPG, HbA1c and TG in T2DM.

  10. Antenatal exposure to the selective serotonin reuptake inhibitor fluoxetine leads to postnatal metabolic and endocrine changes associated with type 2 diabetes in Wistar rats

    Energy Technology Data Exchange (ETDEWEB)

    De Long, Nicole E.; Barry, Eric J. [Department of Obstetrics and Gynecology, McMaster University, Hamilton, ON L8S 4K1 (Canada); Pinelli, Christopher; Wood, Geoffrey A. [Department of Pathobiology, University of Guelph, Guelph, ON N1G 2W1 (Canada); Hardy, Daniel B. [Department of Obstetrics and Gynecology, Physiology and Pharmacology, University of Western, London, ON N6A 3K6 (Canada); Morrison, Katherine M. [Department of Pediatrics, McMaster University, Hamilton, ON L8S 4K1 (Canada); Taylor, Valerie H. [Department of Psychiatry, University of Toronto, Toronto, ON M5S 1A1 (Canada); Gerstein, Hertzel C. [Department of Medicine, McMaster University, Hamilton, ON L8S 4K1 (Canada); Holloway, Alison C., E-mail: hollow@mcmaster.ca [Department of Obstetrics and Gynecology, McMaster University, Hamilton, ON L8S 4K1 (Canada)

    2015-05-15

    Hypothesis: 10–15% of women take antidepressant medications during pregnancy. A recent clinical study reported that the use of selective serotonin reuptake inhibitor antidepressants during pregnancy is linked with an increased risk of postnatal obesity. While obesity is often associated with fatty liver, dyslipidemia and inflammation, to date, the effects of perinatal exposure to SSRIs on these outcomes are unknown. Methods: Female nulliparous Wistar rats were given vehicle (N = 15) or fluoxetine hydrochloride (FLX 10 mg/kg/d; N = 15) orally for 2 weeks prior to mating until weaning. We assessed glucometabolic changes and hepatic pathophysiology in the offspring. Results: Fluoxetine exposed offspring demonstrated altered glucose homeostasis without any alterations to beta cell mass. FLX-exposed offspring had a significant increase in the number of offspring with mild to moderate NASH and dyslipidemia. There was also increased inflammation of the liver in FLX-exposed offspring; males had significant elevations in TNFα, IL6 and monocyte chemoattractant protein 1 (MCP1), while female offspring had higher expression of TNFα, and increased macrophage infiltration (MCP1). Limitations: This is an animal study. Further research examining the metabolic outcomes of children exposed to antidepressants in utero are required, given the increase in childhood obesity and psychiatric medication use during pregnancy. Conclusion: These data demonstrate that fetal and neonatal exposure to FLX results in evidence of increased adiposity, fatty liver and abnormal glycemic control. Since these are all hallmarks of the metabolic syndrome, this raises concerns regarding the long term metabolic sequelae of fetal exposure to SSRIs in human populations. - Highlights: • Antenatal exposure to fluoxetine results in postnatal adiposity in the offspring. • Offspring exposed to fluoxetine have abnormal glycemic control in adulthood. • Maternal exposure to fluoxetine causes fatty liver in

  11. Effects of nitric oxide synthesis inhibitor or fluoxetine treatment on depression-like state and cardiovascular changes induced by chronic variable stress in rats.

    Science.gov (United States)

    Almeida, Jeferson; Duarte, Josiane O; Oliveira, Leandro A; Crestani, Carlos C

    2015-01-01

    Comorbidity between mood disorders and cardiovascular disease has been described extensively. However, available antidepressants can have cardiovascular side effects. Treatment with selective inhibitors of neuronal nitric oxide synthase (nNOS) induces antidepressant effects, but whether the antidepressant-like effects of these drugs are followed by cardiovascular changes has not been previously investigated. Here, we tested in male rats exposed to chronic variable stress (CVS) the hypothesis that nNOS blockers are advantageous compared with conventional antidepressants in terms of cardiovascular side effects. We compared the effects of chronic treatment with the preferential nNOS inhibitor 7-nitroindazole (7-NI) with those evoked by the conventional antidepressant fluoxetine on alterations that are considered as markers of depression (immobility in the forced swimming test, FST, decreased body weight gain and increased plasma corticosterone concentration) and cardiovascular changes caused by CVS. Rats were exposed to a 14-day CVS protocol, while being concurrently treated daily with either 7-NI (30 mg/kg) or fluoxetine (10 mg/kg). Fluoxetine and 7-NI prevented the increase in immobility in the FST induced by CVS and reduced plasma corticosterone concentration in stressed rats. Both these treatments also prevented the CVS-evoked reduction of the depressor response to vasodilator agents and baroreflex changes. Fluoxetine and 7-NI-induced cardiovascular changes independent of stress exposure, including cardiac autonomic imbalance, increased intrinsic heart rate and vascular sympathetic modulation, a reduction of the pressor response to vasoconstrictor agents, and impairment of baroreflex activity. Altogether, these findings provide evidence that fluoxetine and 7-NI have similar effects on the depression-like state induced by CVS and on cardiovascular function.

  12. Both exogenous 5-HT and endogenous 5-HT, released by fluoxetine, enhance distension evoked propulsion in guinea-pig ileum in vitro

    Directory of Open Access Journals (Sweden)

    Rachel M Gwynne

    2014-09-01

    Full Text Available The roles of 5-HT3 and 5-HT4 receptors in the modulation of intestinal propulsion by luminal application of 5-HT and augmentation of endogenous 5-HT effects were studied in segments of guinea-pig ileum in vitro. Persistent propulsive contractions evoked by saline distension were examined using a modified Trendelenburg method. When 5-HT (30 nM, fluoxetine (selective serotonin reuptake inhibitor; 1 nM, 2-methyl-5-HT (5-HT3 receptor agonist; 1 mM or RS 67506 (5-HT4 receptor agonist, 1 µM was infused into the lumen, the pressure needed to initiate persistent propulsive activity fell significantly. A specific 5-HT4 receptor antagonist, SB 207266 (10 nM in lumen, abolished the effects of 5-HT, fluoxetine, and RS 67506, but not those of 2-methyl-5-HT. Granisetron (5-HT3 receptor antagonist; 1 µM in lumen abolished the effect of 5-HT, fluoxetine, RS 67506 and 2-methyl-5-HT. The NK3 receptor antagonist SR 142801 (100 nM in lumen blocked the effects of 5-HT, fluoxetine and 2-methyl-5-HT. SB 207266, granisetron and SR 142801 had no effect by themselves. Higher concentrations of fluoxetine (100 nM and 300 nM and RS 67506 (3 µM and 10 µM had no effect on the distension threshold for propulsive contractions. These results indicate that luminal application of exogenous 5-HT, or increased release of endogenous mucosal 5-HT above basal levels, acts to lower the threshold for propulsive contractions in the guinea-pig ileum via activation of 5-HT3 and 5-HT4 receptors and the release of tachykinins. The results further indicate that basal release of 5-HT is insufficient to alter the threshold for propulsive motor activity.

  13. Study of antinociceptive activity of SSRI (fluoxetine and escitalopram and atypical antidepressants (venlafaxine and mirtazepine and their interaction with morphine and naloxone in mice

    Directory of Open Access Journals (Sweden)

    Pranav Sikka

    2011-01-01

    Full Text Available Objective : to study the probable site of antinociceptive action of SSRI (fluoxetine, escitalopram and atypical antidepressants (mirtazapine, venlafaxine and their interaction with morphine and naloxone. Materials and Methods : the study was conducted on albino mice (25-35 grams of either sex. Different doses of morphine (0.5 and 1 mg/kg, fluoxetine (2, 5 and 10 mg/kg, venlafaxine (30, 40 and 50 mg/kg, mirtazapine (3, 5 and 7 mg/kg and escitalopram (2.5, 5 and 10 mg/kg were administered subcutaneously to obtain their subanalgesic doses using tail flick analgesiometer. Tail flick latencies were obtained at 15, 30, 60 and 120 min. after drug administration. Naloxone (1 mg/kg was administered 10 minutes prior to test drug for testing antagonism. Observations : fluoxetine (5 and 10 mg/kg, mirtazapine (5 and 7 mg/kg and venlafaxine (40 and 50 mg/kg were found to have antinociceptive activity but not at lower doses. Escitalopram failed to show any antinociceptive activity at any of the doses used. The antinociceptive effect of all the drugs was antagonized by naloxone (1 mg/kg. Further, subanalgesic doses of fluoxetine, mirtazapine and venlafaxine showed analgesic activity with suboptimal dose of morphine (0.5 mg/kg. Result and conclusion : fluoxetine, mirtazapine and venlafaxine have antinociceptive activity whereas escitalopram doesn′t; their site of action seems to be the same as that of opioid analgesics (′mue′ receptors. However, other pathways (cholinergic, histaminic, noradrenergic, GABAergic may be involved in mediation of their analgesic activity, deserving further elucidation. Results apparently show that these drugs may be useful in the management of pain as monotherapy or in combination with other opioids.

  14. Effect of comorbid tics on a clinically meaningful response to 8-week open-label trial of fluoxetine in obsessive compulsive disorder.

    Science.gov (United States)

    Husted, David S; Shapira, Nathan A; Murphy, Tanya K; Mann, Giselle D; Ward, Herbert E; Goodman, Wayne K

    2007-01-01

    Currently, there are limited published data evaluating the effects of tics on serotonin reuptake inhibitor (SRI) monotherapy responses in treating obsessive-compulsive disorder (OCD). One retrospective case-controlled analysis of OCD patients treated with SRI monotherapy showed lesser improvement in OCD symptoms in patients with tics than those without. However, more recently there were preliminary reports of OCD subjects treated with SRI monotherapy which did not demonstrate poorer response in subjects with tics or Tourette's Syndrome (TS). The specific aim of this study was to investigate whether the presence of comorbid chronic tics affected "clinically meaningful improvement" [McDougle, C.J., Goodman, W.K., Leckman, J.F., Barr, L.C., Heninger, G.R., Price, L.H., 1993. The efficacy of fluvoxamine in obsessive-compulsive disorder: effects of comorbid chronic tic disorder. Journal of Clinical Psychopharmacology 13, 354-358] of OCD in an 8-week open-label trial of fluoxetine monotherapy. Seventy-four adult subjects (13 patients with comorbid chronic tics and 61 patients without tics) with a primary DSM-IV OCD diagnosis were treated with up to 40mg fluoxetine for 8 weeks and had at least one post-baseline evaluation. The results indicate that there was a significant response by time in both fluoxetine-with-tic subjects and fluoxetine-without-tic subjects. Additionally, there were 3 (23.0%) OCD subjects with tics who had clinically meaningful improvement versus 16 (26.2%) OCD subjects without tics that demonstrated similar levels of improvement. These findings indicate that OCD patients with or without chronic tic disorders did not have a differential response to an 8-week open-label trial of fluoxetine. Limitations include the relatively low number of tic subjects and the open-label nature of the study. Additional data are needed on how comorbid tics may affect SRI treatment response in OCD.

  15. Antenatal exposure to the selective serotonin reuptake inhibitor fluoxetine leads to postnatal metabolic and endocrine changes associated with type 2 diabetes in Wistar rats

    International Nuclear Information System (INIS)

    De Long, Nicole E.; Barry, Eric J.; Pinelli, Christopher; Wood, Geoffrey A.; Hardy, Daniel B.; Morrison, Katherine M.; Taylor, Valerie H.; Gerstein, Hertzel C.; Holloway, Alison C.

    2015-01-01

    Hypothesis: 10–15% of women take antidepressant medications during pregnancy. A recent clinical study reported that the use of selective serotonin reuptake inhibitor antidepressants during pregnancy is linked with an increased risk of postnatal obesity. While obesity is often associated with fatty liver, dyslipidemia and inflammation, to date, the effects of perinatal exposure to SSRIs on these outcomes are unknown. Methods: Female nulliparous Wistar rats were given vehicle (N = 15) or fluoxetine hydrochloride (FLX 10 mg/kg/d; N = 15) orally for 2 weeks prior to mating until weaning. We assessed glucometabolic changes and hepatic pathophysiology in the offspring. Results: Fluoxetine exposed offspring demonstrated altered glucose homeostasis without any alterations to beta cell mass. FLX-exposed offspring had a significant increase in the number of offspring with mild to moderate NASH and dyslipidemia. There was also increased inflammation of the liver in FLX-exposed offspring; males had significant elevations in TNFα, IL6 and monocyte chemoattractant protein 1 (MCP1), while female offspring had higher expression of TNFα, and increased macrophage infiltration (MCP1). Limitations: This is an animal study. Further research examining the metabolic outcomes of children exposed to antidepressants in utero are required, given the increase in childhood obesity and psychiatric medication use during pregnancy. Conclusion: These data demonstrate that fetal and neonatal exposure to FLX results in evidence of increased adiposity, fatty liver and abnormal glycemic control. Since these are all hallmarks of the metabolic syndrome, this raises concerns regarding the long term metabolic sequelae of fetal exposure to SSRIs in human populations. - Highlights: • Antenatal exposure to fluoxetine results in postnatal adiposity in the offspring. • Offspring exposed to fluoxetine have abnormal glycemic control in adulthood. • Maternal exposure to fluoxetine causes fatty liver in

  16. Effects of maternal stress and perinatal fluoxetine exposure on behavioral outcomes of adult male offspring.

    Science.gov (United States)

    Kiryanova, V; Meunier, S J; Vecchiarelli, H A; Hill, M N; Dyck, R H

    2016-04-21

    Women of child-bearing age are the population group at highest risk for depression. In pregnant women, fluoxetine (Flx) is the most widely prescribed selective serotonin reuptake inhibitor (SSRI) used for the treatment of depression. While maternal stress, depression, and Flx exposure have been shown to effect neurodevelopment of the offspring, separately, combined effects of maternal stress and Flx exposure have not been extensively examined. The present study investigated the effects of prenatal maternal stress and perinatal exposure to the SSRI Flx on the behavior of male mice as adults. C57BL/6 dams exposed to chronic unpredictable stress from embryonic (E) day 4 to E18 and non-stressed dams were administered Flx (25 mg/kg/d) in the drinking water from E15 to postnatal day 12. A separate control group consisted of animals that were not exposed to stress or Flx. At 12 days of age, brain levels of serotonin were assessed in the male offspring. At two months of age, the male offspring of mothers exposed to prenatal stress (PS), perinatal Flx, PS and Flx, or neither PS or Flx, went through a comprehensive behavioral test battery. At the end of testing brain-derived neurotropic factor (BDNF) levels were assessed in the frontal cortex of the offspring. Maternal behavior was not altered by either stress or Flx treatment. Treatment of the mother with Flx led to detectible Flx and NorFlx levels and lead to a decrease in serotonin levels in pup brains. In the adult male offspring, while perinatal exposure to Flx increased aggressive behavior, prenatal maternal stress decreased aggressive behavior. Interestingly, the combined effects of stress and Flx normalized aggressive behavior. Furthermore, perinatal Flx treatment led to a decrease in anxiety-like behavior in male offspring. PS led to hyperactivity and a decrease in BDNF levels in the frontal cortex regardless of Flx exposure. Neither maternal stress or Flx altered offspring performance in tests of cognitive

  17. Fluoxetine requires the endfeet protein aquaporin-4 to enhance plasticity of astrocyte processes

    Directory of Open Access Journals (Sweden)

    Barbara eDi Benedetto

    2016-02-01

    Full Text Available Morphological alterations in astrocytes are characteristic for post mortem brains of patients affected by major depressive disorder (MDD. Recently, a significant reduction in the coverage of blood vessels (BVs by aquaporin-4 (AQP-4-positive astrocyte endfeet has been shown in the prefrontal cortex (PFC of MDD patients, suggesting that either alterations in the morphology of endfeet or in AQP-4 distribution might be responsible for the disease phenotype or constitute a consequence of its progress. Antidepressant drugs (ADs regulate the expression of several proteins, including astrocyte-specific ones. Thus, they may target AQP-4 to induce morphological changes in astrocytes and restore their proper shape or relocate AQP-4 to endfeet. Using an animal model of depression, rats selectively bred for high anxiety-like behavior (HAB, we confirmed a reduced coverage of BVs in the adult PFC by AQP-4-immunoreactive (AQP-4-IR astrocyte processes with respect to nonselected Wistar rats (NAB, thereby validating it for our study. A further evaluation of the morphology of astrocyte in brain slices (ex vivo and in vitro using an antibody against the astrocyte-specific cytoskeletal protein glial fibrillary acidic protein (GFAP revealed that HAB astrocytes extended less processes than NAB cells. Furthermore, short-term drug treatment in vitro with the AD fluoxetine (FLX was sufficient to increase the plasticity of astrocyte processes, enhancing their number in NAB-derived cells and recovering their basal number in HAB-derived cells. This enhanced FLX-dependent plasticity occurred, however, only in the presence of intact AQP-4, as demonstrated by the lack of effect after the downregulation of AQP-4 with RNAi in both NAB and HAB cells. Nonetheless, a similar short-term treatment did neither modulate the coverage of BVs with AQP-4-positive astrocyte endfeet in NAB nor in HAB rats, although dosage and time of treatment were sufficient to fully recover GFAP expression

  18. Peripheral and spinal 5-HT receptors participate in the pronociceptive and antinociceptive effects of fluoxetine in rats.

    Science.gov (United States)

    Cervantes-Durán, C; Rocha-González, H I; Granados-Soto, V

    2013-11-12

    The role of 5-HT receptors in fluoxetine-induced nociception and antinociception in rats was assessed. Formalin produced a typical pattern of flinching and licking/lifting behaviors. Local peripheral ipsilateral, but not contralateral, pre-treatment with fluoxetine (0.3-3 nmol/paw) increased in a dose-dependent fashion 0.5% formalin-induced nociception. In contrast, intrathecal pretreatment with fluoxetine (0.3-3 nmol/rat) prevented nociception induced by formalin. The peripheral pronociceptive effect of fluoxetine was prevented by the 5-HT2A (ketanserin, 3-10 pmol/paw), 5-HT2B (3-(2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl)-2,4(1H,3H)-quinazolinedione(+) tartrate, RS-127445, 3-10 pmol/paw), 5-HT2C (8-[5-(2,4-dimethoxy-5-(4-trifluoromethylphenylsulphonamido) phenyl-5-oxopentyl]1,3,8-triazaspiro[4.5] decane-2,4-dione hydrochloride, RS-102221, 3-10 pmol/paw), 5-HT3 (ondansetron, 3-10 nmol/paw), 5-HT4 ([1-[2-methylsulphonylamino ethyl]-4-piperidinyl]methyl 1-methyl-1H-indole-3-carboxylate, GR-113808, 3-100 fmol/paw), 5-HT6 (4-iodo-N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]benzene-sulfonamide hydrochloride, SB-258585, 3-10 pmol/paw) and 5-HT7 ((R)-3-(2-(2-(4-methylpiperidin-1-yl) ethyl) pyrrolidine-1-sulfonyl) phenol hydrochloride, SB-269970, 0.3-1 nmol/paw), but not by the 5-HT1A (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate, WAY-100635, 0.3-1 nmol/paw), 5-HT1B/1D (N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-1,1'-biphenyl-4-carboxamide hydrochloride hydrate, GR-127935, 0.3-1 nmol/paw), 5-HT1B (1'-methyl-5-[[2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine hydrochloride, SB-224289, 0.3-1 nmol/paw), 5-HT1D (4-(3-chlorophenyl)-α-(diphenylmethyl)-1-piperazineethanol hydrochloride, BRL-15572, 0.3-1nmol/paw) nor 5-HT5A ((N-[2-(dimethylamino)ethyl]-N-[[4'-[[(2-phenylethyl)amino]methyl][1,1'-biphenyl]-4

  19. Methylphenidate-induced improvements of various measures of attention in adults with attention deficit hyperactivity disorder.

    Science.gov (United States)

    Tucha, O; Mecklinger, L; Laufkötter, R; Klein, H E; Walitza, S; Lange, K W

    2006-10-01

    The present study examined the effect of the stimulant medication methylphenidate (MPH) on attentional functioning of adults with ADHD. Sixteen adults with a diagnosed ADHD without comorbidity were assessed twice, at baseline off MPH and following MPH treatment. The assessment battery consisted of reaction time tasks of low complexity, including measures of alertness--subdivided into tonic and phasic alertness, vigilance, divided attention, flexibility and such aspects of selective attention as including focused attention, inhibition and integration of sensory information. In addition, 16 healthy participants who were matched to adults with ADHD according to sex, age, education level and intellectual functions were also assessed twice using the same test battery. The results of the present study suggest that adults with ADHD off stimulant medication are seriously impaired in various components of attention including vigilance, divided attention, selective attention and flexibility. These impairments of attention were observed primarily in regard to reaction time and its variability. Treatment of adults with ADHD using individually tailored doses of MPH has a positive effect on measures of alertness, vigilance, selective attention, divided attention and flexibility. However, even on MPH adults with ADHD displayed considerable deficits in vigilance and integration of sensory information. The present findings indicate that adults with ADHD are not differentially impaired in attentional processes but may suffer from a more global deficit of attention. Although MPH treatment has been found to be effective in the treatment of the attention deficit of adults with ADHD, additional treatment appears to be necessary.

  20. The effect of Sertraline, Paroxetine, Fluoxetine and Escitalopram on testicular tissue and oxidative stress parameters in rats

    Directory of Open Access Journals (Sweden)

    Fikret Erdemir

    2014-01-01

    Full Text Available Introduction: The aim of this study was to evaluate the effect of selective serotonin reuptake inhibitors (SSRIs on testicular tissue and serum malondialdehyde (MDA levels in rats. Materials and methods: A total of 40 male Wistar albino rats, 5.5-6 months old, were equally divided at random into five groups: group 1 was the control group, group 2 received sertraline 10mg/kg (p.o, group 3 was administered fluoxetine 10mg/kg (p.o, group 4 received escitalopram 10mg/kg (p.o, and group 5 (n = 8 was administered paroxetine 20mg/kg. Each dose was administered orally for two months. Johnsen’s criteria were used to categorize spermatogenesis. Johnsen’s method assigns a score of 1 to 10 to each tubule cross-section examined. In this system, a Johnsen score of 9 and 10 indicates normal histology. Serum luteinizing hormone (LH, follicle-stimulating hormone (FSH, and testosterone levels were evaluated. Serum MDA levels were also measured. Results: The mean Johnsen scores were 9.36 ± 0.33, 9.29 ± 0.32, 8.86 ± 0.48, 9.10 ± 0.56, and 8.33 ± 0.90 in control group, sertraline group, fluoxetine group, escitalopram group, and paroxetine group, respectively. The Johnsen score was significantly lower for paroxetine group compared with the control group (p < 0.05. The mean FSH level increased only in the sertraline group. With the exception of the fluoxetine group, the testosterone levels were lower in all groups compared with the control group. The total testosterone level was significantly lower in the sertraline group compared with the control group [40.87 (22.37-46.8 vs. 15.87 (13.53-19.88, p < 0.01]. There were no significant differences between the groups with respect to the MDA and LH levels (p = 0.090 and p = 0.092. Conclusion: These data suggest that SSRIs have a negative effect on testicular tissues. This negative impact is markedly greater in the paroxetine group. To determine the exact mechanism of action of these drugs on testicular tissue, well

  1. The burden and management of cytochrome P450 2D6 (CYP2D6)-mediated drug-drug interaction (DDI): co-medication of metoprolol and paroxetine or fluoxetine in the elderly.

    Science.gov (United States)

    Bahar, Muh Akbar; Hak, Eelko; Bos, Jens H J; Borgsteede, Sander D; Wilffert, Bob

    2017-07-01

    Metoprolol and paroxetine/fluoxetine are inevitably co-prescribed because cardiovascular disorders and depression often coexist in the elderly. This leads to CYP2D6-mediated drug-drug interactions (DDI). Because systematic evaluations are lacking, we assessed the burden of metoprolol-paroxetine/fluoxetine interaction in the elderly and how these interactions are managed in Dutch community pharmacies. Dispensing data were collected from the University of Groningen pharmacy database (IADB.nl, 1999-2014) for elderly patients (≥60 years) starting beta-blockers and/or antidepressants. Based on the two main DDI alert systems (G-Standard and Pharmabase), incidences were divided between signalled (metoprolol-fluoxetine/paroxetine) and not-signalled (metoprolol-alternative antidepressants and alternative beta-blockers-paroxetine/fluoxetine) combinations. Incident users were defined as patients starting at least one signalled or a non-signalled combination. G-Standard signalled throughout the study period, whereas Pharmabase stopped after 2005. A total of 1763 patients had 2039 metoprolol-paroxetine/fluoxetine co-prescriptions, despite DDI alert systems, and about 57.3% were signalled. The number of metoprolol-alternative antidepressant combinations (incidences = 3150) was higher than alternative beta-blocker-paroxetine/fluoxetine combinations (incidences = 1872). Metoprolol users are more likely to be co-medicated with an alternative antidepressant (incidences = 2320) than paroxetine/fluoxetine users (incidences = 1232) are. The number of paroxetine/fluoxetine users co-prescribed with alternative beta-blockers was comparable to those co-medicated with metoprolol (about 50%). Less than 5% of patients received a substitute therapy after using metoprolol-paroxetine/fluoxetine. Most of the metoprolol users (90%) received a low dose (mean DDD = 0.47) regardless whether they were prescribed paroxetine/fluoxetine. Despite the signalling software, metoprolol-paroxetine/fluoxetine

  2. Fluoxetine reverts chronic restraint stress-induced depression-like behaviour and increases neuropeptide Y and galanin expression in mice

    DEFF Research Database (Denmark)

    Christiansen, Søren Hofman Oliveira; Olesen, Mikkel Vestergaard; Wörtwein, Gitta

    2011-01-01

    Stressful life events and chronic stress are implicated in the development of depressive disorder in humans. Neuropeptide Y (NPY) and galanin have been shown to modulate the stress response, and exert antidepressant-like effects in rodents. To further investigate these neuropeptides in depression......-like behaviour, NPY and galanin gene expression was studied in brains of mice subjected to chronic restraint stress (CRS) and concomitant treatment with the antidepressant fluoxetine (FLX). CRS caused a significant increase in depression-like behaviour that was associated with increased NPY mRNA levels...... in the medial amygdala. Concomitant FLX treatment reverted depression-like effects of CRS and led to significant increases in levels of NPY and galanin mRNA in the dentate gyrus, amygdala, and piriform cortex. These findings suggest that effects on NPY and galanin gene expression could play a role...

  3. Removal of toxicity the pharmaceutical propranolol and your mixture with fluoxetine hydrochloride in aqueous solution using radiation with electron beam

    International Nuclear Information System (INIS)

    Boiani, Nathalia Fonseca

    2016-01-01

    Environmental health has been damage due to incorrect disposal of products and by-products. Among emerging pollutants it is possible to account with several pharmaceuticals, causing those problems when disposed in the environment by effluents. Conventional processing techniques are insufficient in removal of the pharmaceuticals, for having resistant waste and low biodegradability. Thus the advanced oxidation processes have been studied as an alternative for the treatment of different types of effluents. The objective of this study was to apply the process of irradiation with electron beam in order to reduce the toxic effects of propranolol, and the mixture with fluoxetine hydrochloride in aqueous solution. Ecotoxicological tests conducted with propranolol, and the mixture with fluoxetine hydrochloride, for Daphnia similis microcrustacean, and the Vibrio fischeri bacterium. It was observed that D. similis was more sensitive to propranolol drug and to the mixture, when compared to bacterium V.fischeri. After being subjected to the treatment with ionizing radiation, all applied doses to the propranolol and the mixture, showed significant reduction of toxicity, for D. similis. Different were the results for V. fischeri, when only 5.0 kGy reduced toxicity to propranolol. The mixture of pharmaceuticals required 2.5 and 5.0 kGy for reducing toxicity. 5.0 kGy showed the best removal efficiency for toxicity: 79.94 % for D. similis and 15.64 % for V. fischeri, when exposed to propranolol. The mixture reduction efficacy were 81.59% and 26.93 % for D.similis and V.fischeri, respectively. (author)

  4. Effects of sertraline and fluoxetine on p-glycoprotein at barrier sites: in vivo and in vitro approaches.

    Directory of Open Access Journals (Sweden)

    Amita Kapoor

    Full Text Available Retention of substances from systemic circulation in the brain and testes are limited due to high levels of P-glycoprotein (P-gp in the luminal membranes of brain and testes capillary endothelial cells. From a clinical perspective, P-gp rapidly extrudes lipophilic therapeutic agents, which then fail to reach efficacious levels. Recent studies have demonstrated that acute administration of selective serotonin reuptake inhibitors (SSRI can affect P-gp function, in vitro and in vivo. However, little is known concerning the time-course of these effects or the effects of different SSRI in vivo.The P-gp substrate, tritiated digoxin ([(3H] digoxin, was co-administered with fluoxetine or sertraline to determine if either compound increased drug accumulation within the brains and testes of mice due to inhibition of P-gp activity. We undertook parallel studies in endothelial cells derived from brain microvessels to determine the dose-response and time-course of effects.In vitro, sertraline resulted in rapid and potent inhibition of P-gp function in brain endothelial cells, as determined by cellular calcein accumulation. In vivo, a biphasic effect was demonstrated. Brain accumulation of [(3H] digoxin was increased 5 minutes after treatment with sertraline, but by 60 minutes after sertraline treatment, brain accumulation of digoxin was reduced compared to control. By 240 minutes after sertraline treatment brain digoxin accumulation was elevated compared to control. A similar pattern of results was obtained in the testes. There was no significant effect of fluoxetine on P-gp function, in vitro or in vivo.Acute sertraline administration can modulate P-gp activity in the blood-brain barrier and blood-testes barrier. This clearly has implications for the ability of therapeutic agents that are P-gp substrates, to enter the brain when co-administered with SSRI.

  5. Effects of fluoxetine on fine motor performance in dysthymia: an 8-week, nonrandomized, open-label study.

    Science.gov (United States)

    Schrijvers, Didier; Maas, Yvonne J; Sabbe, Bernard G C

    2009-01-01

    Present findings on psychomotor retardation in dysthymia are inconsistent and changes in psychomotor performance during antidepressant treatment have not been investigated in this population to date. The present study aims to explore the psychomotor effects of an 8-week regimen of fluoxetine in dysthymic patients. Dysthymic patients (both inpatients and outpatients of the Psychiatric Hospital Sint-Norbertus, Duffel, Belgium), presenting over a period of 2 years, meeting the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria for dysthymia, and having Hamilton Depression Rating Scale scores of > or = 12 were enrolled. During 8 weeks of treatment with fluoxetine 20 mg/d, depression severity and graphic motor activity were assessed 4 times by recording the time (a reaction time [RT] and a movement time [MT]) participants needed to copy single lines and simple and complex figures. The patients' outcomes were compared with those of untreated, healthy controls, matched for sex and comparable age and education. The assessors were masked to treatment and group. Eighteen dysthymic patients (mean age, 40 years; male/female ratio, 4/14; mean weight, 70 kg; all white) were treated; 18 healthy controls (mean age, 40 years; male/female ratio, 4/14; mean weight, 72 kg; all white) were used as comparison. The overall patient group experienced significant psychomotor changes only in association with the complex figure-copying task (RT: F = 5.67, P 40% decrease in severity scores), significant improvements were observed only for the RT of the line- (F = 4.75, P dysthymia.

  6. Chronic fluoxetine treatment directs energy metabolism towards the citric acid cycle and oxidative phosphorylation in rat hippocampal nonsynaptic mitochondria.

    Science.gov (United States)

    Filipović, Dragana; Costina, Victor; Perić, Ivana; Stanisavljević, Andrijana; Findeisen, Peter

    2017-03-15

    Fluoxetine (Flx) is the principal treatment for depression; however, the precise mechanisms of its actions remain elusive. Our aim was to identify protein expression changes within rat hippocampus regulated by chronic Flx treatment versus vehicle-controls using proteomics. Fluoxetine-hydrohloride (15mg/kg) was administered daily to adult male Wistar rats for 3weeks, and cytosolic and nonsynaptic mitochondrial hippocampal proteomes were analyzed. All differentially expressed proteins were functionally annotated according to biological process and molecular function using Uniprot and Blast2GO. Our comparative study revealed that in cytosolic and nonsynaptic mitochondrial fractions, 60 and 3 proteins respectively, were down-regulated, and 23 and 60 proteins, respectively, were up-regulated. Proteins differentially regulated in cytosolic and nonsynaptic mitochondrial fractions were primarily related to cellular and metabolic processes. Of the identified proteins, the expressions of calretinin and parvalbumine were confirmed. The predominant molecular functions of differentially expressed proteins in both cell hippocampal fractions were binding and catalytic activity. Most differentially expressed proteins in nonsynaptic mitochondria were catalytic enzymes involved in the pyruvate metabolism, citric acid cycle, oxidative phosphorylation, ATP synthesis, ATP transduction and glutamate metabolism. Results indicate that chronic Flx treatment may influence proteins involved in calcium signaling, cytoskeletal structure, chaperone system and stimulates energy metabolism via the upregulation of GAPDH expression in cytoplasm, as well as directing energy metabolism toward the citric acid cycle and oxidative phosphorylation in nonsynaptic mitochondria. This approach provides new insight into the chronic effects of Flx treatment on protein expression in a key brain region associated with stress response and memory. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Evaluation of the role of NMDA receptor function in antidepressant-like activity. A new study with citalopram and fluoxetine in the forced swim test in mice.

    Science.gov (United States)

    Wolak, Małgorzata; Siwek, Agata; Szewczyk, Bernadeta; Poleszak, Ewa; Bystrowska, Beata; Moniczewski, Andrzej; Rutkowska, Anita; Młyniec, Katarzyna; Nowak, Gabriel

    2015-06-01

    The NMDA/glutamate receptors are involved in the mechanism of antidepressant activity. The present study was designed to investigate the effect of NMDA receptor ligands (agonists and antagonists of glutamate sites) on the antidepressant-like activity of selective serotonin reuptake inhibitors (SSRIs), citalopram and fluoxetine, in the forced swim test in mice. The antidepressant activity (reduction in immobility time) of citalopram but not of fluoxetine was antagonized by N-methyl-D-aspartate acid and enhanced by CGP37849 (antagonist of the NMDA receptor). The present literature data indicate that the antidepressant-like activity of conventional antidepressants is generally affected by the NMDA receptor, although by modulation from different sites of the complex. Thus, it supports the issue of the ability of NMDA receptor antagonists to enhance the antidepressant action in human depression. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  8. A comparison of patterns of spontaneous adverse drug reaction reporting with St. John's Wort and fluoxetine during the period 2000-2013.

    Science.gov (United States)

    Hoban, Claire L; Byard, Roger W; Musgrave, Ian F

    2015-07-01

    Herbal medicines are perceived to be safe by the general public and medical practitioners, despite abundant evidence from clinical trials and case reports that show herbal preparations can have significant adverse effects. The overall impact of adverse events to herbal medicines in Australia is currently unknown. Post marketing surveillance of medications through spontaneous adverse drug reaction (ADR) reports to the Therapeutic Goods Administration (TGA) is one way to estimate this risk. The patterns of spontaneously reported ADRs provide insight to herbal dangers, especially when compared with patterns of a mechanistically similar conventional drug. The study compared the pattern of spontaneously reported ADRs to St. John's Wort (Hypericum perforatum), a common herbal treatment for depression which contains selective serotonin reuptake inhibitors (SSRI), to fluoxetine, a commonly prescribed synthetic SSRI antidepressant. Spontaneous ADR reports sent to the TGA between 2000-2013 for St. John's Wort (n = 84) and fluoxetine (n = 447) were obtained and analysed. The demographic information, types of interaction, severity of the ADR, and the body systems affected (using the Anatomical Therapeutic Chemical classification system) were recorded for individual ADR cases. The majority of spontaneously reported ADRs for St. John's Wort and fluoxetine were concerning females aged 26-50 years (28.6%, 22.8%). The organ systems affected by ADRs to St John's Wort and fluoxetine have a similar profile, with the majority of cases affecting the central nervous system (45.2%, 61.7%). This result demonstrates that herbal preparations can result in ADRs similar to those of prescription medications. © 2015 Wiley Publishing Asia Pty Ltd.

  9. Beneficial effects of fluoxetine, reboxetine, venlafaxine, and voluntary running exercise in stressed male rats with anxiety- and depression-like behaviors.

    Science.gov (United States)

    Lapmanee, Sarawut; Charoenphandhu, Jantarima; Charoenphandhu, Narattaphol

    2013-08-01

    Rodents exposed to mild but repetitive stress may develop anxiety- and depression-like behaviors. Whether this stress response could be alleviated by pharmacological treatments or exercise interventions, such as wheel running, was unknown. Herein, we determined anxiety- and depression-like behaviors in restraint stressed rats (2h/day, 5 days/week for 4 weeks) subjected to acute diazepam treatment (30min prior to behavioral test), chronic treatment with fluoxetine, reboxetine or venlafaxine (10mg/kg/day for 4 weeks), and/or 4-week voluntary wheel running. In elevated plus-maze (EPM) and forced swimming tests (FST), stressed rats spent less time in the open arms and had less swimming duration than the control rats, respectively, indicating the presence of anxiety- and depression-like behaviors. Stressed rats also developed learned fear as evaluated by elevated T-maze test (ETM). Although wheel running could reduce anxiety-like behaviors in both EPM and ETM, only diazepam was effective in the EPM, while fluoxetine, reboxetine, and venlafaxine were effective in the ETM. Fluoxetine, reboxetine, and wheel running, but not diazepam and venlafaxine, also reduced depression-like behavior in FST. Combined pharmacological treatment and exercise did not further reduce anxiety-like behavior in stressed rats. However, stressed rats treated with wheel running plus reboxetine or venlafaxine showed an increase in climbing duration in FST. In conclusion, regular exercise (voluntary wheel running) and pharmacological treatments, especially fluoxetine and reboxetine, could alleviate anxiety- and depression-like behaviors in stressed male rats. Copyright © 2013 Elsevier B.V. All rights reserved.

  10. Comparison of fluoxetine and 1-methyl-L-tryptophan in treatment of depression-like illness in Bacillus Calmette-Guerin-induced inflammatory model of depression in mice.

    Science.gov (United States)

    Rana, Proteesh; Sharma, Amit K; Jain, Smita; Deshmukh, Pravin; Bhattacharya, S K; Banerjee, B D; Mediratta, Pramod K

    2016-11-01

    The inflammatory response system has been implicated in the pathophysiology of major depression. The pro-inflammatory cytokines like interferon-γ induce the enzyme indoleamine-2,3-dioxygenase (IDO) of the kynurenine pathway of tryptophan metabolism. The induction of IDO reduces the availability of tryptophan for serotonin synthesis. Furthermore, the metabolites of kynurenine pathway have neurotoxic property, which along with decreased serotonin may account for depression-like illness. The aim of this study was to compare the effects of treatment with fluoxetine and 1-methyl-L-tryptophan (1-MT) on Bacillus Calmette-Guerin (BCG)-induced inflammatory model of depression in mice. Behavioral tests included locomotor activity, forced swim test (FST) and tail suspension test (TST). Oxidative stress was assessed by examining the levels of thiobarbituric acid reactive species (TBARS) and non-protein thiols (NP-SH) in homogenized whole brain samples. Comet assays were performed to assess neurotoxicity. The results of this study demonstrate that BCG treatment resulted in an increase in duration of immobility in FST and TST as compared to the saline group. Further, it produced a significant increase in the brain TBARS levels and decrease in the brain NP-SH levels. The hippocampal tissue from BCG group had significantly more comet cells than the saline group. 1-MT and fluoxetine were able to reverse the BCG-induced depression-like behavior and the derangement in oxidative stress parameters. Fluoxetine and 1-MT also reversed the BCG-induced neurotoxicity in such mice. 1-Methyl-L-tryptophan exhibits antidepressant-like effect comparable to that of fluoxetine in treating BCG-induced depression-like behavior in mice.

  11. Subchronic treatment with fluoxetine and ketanserin increases hippocampal brain-derived neurotrophic factor, β-catenin and antidepressant-like effects.

    Science.gov (United States)

    Pilar-Cuéllar, F; Vidal, R; Pazos, A

    2012-02-01

    5-HT(2A) receptor antagonists improve antidepressant responses when added to 5-HT-selective reuptake inhibitors (SSRIs) or tricyclic antidepressants. Here, we have studied the involvement of neuroplasticity pathways and/or the 5-hydroxytryptaminergic system in the antidepressant-like effect of this combined treatment, given subchronically. Expression of brain-derived neurotrophic factor (BDNF) and its receptor (TrkB), 5-bromo-2'-deoxyuridine (BrdU) incorporation, and β-catenin protein expression in different cellular fractions, as well as 5-HT(1A) receptor function were measured in the hippocampus of rats treated with fluoxetine, ketanserin and fluoxetine + ketanserin for 7 days, followed by a forced swimming test (FST) to analyse antidepressant efficacy. mRNA for BDNF was increased in the CA3 field and dentate gyrus of the hippocampus by combined treatment with fluoxetine + ketanserin. Expression of β-catenin was increased in total hippocampal homogenate and in the membrane fraction, but unchanged in the nuclear fraction after combined treatment with fluoxetine + ketanserin. These effects were paralleled by a decreased immobility time in the FST. There were no changes in BrdU incorporation, TrkB expression and 5-HT(1A) receptor function in any of the groups studied. The antidepressant-like effect induced by subchronic co-treatment with a SSRI and a 5-HT(2A) receptor antagonist may mainly be because of modifications in hippocampal neuroplasticity (BDNF and membrane-associated β-catenin), without a significant role for other mechanisms involved in chronic antidepressant response, such as hippocampal neuroproliferation or 5-HT(1A) receptor desensitization in the dorsal raphe nucleus. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

  12. Effects of periadolescent fluoxetine and paroxetine on elevated plus-maze, acoustic startle, and swimming immobility in rats while on and off-drug.

    Science.gov (United States)

    Vorhees, Charles V; Morford, LaRonda R; Graham, Devon L; Skelton, Matthew R; Williams, Michael T

    2011-10-05

    Whether selective serotonin reuptake inhibitors (SSRIs) exposure during adolescent brain development causes lasting effects remains unresolved. Assess the effects of fluoxetine and paroxetine 60 days after adolescent exposure compared with when on-drug. Male Sprague-Dawley littermates (41 litters) were gavaged on postnatal days 33-53 with fluoxetine (3 or 10 mg/kg/day), paroxetine (3, 10 or, 17 mg/kg/day), or water; half were tested while on-drug (21 litters) and half after 60 days off-drug (20 litters). The highest dose of the drugs reduced body weight gain during treatment that rebounded 1 week post-treatment. On-drug, no significant group differences were found on elevated plus maze time-in-open, zone entries, or latency to first open entry; however, the high dose of paroxetine significantly reduced head-dips (N=20/group). No significant effects were found on-drug for acoustic startle response/prepulse inhibition (ASR/PPI) although a trend (pfluoxetine and paroxetine (N=20-21/group). No differences on immobility time were seen in the Porsolt forced swim test or in plasma corticosterone at the end of forced swim (N-19-21/group). Off-drug, no effects were seen in the elevated plus maze (N=16/group), ASR/PPI (N=20/group), forced swim (N=19-20/group), or plasma corticosterone (N=19/group). At the doses tested, fluoxetine and paroxetine induced minor effects with drug on-board but no residual, long-term adverse effects in rats 60 days after drug discontinuation. The data provide no evidence that fluoxetine or paroxetine have long-term adverse effects on the behaviors measured here after adolescent to young adult exposure.

  13. Omega-3 Fatty Acid Deficiency Does Not Alter the Effects of Chronic Fluoxetine Treatment on Central Serotonin Turnover or Behavior in the Forced Swim Test in Female Rats

    OpenAIRE

    McNamara, Robert K.; Able, Jessica A.; Liu, Yanhong; Jandacek, Ronald; Rider, Therese; Tso, Patrick; Lipton, Jack W.

    2013-01-01

    While translational evidence suggests that long-chain omega-3 fatty acid status is positively associated with the efficacy of selective serotonin reuptake inhibitor drugs, the neurochemical mechanisms mediating this interaction are not known. Here we investigated the effects of dietary omega-3 (n-3) fatty acid insufficiency on the neurochemical and behavioral effects of chronic fluoxetine (FLX) treatment. Female rats were fed diets with (CON, n=56) or without (DEF, n=40) the n-3 fatty acids d...

  14. Both chronic treatments by epothilone D and fluoxetine increase the short-term memory and differentially alter the mood status of STOP/MAP6 KO mice.

    Science.gov (United States)

    Fournet, Vincent; de Lavilléon, Gaetan; Schweitzer, Annie; Giros, Bruno; Andrieux, Annie; Martres, Marie-Pascale

    2012-12-01

    Recent evidence underlines the crucial role of neuronal cytoskeleton in the pathophysiology of psychiatric diseases. In this line, the deletion of STOP/MAP6 (Stable Tubule Only Polypeptide), a microtubule-stabilizing protein, triggers various neurotransmission and behavioral defects, suggesting that STOP knockout (KO) mice could be a relevant experimental model for schizoaffective symptoms. To establish the predictive validity of such a mouse line, in which the brain serotonergic tone is dramatically imbalanced, the effects of a chronic fluoxetine treatment on the mood status of STOP KO mice were characterized. Moreover, we determined the impact, on mood, of a chronic treatment by epothilone D, a taxol-like microtubule-stabilizing compound that has previously been shown to improve the synaptic plasticity deficits of STOP KO mice. We demonstrated that chronic fluoxetine was either antidepressive and anxiolytic, or pro-depressive and anxiogenic, depending on the paradigm used to test treated mutant mice. Furthermore, control-treated STOP KO mice exhibited paradoxical behaviors, compared with their clear-cut basal mood status. Paradoxical fluoxetine effects and control-treated STOP KO behaviors could be because of their hyper-reactivity to acute and chronic stress. Interestingly, both epothilone D and fluoxetine chronic treatments improved the short-term memory of STOP KO mice. Such treatments did not affect the serotonin and norepinephrine transporter densities in cerebral areas of mice. Altogether, these data demonstrated that STOP KO mice could represent a useful model to study the relationship between cytoskeleton, mood, and stress, and to test innovative mood treatments, such as microtubule-stabilizing compounds. © 2012 The Authors Journal of Neurochemistry © 2012 International Society for Neurochemistry.

  15. Perinatal fluoxetine effects on social play, the HPA system, and hippocampal plasticity in pre-adolescent male and female rats: Interactions with pre-gestational maternal stress.

    Science.gov (United States)

    Gemmel, Mary; Hazlett, Mariah; Bögi, Eszter; De Lacalle, Sonsoles; Hill, Lesley A; Kokras, Nikolaos; Hammond, Geoffrey L; Dalla, Christina; Charlier, Thierry D; Pawluski, Jodi L

    2017-10-01

    Selective serotonin reuptake inhibitor medications (SSRIs) are the first lines of treatment for maternal affective disorders, and are prescribed to up to 10% of pregnant women. Concern has been raised about how perinatal exposure to these medications affect offspring neurobehavioral outcomes, particularly those related to social interactions, as recent research has reported conflicting results related to autism spectrum disorder (ASD) risk in children prenatally exposed to SSRIs. Therefore, the aim of this work was to investigate the effects of perinatal exposure to the SSRI fluoxetine on social play behaviors and the hypothalamic pituitary adrenal system, using a model of pre-gestational maternal stress. We also investigated synaptic proteins in the CA2, CA3, and dentate gyrus of the hippocampus, as well as number of immature neurons in the granule cell layer, as both measures of plasticity in the hippocampus have been linked to social behaviors. In pre-adolescent male and female Sprague-Dawley rat offspring, main findings show that perinatal fluoxetine prevents the negative effect of maternal stress on sibling play behavior. However, perinatal fluoxetine increased social aggressive play with a novel conspecific in both sexes and decreased time grooming a novel conspecific in males only. Perinatal fluoxetine also increased serum corticosteroid binding globulin levels, 5-HT levels in the hippocampus, and pre-synaptic density assessed via synaptophysin in the dentate gyrus. Social interaction was significantly correlated with changes in plasticity in the CA2 region of the hippocampus. Pre-gestational maternal stress exposure resulted in significantly decreased rates of hippocampal neurogenesis and synaptophysin density in the dentate gyrus of pre-adolescent males, but not females. Together, these results further characterize the role of perinatal SSRIs, maternal stress prior to conception, and sex/gender on developing social behaviors and related plasticity in the

  16. Fluoxetine and its active metabolite norfluoxetine disrupt estrogen synthesis in a co-culture model of the feto-placental unit.

    Science.gov (United States)

    Hudon Thibeault, Andrée-Anne; Laurent, Laetitia; Vo Duy, Sung; Sauvé, Sébastien; Caron, Patrick; Guillemette, Chantal; Sanderson, J Thomas; Vaillancourt, Cathy

    2017-02-15

    The effects of fluoxetine, one of the most prescribed selective serotonin-reuptake inhibitors (SSRIs) during pregnancy, and its active metabolite norfluoxetine were studied on placental aromatase (CYP19) and feto-placental steroidogenesis. Fluoxetine did not alter estrogen secretion in co-culture of fetal-like adrenocortical (H295R) and trophoblast-like (BeWo) cells used as a model of the feto-placental unit, although it induced CYP19 activity, apparently mediated by the serotonin (5-HT) 2A receptor/PKC signaling pathway. Norfluoxetine decreased estrogen secretion in the feto-placental co-culture and competitively inhibited catalytic CYP19 activity in BeWo cells. Decreased serotonin transporter (SERT) activity in the co-culture was comparable to 17β-estradiol treatment of BeWo cells. This work shows that the complex interaction of fluoxetine and norfluoxetine with placental estrogen production, involves 5-HT-dependent and -independent mechanisms. Considering the crucial role of estrogens during pregnancy, our results raise concern about the impact of SSRI treatment on placental function and fetal health. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  17. Plasma fluoxetine concentrations and clinical improvement in an adolescent sample diagnosed with major depressive disorder, obsessive-compulsive disorder, or generalized anxiety disorder.

    Science.gov (United States)

    Blázquez, Ana; Mas, Sergi; Plana, Maria Teresa; Gassó, Patricia; Méndez, Iria; Torra, Mercè; Arnaiz, Joan Albert; Lafuente, Amàlia; Lázaro, Luisa

    2014-06-01

    Fluoxetine (FLX) has been one of the most widely studied selective serotonin reuptake inhibitors in adolescents. Despite its efficacy, however, 30% to 40% of patients do not respond to treatment. The aim of this study was to evaluate whether clinical improvement or adverse events are related to the corrected dose of FLX at 8 and 12 weeks after starting treatment in a sample of adolescents diagnosed with major depressive disorder, obsessive-compulsive disorder, or generalized anxiety disorder. Seventy-four subjects aged between 10 and 17 years participated in the study. Clinical improvement was measured with the Clinical Global Impression-Improvement Scale, whereas the UKU (Udvalg for Klinske Undersogelser) scale was administered to assess adverse effects of treatment. Fluoxetine per kilograms of body weight was related to serum concentration of FLX, NORFLX (norfluoxetine), FLX + NORFLX, and FLX/NORFLX. No relationship was found between dose-corrected FLX levels and therapeutic or adverse effects. No differences in serum concentrations were found between responders and nonresponders to treatment. Sex differences were observed in relation to dose and FLX serum concentration. The analysis by diagnosis revealed differences in FLX dose between obsessive-compulsive disorder patients and both generalized anxiety disorder and major depressive disorder patients. Fluoxetine response seems to be influenced by factors such as sex, diagnosis, or certain genes that might be involved in the drug's pharmacokinetics and pharmacodynamics. Clinical and pharmacogenetic studies are needed to elucidate further the differences between treatment responders and nonresponders.

  18. Effects of periadolescent fluoxetine and paroxetine on elevated plus-maze, acoustic startle, and swimming immobility in rats while on and off-drug

    Directory of Open Access Journals (Sweden)

    Williams Michael T

    2011-10-01

    Full Text Available Abstract Rationale Whether selective serotonin reuptake inhibitors (SSRIs exposure during adolescent brain development causes lasting effects remains unresolved. Objective Assess the effects of fluoxetine and paroxetine 60 days after adolescent exposure compared with when on-drug. Methods Male Sprague-Dawley littermates (41 litters were gavaged on postnatal days 33-53 with fluoxetine (3 or 10 mg/kg/day, paroxetine (3, 10 or, 17 mg/kg/day, or water; half were tested while on-drug (21 litters and half after 60 days off-drug (20 litters. Results The highest dose of the drugs reduced body weight gain during treatment that rebounded 1 week post-treatment. On-drug, no significant group differences were found on elevated plus maze time-in-open, zone entries, or latency to first open entry; however, the high dose of paroxetine significantly reduced head-dips (N = 20/group. No significant effects were found on-drug for acoustic startle response/prepulse inhibition (ASR/PPI although a trend (p Conclusions The data provide no evidence that fluoxetine or paroxetine have long-term adverse effects on the behaviors measured here after adolescent to young adult exposure.

  19. Effects of fluoxetine treatment on striatal dopamine transporter binding and cerebrospinal fluid insulin-like growth factor-1 in children with autism.

    Science.gov (United States)

    Makkonen, I; Kokki, H; Kuikka, J; Turpeinen, U; Riikonen, R

    2011-10-01

    A positive effect of fluoxetine has been shown in some children with autism. The present study was undertaken to correlate striatal dopamine transporter (DAT) binding and cerebrospinal fluid insulin-like growth factor-1 (CSF-IGF-1) with clinical response in autistic children (n=13, age 5-16 years) after a 6-month fluoxetine treatment. Good clinical responders (n=6) had a decrease (p=0.031) in DAT binding as assessed using single-photon emission computed tomography with [123I]-nor-β-CIT, whereas poor responders had a trend to an increase. An increase in CSF-IGF-1 (p=0.003) was detected after the treatment period, but no correlation between the clinical response and CSF-IGF-1 was found. In conclusion, fluoxetine decreases DAT binding indicating alleviation of the hyperdopaminergic state and increases CSF-IGF-1 concentration, which may also have a neuroprotective effect against dopamine-induced neurotoxicity in autistic children. © Georg Thieme Verlag KG Stuttgart · New York.

  20. Cost-effectiveness and cost-utility of cognitive therapy, rational emotive behavioral therapy, and fluoxetine (Prozac) in treating depression: a randomized clinical trial.

    Science.gov (United States)

    Sava, Florin A; Yates, Brian T; Lupu, Viorel; Szentagotai, Aurora; David, Daniel

    2009-01-01

    Cost-effectiveness and cost-utility of cognitive therapy (CT), rational emotive behavioral therapy (REBT), and fluoxetine (Prozac) for major depressive disorder (MDD) were compared in a randomized clinical trial with a Romanian sample of 170 clients. Each intervention was offered for 14 weeks, plus three booster sessions. Beck Depression Inventory (BDI) scores were obtained prior to intervention, 7 and 14 weeks following the start of intervention, and 6 months following completion of intervention. CT, REBT, and fluoxetine did not differ significantly in changes in the BDI, depression-free days (DFDs), or Quality-Adjusted Life Years (QALYs). Average BDI scores decreased from 31.1 before treatment to 9.7 six months following completion of treatment. Due to lower costs, both psychotherapies were more cost-effective, and had better cost-utility, than pharmacotherapy: median $26.44/DFD gained/month for CT and $23.77/DFD gained/month for REBT versus $34.93/DFD gained/month for pharmacotherapy, median $/QALYs=$1,638, $1,734, and $2,287 for CT, REBT, and fluoxetine (Prozac), respectively. (c) 2008 Wiley Periodicals, Inc.

  1. Drug-, dose- and sex-dependent effects of chronic fluoxetine, reboxetine and venlafaxine on open-field behavior and spatial memory in rats.

    Science.gov (United States)

    Gray, Vanessa C; Hughes, Robert N

    2015-03-15

    In an effort to address the need to include both sexes in studies of effects of the SSRI fluoxetine, the NRI reboxetine and the SNRI venlafaxine on anxiety-related behavior and memory along with the use of chronic drug administration, male and female PVG/c rats were fed diets containing two doses of each drug for 21 days. The rats' anxiety level was then assessed in an open field. Short-term spatial memory for a brightness change in a Y maze was also measured. While there was little evidence of anxiolytic effects of any of the drugs, both fluoxetine and, to a lesser extent, venlafaxine appeared to be mainly anxiogenic in their action depending on both dose and sex. Reboxetine was relatively ineffective in this respect. Ability to locate the Y-maze arm that had changed (from white to black) seemed to be impaired for male (but not female) rats by both fluoxetine and venlafaxine and, to a much lesser extent, by reboxetine. Given the relative ineffectiveness of reboxetine in either test, it is possible that the effects of the other two drugs on both anxiety and memory were mainly due to their serotonin reuptake inhibiting properties. The differences that occurred between males and females in responsiveness to all three drugs supported the long-held view that both sexes should be investigated in studies of this sort, especially in view of reports of sex differences in effects of clinically prescribed antidepressants. Copyright © 2014 Elsevier B.V. All rights reserved.

  2. Systematic analysis of cell cycle effects of common drugs leads to the discovery of a suppressive interaction between gemfibrozil and fluoxetine.

    Science.gov (United States)

    Hoose, Scott A; Duran, Camille; Malik, Indranil; Eslamfam, Shabnam; Shasserre, Samantha C; Downing, S Sabina; Hoover, Evelyn M; Dowd, Katherine E; Smith, Roger; Polymenis, Michael

    2012-01-01

    Screening chemical libraries to identify compounds that affect overall cell proliferation is common. However, in most cases, it is not known whether the compounds tested alter the timing of particular cell cycle transitions. Here, we evaluated an FDA-approved drug library to identify pharmaceuticals that alter cell cycle progression in yeast, using DNA content measurements by flow cytometry. This approach revealed strong cell cycle effects of several commonly used pharmaceuticals. We show that the antilipemic gemfibrozil delays initiation of DNA replication, while cells treated with the antidepressant fluoxetine severely delay progression through mitosis. Based on their effects on cell cycle progression, we also examined cell proliferation in the presence of both compounds. We discovered a strong suppressive interaction between gemfibrozil and fluoxetine. Combinations of interest among diverse pharmaceuticals are difficult to identify, due to the daunting number of possible combinations that must be evaluated. The novel interaction between gemfibrozil and fluoxetine suggests that identifying and combining drugs that show cell cycle effects might streamline identification of drug combinations with a pronounced impact on cell proliferation.

  3. Systematic analysis of cell cycle effects of common drugs leads to the discovery of a suppressive interaction between gemfibrozil and fluoxetine.

    Directory of Open Access Journals (Sweden)

    Scott A Hoose

    Full Text Available Screening chemical libraries to identify compounds that affect overall cell proliferation is common. However, in most cases, it is not known whether the compounds tested alter the timing of particular cell cycle transitions. Here, we evaluated an FDA-approved drug library to identify pharmaceuticals that alter cell cycle progression in yeast, using DNA content measurements by flow cytometry. This approach revealed strong cell cycle effects of several commonly used pharmaceuticals. We show that the antilipemic gemfibrozil delays initiation of DNA replication, while cells treated with the antidepressant fluoxetine severely delay progression through mitosis. Based on their effects on cell cycle progression, we also examined cell proliferation in the presence of both compounds. We discovered a strong suppressive interaction between gemfibrozil and fluoxetine. Combinations of interest among diverse pharmaceuticals are difficult to identify, due to the daunting number of possible combinations that must be evaluated. The novel interaction between gemfibrozil and fluoxetine suggests that identifying and combining drugs that show cell cycle effects might streamline identification of drug combinations with a pronounced impact on cell proliferation.

  4. No effect of C1473G polymorphism in the tryptophan hydroxylase 2 gene on the response of the brain serotonin system to chronic fluoxetine treatment in mice.

    Science.gov (United States)

    Bazhenova, Ekaterina Y; Sinyakova, Nadezhda A; Kulikova, Elizabeth A; Kazarinova, Irina A; Bazovkina, Daria V; Gainetdinov, Raul R; Kulikov, Alexander V

    2017-07-13

    Selective serotonin reuptake inhibitors (SSRIs) are antidepressants that block serotonin transporter (SERT) and increase serotonin (5-HT) level in the synaptic cleft. The interaction between SERT and the key enzyme of 5-HT synthesis in the brain, tryptophan hydroxylase 2 (TPH2), is essential to maintain the brain 5-HT level. The G allele of C1473G polymorphism in Tph2 gene decreases enzyme activity by half in mouse brain. Here we studied effect of C1473G polymorphism on the reaction of brain 5-HT system to chronic fluoxetine treatment (120mg/l in drinking water, for 3 weeks) in adult males of the congenic B6-1473C and B6-1473G mouse lines with high and low enzyme activity, respectively. The polymorphism did not affect the levels of 5-HT, its metabolite, 5-hydroxyindoleacetic acid (5-HIAA) and Tph2 gene mRNA in the brain. Fluoxetine significantly attenuated 5-HT levels in the cortex and striatum, 5-HIAA concentrations in the cortex, hippocampus, striatum and midbrain, and Tph2 gene expression in the midbrain. However, we did not observed any effect of the genotype x treatment interaction on these neurochemical characteristics. Therefore, C1473G polymorphism does not seem to play an essential role in the reaction of the brain 5-HT system to chronic fluoxetine treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Effects of aspirin on immobile behavior and endocrine and immune changes in the forced swimming test: comparison to fluoxetine and imipramine.

    Science.gov (United States)

    Guan, Xi-ting; Shao, Feng; Xie, Xi; Chen, Lin; Wang, Weiwen

    2014-09-01

    Aspirin (ASP) is the most commonly used non-steroidal anti-inflammatory drug in the world. Recent clinical and preclinical evidence suggests that ASP may also exert psychoactive effects. It remains unclear whether ASP has antidepressant-like activity, and any molecular mechanisms underlying such activity have yet to be elucidated. Using the forced swimming test (FST), a well-established animal model of depression widely used to screen potential antidepressants in rodents, we investigated the effects of subacute treatment with ASP (0, 6, 12, 25, and 50mg/kg, i.p.) on immobility in the FST, and on FST-induced changes in endocrine and immune parameters in rats, in comparison to the clinical antidepressants imipramine (IMI) and fluoxetine (FLU). Serum levels of corticosterone, pro-inflammatory cytokine interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were determined by enzyme-linked immunosorbent assay. ASP dose-dependently decreased immobility in the FST, without altering the locomotor activity in the open-field test. The inhibitory effects of higher doses (25 and 50mg/kg) of ASP on immobility were similar to that of FLU and IMI at a dose of 10mg/kg. In addition, the levels of corticosterone, IL-6, and TNF-α in peripheral blood were significantly increased after the FST exposure. IMI, but not FLU and ASP at any dose tested, significantly attenuated corticosterone responses in the FST. Both FLU and IMI treatment reduced the increase of IL-6 and TNF-α levels following the FST exposure. ASP dose-dependently decreased FST-induced increase of cytokine levels, as manifested by significantly stronger effects on IL-6 and TNF-α levels at higher doses (25 and 50mg/kg) than the lowest dose of ASP (6 mg/kg). In all, these results indicate that ASP treatment dose-dependently decreased the immobility time and the release of pro-inflammatory cytokines in the FST, suggesting that the anti-inflammatory effects of ASP might be involved in the antidepressant-like effect

  6. Effects of an alkaloid-rich extract from Mitragyna speciosa leaves and fluoxetine on sleep profiles, EEG spectral frequency and ethanol withdrawal symptoms in rats.

    Science.gov (United States)

    Cheaha, Dania; Keawpradub, Niwat; Sawangjaroen, Kitja; Phukpattaranont, Pimpimol; Kumarnsit, Ekkasit

    2015-10-15

    Many antidepressants are effective in alleviating ethanol withdrawal symptoms. However, most of them suppress rapid eye movement (REM) sleep. Thus, development of antidepressants without undesirable side effects would be preferable. Previously, crude alkaloid extract from Mitragyna speciosa (MS) Korth was found to produce antidepressant activities. It was hypothesized that the alkaloid extract from MS may attenuate ethanol withdrawal without REM sleep disturbance. Adult male Wistar rats implanted with electrodes over the frontal and parietal cortices were used for two separated studies. For an acute study, 10 mg/kg fluoxetine or 60 mg/kg alkaloid extract from MS were administered intragastrically. Electroencephalographic (EEG) signals were recorded for 3 h to examine sleep profiles and EEG fingerprints. Another set of animal was used for an ethanol withdrawal study. They were rendered dependent on ethanol via a modified liquid diet (MLD) containing ethanol ad libitum for 28 days. On day 29, fluoxetine (10 mg/kg) or alkaloid extract from MS (60 mg/kg) were administered 15 min before the ethanol-containing MLD was replaced with an isocaloric ethanol-free MLD to induced ethanol withdrawal symptoms. The sleep analysis revealed that alkaloid extract from MS did not change any REM parameters which included average duration of each REM episode, total REM time, number of REM episode and REM latency whereas fluoxetine significantly suppressed all REM parameters and delayed REM latency. However, power spectral analysis revealed similar fingerprints for fluoxetine and alkaloid extract from MS characterized by decreasing powers in the slow frequency range in frontal and parietal cortical EEG. Neither treatment affected spontaneous motor activity. Finally, both alkaloid extract from MS and fluoxetine were found to significantly attenuate ethanol withdrawal-induced hyperexcitability (increases gamma activity) in both cortices and to reduce locomotor activity. The present study

  7. Benefits from antidepressants: synthesis of 6-week patient-level outcomes from double-blind placebo-controlled randomized trials of fluoxetine and venlafaxine.

    Science.gov (United States)

    Gibbons, Robert D; Hur, Kwan; Brown, C Hendricks; Davis, John M; Mann, J John

    2012-06-01

    Some meta-analyses suggest that efficacy of antidepressants for major depression is overstated and limited to severe depression. To determine the short-term efficacy of antidepressants for treating major depressive disorder in youth, adult, and geriatric populations. Reanalysis of all intent-to-treat person-level longitudinal data during the first 6 weeks of treatment of major depressive disorder from 12 adult, 4 geriatric, and 4 youth randomized controlled trials of fluoxetine hydrochloride and 21 adult trials of venlafaxine hydrochloride. All sponsor-conducted randomized controlled trials of fluoxetine and venlafaxine. Children's Depression Rating Scale-Revised scores (youth population), Hamilton Depression Rating Scale scores (adult and geriatric populations), and estimated response and remission rates at 6 weeks were analyzed for 2635 adults, 960 geriatric patients, and 708 youths receiving fluoxetine and for 2421 adults receiving immediate-release venlafaxine and 2461 adults receiving extended-release venlafaxine. Patients in all age and drug groups had significantly greater improvement relative to control patients receiving placebo. The differential rate of improvement was largest for adults receiving fluoxetine (34.6% greater than those receiving placebo). Youths had the largest treated vs control difference in response rates (24.1%) and remission rates (30.1%), with adult differences generally in the 15.6% (remission) to 21.4% (response) range. Geriatric patients had the smallest drug-placebo differences, an 18.5% greater rate of improvement, 9.9% for response and 6.5% for remission. Immediate-release venlafaxine produced larger effects than extended-release venlafaxine. Baseline severity could not be shown to affect symptom reduction. To our knowledge, this is the first research synthesis in this area to use complete longitudinal person-level data from a large set of published and unpublished studies. The results do not support previous findings that

  8. Chiral high-performance liquid chromatographic analysis of fluoxetine and norfluoxetine in rabbit plasma, urine, and vitreous humor using an acetylated beta-cyclodextrin column.

    Science.gov (United States)

    Yee, L; Wong, S H; Skrinska, V A

    2000-10-01

    Fluoxetine (Prozac) is a potent selective serotonin reuptake inhibitor used for the treatment of major depression. Both fluoxetine (F) and its demethylated metabolite, norfluoxetine (NF), are racemic. S-Fluoxetine (SF) and S-norfluoxetine (SNF) are more potent inhibitors of serotonin reuptake than R-fluoxetine (RF) and R-norfluoxetine (RNF). Quantitation of individual enantiomers may provide a greater understanding of pharmacokinetic properties. The objective of this study was to perform a limited chiral selectivity study using rabbit plasma, urine, and vitreous humor analyzed by a solid-phase extraction protocol and a newly developed chiral analysis with an acetylated beta-cyclodextrin (CD) column. Liquid chromatographic parameters for CD were as follows: a mobile phase composition of methanol/0.3% triethylamine buffer, pH 5.6, (30:70), a flow rate of 1 mL/min, detection at 214 nm, and a temperature of 40 degrees C. Elution order was SNF, SF, RNF, and RF with capacity factors of 6, 7, 8, and 9, respectively. The corresponding resolution factors were as follows: R1,2 = 0.8, R2,3 = 1.2, and R3,4 = 0.9. The conditions for solid-phase extraction were optimized for Varian Bond Elut Certify columns. Following sample application, the column was rinsed with water, acetic acid, and then with methanol. Drug enantiomers were eluted with methylene chloride, isopropanol, and ammonium hydroxide (78:20:2). After extract evaporation, the extract residue was reconstituted for high-performance liquid chromatographic analysis. To investigate chiral pharmacology, a biodistribution study was performed by administering 2 mg/kg of F to five rabbits. Blood, urine, and vitreous specimens were collected. Plasma samples collected 45 min postinjection showed nearly equal concentrations of RF and SE After 24 h, the only metabolite detected in plasma was RNF. Drugs were not detectable in vitreous humor. Urine concentrations of SNF, SF, RNF, and RF were 51, 76, 34, and 8 microg/L, respectively

  9. Antidepressant behavioral effects of duloxetine and fluoxetine in the rat forced swimming test Efeitos antidepressivos da duloxetina e da fluoxetina no teste do nado forçado em ratos

    Directory of Open Access Journals (Sweden)

    Leandro Ciulla

    2007-10-01

    Full Text Available PURPOSE: To compare the effects of the antidepressant drugs duloxetine and fluoxetine on depressive behaviors in rodents. METHODS: Eighteen male Wistar rats were given systemic injections of duloxetine, fluoxetine, or saline prior to a Forced Swimming Test (FST. Immobility and number of stops were measured. RESULTS: Rats given injections of fluoxetine displayed significantly less immobility (p = 0.02 and fewer stops than the control group (p = 0.003. Duloxetine significanlty reduced the number of stops (p = 0.003, but did not effect immobility (p = 0.48. CONCLUSION: Duloxetine and fluoxetine reduced depressive behaviors in the Forced FST. However, our findings suggest that fluoxetine is more effective than duloxetine.OBJETIVO: Comparar o efeito antidepressivo da droga cloridrato de duloxetina com a fluoxetina. MÉTODOS: O teste do nado forçado, teste comportamental que avalia a atividade antidepressiva em ratos, foi utilizado em 18 ratos Wistar, machos adultos, divididos em três grupos iguais: duloxetina, fluoxetina e controle. RESULTADOS: Os dados do teste do nado forçado foram analisados pelo teste One-way ANOVA, Mann Whitney e Kruskall-Wallis.Houve diferença significativa (p = 0,003 entre o número de paradas dos grupos duloxetina e fluoxetina e o grupo controle. CONCLUSÃO: A duloxetina e a fluoxetina tiveram frequência de paradas similares. A fluoxetina mostrou ser mais efetiva que a duloxetina no teste do nado forçado em ratos.

  10. Spectrophotometric determination of fluoxetine by molecularly imprinted polypyrrole and optimization by experimental design, artificial neural network and genetic algorithm

    Science.gov (United States)

    Nezhadali, Azizollah; Motlagh, Maryam Omidvar; Sadeghzadeh, Samira

    2018-02-01

    A selective method based on molecularly imprinted polymer (MIP) solid-phase extraction (SPE) using UV-Vis spectrophotometry as a detection technique was developed for the determination of fluoxetine (FLU) in pharmaceutical and human serum samples. The MIPs were synthesized using pyrrole as a functional monomer in the presence of FLU as a template molecule. The factors that affecting the preparation and extraction ability of MIP such as amount of sorbent, initiator concentration, the amount of monomer to template ratio, uptake shaking rate, uptake time, washing buffer pH, take shaking rate, Taking time and polymerization time were considered for optimization. First a Plackett-Burman design (PBD) consists of 12 randomized runs were applied to determine the influence of each factor. The other optimization processes were performed using central composite design (CCD), artificial neural network (ANN) and genetic algorithm (GA). At optimal condition the calibration curve showed linearity over a concentration range of 10- 7-10- 8 M with a correlation coefficient (R2) of 0.9970. The limit of detection (LOD) for FLU was obtained 6.56 × 10- 9 M. The repeatability of the method was obtained 1.61%. The synthesized MIP sorbent showed a good selectivity and sensitivity toward FLU. The MIP/SPE method was used for the determination of FLU in pharmaceutical, serum and plasma samples, successfully.

  11. Spectrophotometric determination of fluoxetine by molecularly imprinted polypyrrole and optimization by experimental design, artificial neural network and genetic algorithm.

    Science.gov (United States)

    Nezhadali, Azizollah; Motlagh, Maryam Omidvar; Sadeghzadeh, Samira

    2018-02-05

    A selective method based on molecularly imprinted polymer (MIP) solid-phase extraction (SPE) using UV-Vis spectrophotometry as a detection technique was developed for the determination of fluoxetine (FLU) in pharmaceutical and human serum samples. The MIPs were synthesized using pyrrole as a functional monomer in the presence of FLU as a template molecule. The factors that affecting the preparation and extraction ability of MIP such as amount of sorbent, initiator concentration, the amount of monomer to template ratio, uptake shaking rate, uptake time, washing buffer pH, take shaking rate, Taking time and polymerization time were considered for optimization. First a Plackett-Burman design (PBD) consists of 12 randomized runs were applied to determine the influence of each factor. The other optimization processes were performed using central composite design (CCD), artificial neural network (ANN) and genetic algorithm (GA). At optimal condition the calibration curve showed linearity over a concentration range of 10 -7 -10 -8 M with a correlation coefficient (R 2 ) of 0.9970. The limit of detection (LOD) for FLU was obtained 6.56×10 -9 M. The repeatability of the method was obtained 1.61%. The synthesized MIP sorbent showed a good selectivity and sensitivity toward FLU. The MIP/SPE method was used for the determination of FLU in pharmaceutical, serum and plasma samples, successfully. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Uso da fluoxetina no tratamento da tricotilomania felina Use of fluoxetine in the treatment of feline psycogenic alopecia

    Directory of Open Access Journals (Sweden)

    Marlos Gonçalves Sousa

    2004-06-01

    Full Text Available A tricotilomania ou alopecia psicogênica felina é uma dermatopatia de origem psicogênica, decorrente da lambedura compulsiva do pelame, realizada pelo gato em situações de estresse. Tal distúrbio decorre de alterações neuro-hormonais e pode associar-se à introdução de novos animais e/ou crianças no ambiente. Além de mudanças de manejo e atitude para com o animal, sugere-se o emprego de ansiolíticos no tratamento da doença. A fluoxetina foi utilizada no tratamento de cinco gatos domésticos com tricotilomania, apresentando inibição do comportamento de lambedura, com repilação após dois a três meses de terapia.Feline psycogenic alopecia occurs when cats lick their hair compulsively. Stress situations play a role in this disturbance, due to changes in neurohormone mechanisms. The introduction of a new animal or baby in the household can also be associated. Besides behavioral changes towards the animal, the use of anxiolytics is suggested to treat the disease. Fluoxetine was used in the treatment of 5 domestic cats with psycogenic alopecia, showing showing inhibition of licking attitude, with repilation within two to three months of use.

  13. Assessing the environmental hazard of individual and combined pharmaceuticals: acute and chronic toxicity of fluoxetine and propranolol in the crustacean Daphnia magna.

    Science.gov (United States)

    Varano, Valentina; Fabbri, Elena; Pasteris, Andrea

    2017-08-01

    Pharmaceuticals are widespread emerging contaminants and, like all pollutants, are present in combination with others in the ecosystems. The aim of the present work was to evaluate the toxic response of the crustacean Daphnia magna exposed to individual and combined pharmaceuticals. Fluoxetine, a selective serotonin re-uptake inhibitor widely prescribed as antidepressant, and propranolol, a non-selective β-adrenergic receptor-blocking agent used to treat hypertension, were tested. Several experimental trials of an acute immobilization test and a chronic reproduction test were performed. Single chemicals were first tested separately. Toxicity of binary mixtures was then assessed using a fixed ratio experimental design. Five concentrations and 5 percentages of each substance in the mixture (0, 25, 50, 75, and 100%) were tested. The MIXTOX model was applied to analyze the experimental results. This tool is a stepwise statistical procedure that evaluates if and how observed data deviate from a reference model, either concentration addition (CA) or independent action (IA), and provides significance testing for synergism, antagonism, or more complex interactions. Acute EC50 values ranged from 6.4 to 7.8 mg/L for propranolol and from 6.4 to 9.1 mg/L for fluoxetine. Chronic EC50 values ranged from 0.59 to 1.00 mg/L for propranolol and from 0.23 to 0.24 mg/L for fluoxetine. Results showed a significant antagonism between chemicals in both the acute and the chronic mixture tests when CA was adopted as the reference model, while absence of interactive effects when IA was used.

  14. Depression-like behavior and mechanical allodynia are reduced by bis selenide treatment in mice with chronic constriction injury: a comparison with fluoxetine, amitriptyline, and bupropion.

    Science.gov (United States)

    Jesse, Cristiano R; Wilhelm, Ethel A; Nogueira, Cristina W

    2010-12-01

    Neuropathic pain is associated with significant co-morbidities, including depression, which impact considerably on the overall patient experience. Pain co-morbidity symptoms are rarely assessed in animal models of neuropathic pain. Neuropathic pain is characterized by hyperexcitability within nociceptive pathways and remains difficult to treat with standard analgesics. The present study determined the effect of bis selenide and conventional antidepressants (fluoxetine, amitriptyline, and bupropion) on neuropathic pain using mechanical allodynic and on depressive-like behavior. Male mice were subjected to chronic constriction injury (CCI) or sham surgery and were assessed on day 14 after operation. Mice received oral treatment with bis selenide (1-5 mg/kg), fluoxetine, amitriptyline, or bupropion (10-30 mg/kg). The response frequency to mechanical allodynia in mice was measured with von Frey hairs. Mice were evaluated in the forced swimming test (FST) test for depression-like behavior. The CCI procedure produced mechanical allodynia and increased depressive-like behavior in the FST. All of the drugs produced antiallodynic effects in CCI mice and produced antidepressant effects in control mice without altering locomotor activity. In CCI animals, however, only the amitriptyline and bis selenide treatments significantly reduced immobility in the FST. These data demonstrate an important dissociation between the antiallodynic and antidepressant effects in mice when tested in a model of neuropathic pain. Depressive behavior in CCI mice was reversed by bis selenide and amitriptyline but not by the conventional antidepressants fluoxetine and buproprion. Bis selenide was more potent than the other drugs tested for antidepressant-like and antiallodynic effects in mice.

  15. Residual sleep disturbance and risk of relapse during the continuation/maintenance phase treatment of major depressive disorder with the selective serotonin reuptake inhibitor fluoxetine

    Directory of Open Access Journals (Sweden)

    McGrath Patrick J

    2010-02-01

    Full Text Available Abstract Background Relapse of major depressive disorder (MDD is a common clinical problem. This study was designed to determine whether residual sleep disturbance (insomnia and hypersomnia predict risk of relapse during the continuation and maintenance treatment of MDD. Methods A total of 570 patients with MDD were treated with open-label, flexible dose fluoxetine (range 20 to 60 mg; mean dose = 45.8 mg/day; SD = 15.1 for 12 weeks. Under double blind conditions, 262 patients who achieved clinical response were randomly assigned to continue fluoxetine or to switch to placebo for 52 weeks or until relapse. Residual sleep disturbance during the baseline visit of the double-blind phase was assessed using items 4, 5, 6 (insomnia and 22, 23, 24 (hypersomnia of the Hamilton Depression Rating Scale (HDRS. Survival analysis was utilized to determine the effect of residual sleep disturbance on risk of relapse. Results The severities of early (P > 0.05, middle (P > 0.05, late (P > 0.05, or total (P > 0.05 residual insomnia were not found to significantly predict risk of relapse during continuation and maintenance-phase treatment. Similarly, the severities of early bedtime (P > 0.05, oversleeping (P > 0.05, napping (P > 0.05, or total (P > 0.05 residual hypersomnia were not found to significantly predict risk of relapse during continuation and maintenance-phase treatment. Conclusion The present study did not identify the severity of residual sleep disturbance among fluoxetine responders to predict risk of MDD relapse. The size of our sample may have precluded us from identifying more modest effects of residual sleep disturbance on the risk of relapse in MDD patients. Future studies are needed to further explore the relationship between residual sleep disturbance and relapse in MDD. Trial Registration ClinicalTrials.gov Identifier: NCT00427128

  16. Evidence of low dose effects of the antidepressant fluoxetine and the fungicide prochloraz on the behavior of the keystone freshwater invertebrate Gammarus pulex.

    Science.gov (United States)

    De Castro-Català, N; Muñoz, I; Riera, J L; Ford, A T

    2017-12-01

    In recent years, behavior-related endpoints have been proposed as rapid and reliable ecotoxicological tools for risk assessment. In particular, the use of detritivores to test the toxicity of pollutants through feeding is currently becoming a well-known method. Experiments combining feeding with other behavioral endpoints can provide relevant information about direct and indirect toxicological effects of chemicals. We carried out a feeding experiment with the shredder Gammarus pulex in order to detect indirect (through leaf conditioning) and direct effects (through water exposure) of two pollutants at environmentally relevant concentrations: the fungicide prochloraz (6 μg/L) and the antidepressant fluoxetine (100 ng/L). Prochloraz inhibited fungal growth on leaves, but it did not affect either the microbial breakdown rates or the C:N ratio of the leaves. Individuals of G. pulex that were fed with treated leaves presented lower consumption rates, not only those fed with prochloraz-treated leaves, but also those fed with fluoxetine-treated leaves, and those fed with the mixture-treated leaves. Mixed-effects models revealed that the swimming velocity of the amphipods after the experiment was modulated by the exposure to fluoxetine, and also by the exposure to prochloraz. We demonstrate that both the antidepressant and the fungicide may cause significant sublethal effects at low concentrations. The combination of behavioral endpoints together with the application of mixed models provided a useful tool for early detection of the effects of toxicity mixtures in freshwater ecosystems. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  17. Genotoxic and immunotoxic potential effects of selected psychotropic drugs and antibiotics on blue mussel (Mytilus edulis) hemocytes

    International Nuclear Information System (INIS)

    Lacaze, Emilie; Pédelucq, Julie; Fortier, Marlène; Brousseau, Pauline; Auffret, Michel; Budzinski, Hélène; Fournier, Michel

    2015-01-01

    The potential toxicity of pharmaceuticals towards aquatic invertebrates is still poorly understood and sometimes controversial. This study aims to document the in vitro genotoxicity and immunotoxicity of psychotropic drugs and antibiotics on Mytilus edulis. Mussel hemocytes were exposed to fluoxetine, paroxetine, venlafaxine, carbamazepine, sulfamethoxazole, trimethoprim and erythromycin, at concentrations ranging from μg/L to mg/L. Paroxetine at 1.5 μg/L led to DNA damage while the same concentration of venlafaxine caused immunomodulation. Fluoxetine exposure resulted in genotoxicity, immunotoxicity and cytotoxicity. In the case of antibiotics, trimethoprim was genotoxic at 200 μg/L and immunotoxic at 20 mg/L whereas erythromycin elicited same detrimental effects at higher concentrations. DNA metabolism seems to be a highly sensitive target for psychotropic drugs and antibiotics. Furthermore, these compounds affect the immune system of bivalves, with varying intensity. This attests the relevance of these endpoints to assess the toxic mode of action of pharmaceuticals in the aquatic environment. - Highlights: • Psychotropic drugs and antibiotics affect the immune system of Mytilus edulis. • Genotoxic and immunotoxic endpoints were relevant to assess pharmaceuticals toxicity. • DNA metabolism is a highly sensitive target for pharmaceuticals. • Fluoxetine and paroxetine were the most toxic compounds on mussel hemocytes. - Psychotropic drugs and antibiotics have the potential to cause immune toxicity and genotoxicity on Mytilus edulis hemocytes

  18. Copper(II)-catalyzed enantioselective hydrosilylation of halo-substituted alkyl aryl and heteroaryl ketones: asymmetric synthesis of (R)-fluoxetine and (S)-duloxetine.

    Science.gov (United States)

    Zhou, Ji-Ning; Fang, Qiang; Hu, Yi-Hu; Yang, Li-Yao; Wu, Fei-Fei; Xie, Lin-Jie; Wu, Jing; Li, Shijun

    2014-02-14

    A set of reaction conditions has been established to facilitate the non-precious copper-catalyzed enantioselective hydrosilylation of a number of structurally diverse β-, γ- or ε-halo-substituted alkyl aryl ketones and α-, β- or γ-halo-substituted alkyl heteroaryl ketones under air to afford a broad spectrum of halo alcohols in high yields and good to excellent enantioselectivities (up to 99% ee). The developed procedure has been successfully applied to the asymmetric synthesis of antidepressant drugs (R)-fluoxetine and (S)-duloxetine, which highlighted its synthetic utility.

  19. Beneficial Effect of Fluoxetine and Sertraline on Chronic Stress-Induced Tumor Growth and Cell Dissemination in a Mouse Model of Lymphoma: Crucial Role of Antitumor Immunity

    Directory of Open Access Journals (Sweden)

    María Emilia Di Rosso

    2018-06-01

    Full Text Available Clinical data and experimental studies have suggested a relationship between psychosocial factors and cancer prognosis. Both, stress effects on the immune system and on tumor biology were analyzed independently. However, there are few studies regarding the stress influence on the interplay between the immune system and tumor biology. Moreover, antidepressants have been used in patients with cancer to alleviate mood disorders. Nevertheless, there is contradictory evidence about their action on cancer prognosis. In this context, we investigated the effect of chronic stress on tumor progression taking into account both its influence on the immune system and on tumor biology. Furthermore, we analyzed the action of selective serotonin reuptake inhibitors, fluoxetine and sertraline, in these effects. For this purpose, C57BL/6J mice submitted or not to a chronic stress model and treated or not with fluoxetine or sertraline were subcutaneously inoculated with EL4 cells to develop solid tumors. Our results indicated that chronic stress leads to an increase in both tumor growth and tumor cell dissemination. The analysis of cell cycle regulatory proteins showed that stress induced an increase in the mRNA levels of cyclins A2, D1, and D3 and a decrease in mRNA levels of cell cycle inhibitors p15, p16, p21, p27, stimulating cell cycle progression. Moreover, an augment of mRNA levels of metalloproteases (MMP-2 and MMP-9, a decrease of inhibitors of metalloproteases mRNA levels (TIMP 1, 2, and 3, and an increase in migration ability were found in tumors from stressed animals. In addition, a significant decrease of antitumor immune response in animals under stress was found. Adoptive lymphoid cell transfer experiments indicated that the reduced immune response in stressed animals influenced both the tumor growth and the metastatic capacity of tumor cells. Finally, we found an important beneficious effect of fluoxetine or sertraline treatment on cancer

  20. 125I-labelled iodothyronines. Useful tools for studies of effects of an antidepressant drug fluoxetine in the rat

    International Nuclear Information System (INIS)

    Stanislav Pavelka; Masaryk University, Brno

    2010-01-01

    Thyroid hormones (TH) are supposed to control the activity of some neurotransmitters (e.g., serotonin), which are hypothetically involved in the pathogenesis of depressive illness. A new group of non-tricyclic antidepressant drugs includes selective serotonine re-uptake inhibitors. The most frequently used representative of this group is fluoxetine (Fluox). We followed in the present paper the effects of Fluox, administered subchronicaly (for 25 days) to Wistar rats by itself, or in combination with 3,3',5-triiodo-l-thyronine (T 3 ). In studies of the interaction of Fluox with the metabolism of TH, we applied adapted radiometric enzyme assays for iodothyronine sulfotransferases (ST) and uridine 5'-diphospho-glucuronyltransferase (UDP-GT), as well as our newly developed radiometric assays for iodothyronine deiodinases (IDs) of types 1, 2 and 3 (D1, D2 and D3), using 125 I-labelled iodothyronines of high specific radioactivity as substrates. We found about two-fold higher UDP-GT enzyme activities in samples of liver microsomes of rats treated with Fluox, in comparison with control rats. In contrast, the radiometric determination of ST activities in liver and kidney cytosolic fractions did not demonstrate any significant effects of the administration of Fluox, alone or together with T 3 , on the induction of these enzymes. However, profound changes in enzyme activities were determined in case of IDs, especially in the pituitary and cerebellum of treated rats. The adapted and newly elaborated radiometric enzyme assays proved to be very sensitive and rapid and, at the same time, reliable and robust. (author)

  1. Population PK modelling and simulation based on fluoxetine and norfluoxetine concentrations in milk: a milk concentration-based prediction model.

    Science.gov (United States)

    Tanoshima, Reo; Bournissen, Facundo Garcia; Tanigawara, Yusuke; Kristensen, Judith H; Taddio, Anna; Ilett, Kenneth F; Begg, Evan J; Wallach, Izhar; Ito, Shinya

    2014-10-01

    Population pharmacokinetic (pop PK) modelling can be used for PK assessment of drugs in breast milk. However, complex mechanistic modelling of a parent and an active metabolite using both blood and milk samples is challenging. We aimed to develop a simple predictive pop PK model for milk concentration-time profiles of a parent and a metabolite, using data on fluoxetine (FX) and its active metabolite, norfluoxetine (NFX), in milk. Using a previously published data set of drug concentrations in milk from 25 women treated with FX, a pop PK model predictive of milk concentration-time profiles of FX and NFX was developed. Simulation was performed with the model to generate FX and NFX concentration-time profiles in milk of 1000 mothers. This milk concentration-based pop PK model was compared with the previously validated plasma/milk concentration-based pop PK model of FX. Milk FX and NFX concentration-time profiles were described reasonably well by a one compartment model with a FX-to-NFX conversion coefficient. Median values of the simulated relative infant dose on a weight basis (sRID: weight-adjusted daily doses of FX and NFX through breastmilk to the infant, expressed as a fraction of therapeutic FX daily dose per body weight) were 0.028 for FX and 0.029 for NFX. The FX sRID estimates were consistent with those of the plasma/milk-based pop PK model. A predictive pop PK model based on only milk concentrations can be developed for simultaneous estimation of milk concentration-time profiles of a parent (FX) and an active metabolite (NFX). © 2014 The British Pharmacological Society.

  2. Sex and age differences in the antidepressant-like effect of fluoxetine in the forced swim test.

    Science.gov (United States)

    Fernández-Guasti, Alonso; Olivares-Nazario, Maribel; Reyes, Rebeca; Martínez-Mota, Lucía

    2017-01-01

    This study compared in males and females of three representative ages: young adults (3-5months old), middle-aged (12-15months old) and senescent (23-25months old) the antidepressant-like effect of fluoxetine (FLX, 5.0 and 10mg/kg) in the forced swim test (FST). Intact (non gonadectomized) rats were evaluated. Young adult females were chosen in proestrus/estrus or in metestrus/diestrus, while middle-aged and senescent females were selected in metestrus/diestrus. Locomotion and motor coordination were also recorded. Under basal conditions (without FLX), young adult and middle-aged females showed less immobility than males. This sex difference disappeared at senescence because males diminished their levels of immobility. Thus, senescent males showed lower immobility than middle-aged and young males. FLX (5 and 10mg/kg) produced similar actions in young females irrespective of their estrous cycle phase, therefore, these subgroups were pooled in a single one. Young adult and middle aged females clearly responded to 5 and 10mg/kg of FLX with a reduction in immobility, while young adult and middle-aged males only did to 10mg/kg. In senescent females 10mg/kg FLX reduced immobility. Remarkably, in senescent males this FLX dose did not produce an antidepressant-like effect. FLX marginally affected locomotion; however, at its highest dose (10mg/kg), and only in senescent males, interfered with motor coordination tested in the rotarod. These data show that sex and aging influence behavioral despair without treatment and after FLX. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Simple spectrophotometric methods for determination of fluoxetine and clomipramine hydrochlorides in dosage forms and in some post-mortem biological fluids samples

    Directory of Open Access Journals (Sweden)

    Emam A. Ali

    2016-12-01

    Full Text Available Sensitive, simple and rapid spectrophotometric methods for micro determination of fluoxetine hydrochloride (FLU and clomipramine hydrochloride (CLO. The methods are based on the reaction between the examined drugs and acid dyes, namely; bromocresol green (BCG, phenol red (PhR and metanil yellow (MY producing yellow ion-pair complexes followed by their extraction with methylene chloride and measured at 412, 407 and 409 nm for FLU with BCG, PhR and MY, respectively; whereas for CLO at 409, 406 and 407 nm, respectively. All variables that affect the performance of the proposed methods were carefully studied and optimized. Beer’s law was obeyed in the concentration ranges 0.86–24.32 μg/mL, 8.64–41.30 μg/mL, 0.86–34.76 μg/mL for FLU and 1.75–24.55 μg/mL, 7.0–50 μg/mL, 1.65–34.78 μg/mL for CLO using BCG, PhR and MY respectively. The methods were validated in terms of accuracy and precision. The proposed methods were successfully applied to the determination of fluoxetine hydrochloride and clomipramine hydrochloride in pure samples, pharmaceutical formulations, spiked post-mortem urine and blood samples.

  4. Age-related changes in the antidepressant-like effect of desipramine and fluoxetine in the rat forced-swim test.

    Science.gov (United States)

    Olivares-Nazario, Maribel; Fernández-Guasti, Alonso; Martínez-Mota, Lucía

    2016-02-01

    Some reports suggest that older patients are less responsive to antidepressants than young adults, but this idea has not been fully supported. Here, we investigated the role of aging in the behavioral effects of the antidepressants, desipramine (DMI) (5, 10, and 20 mg/kg) and fluoxetine (FLX) (5, 10, and 20 mg/kg) in young adults (3-5 months), middle-aged (MA, 12-15 months), and senescent (SE, 23-25 months) male rats in the forced-swim test. In addition, locomotor activity and motor coordination were assessed as side-effects. DMI and fluoxetine produced an antidepressant-like effect in YA and MA animals, although in the latter group, a shift to the right in the dose-response curve was found for DMI. Importantly, neither drug was effective in SE animals. Motor side-effects were produced mainly by DMI in MA and SE rats. Therefore, a decrease in the antidepressant-like effect is associated strongly with senescence as well as an increased vulnerability to motor side-effects, particularly of tricyclics. This study is significant because SE animals are scarcely studied in pharmacological screening tests, and our findings might be useful for improving antidepressant treatments for the increasing aged population.

  5. Duloxetine and 8-OH-DPAT, but not fluoxetine, reduce depression-like behaviour in an animal model of chronic neuropathic pain.

    Science.gov (United States)

    Hu, Bing; Doods, Henri; Treede, Rolf-Detlef; Ceci, Angelo

    2016-04-21

    The current study assessed whether antidepressant and/or antinociceptive drugs, duloxetine, fluoxetine as well as (±)-8-hydroxy-2-[di-n-propylamino] tetralin (8-OH-DPAT), are able to reverse depression-like behaviour in animals with chronic neuropathic pain. Chronic constriction injury (CCI) of the sciatic nerve in rats was selected as neuropathic pain model. Mechanical hypersensitivity and depression-like behaviour were evaluated 4 weeks after surgery by "electronic algometer" and forced swimming test (FST), which measured the time of immobility, and active behaviours climbing and swimming. The selective noradrenergic and serotonergic uptake blocker duloxetine (20mg/kg) and the selective 5-HT1A agonist 8-OH-DPAT (0.5mg/kg) significantly reversed both mechanical hypersensitivity and depression-like behaviour in CCI animals. Duloxetine significantly reversed depression-like behaviour in CCI rats by increasing the time of climbing and swimming, while 8-OH-DPAT attenuated depression-like behaviour mainly by increasing the time of swimming. However, the selective serotonergic uptake blocker fluoxetine (20mg/kg) failed to attenuate mechanical hypersensitivity and depression-like behaviour, possibly due to confounding pro-nociceptive actions at 5-HT3 receptors. These data suggest to target noradrenergic and 5-HT1A receptors for treatment of chronic pain and its comorbidity depression. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  6. Social learning requires plasticity enhanced by fluoxetine through prefrontal Bdnf-TrkB signaling to limit aggression induced by post-weaning social isolation

    Science.gov (United States)

    Umemori, Juzoh; Tóth, Máté; Biró, László; Miskolczi, Christina; Balázsfi, Diána; Zelena, Dóra; Castrén, Eero

    2017-01-01

    Escalated or abnormal aggression induced by early adverse experiences is a growing issue of social concern and urges the development of effective treatment strategies. Here we report that synergistic interactions between psychosocial and biological factors specifically ameliorate escalated aggression induced by early adverse experiences. Rats reared in isolation from weaning until early adulthood showed abnormal forms of aggression and social deficits that were temporarily ameliorated by re-socialization, but aggression again escalated in a novel environment. We demonstrate that when re-socialization was combined with the antidepressant fluoxetine, which has been shown to reactivate juvenile-like state of plasticity, escalated aggression was greatly attenuated, while neither treatment alone was effective. Early isolation induced a permanent, re-socialization resistant reduction in Bdnf expression in the amygdala and the infralimbic cortex. Only the combined treatment of fluoxetine and re-socialization was able to recover Bdnf expression via epigenetic regulation. Moreover, the behavior improvement after the combined treatment was dependent on TrkB activity. Combined treatment specifically strengthened the input from the ventral hippocampus to the mPFC suggesting that this pathway is an important mediator of the beneficial behavioral effects of the combined psychosocial and pharmacological treatment of abnormal aggression. Our findings suggest that synergy between pharmacological induction of plasticity and psychosocial rehabilitation could enhance the efficacy of therapies for pathological aggression. PMID:28685757

  7. The burden and management of cytochrome P450 2D6 (CYP2D6)-mediated drug–drug interaction (DDI) : Co-medication of metoprolol and paroxetine or fluoxetine in the elderly

    NARCIS (Netherlands)

    Bahar, Muh Akbar; Hak, Eelko; Bos, Jens H. J.; Borgsteede, Sander D.; Wilffert, Bob

    Purpose: Metoprolol and paroxetine/fluoxetine are inevitably co-prescribed because cardiovascular disorders and depression often coexist in the elderly. This leads to CYP2D6-mediated drug-drug interactions (DDI). Because systematic evaluations are lacking, we assessed the burden of

  8. Simultaneous determination of fluoxetine and norfluoxetine in dried blood spots using high-performance liquid chromatography-tandem mass spectrometry.

    Science.gov (United States)

    da Silva, Anne Caroline Cezimbra; Raasch, Juliana Raquel; Vargas, Tainara Gomes; Peteffi, Giovana Piva; Hahn, Roberta Zilles; Antunes, Marina Venzon; Perassolo, Magda Susana; Linden, Rafael

    2018-02-01

    Therapeutic drug monitoring (TDM) of the widely prescribed antidepressant fluoxetine (FLU) is recommended in certain situations, such as occurrence of toxicity, inadequate response or suspect of poor adherence. Dried blood spot (DBS) sampling is an increasingly studied alternative for TDM, particularly for outpatients, due to its ease of collection and inherent stability. The aim of this study was to develop and validate an LC-MS/MS assay for the simultaneous quantification of FLU and norfluoxetine (NFLU) in DBS. The assay is based on a liquid extraction of single DBS with 8mm of diameter, using FLU-D6 as the internal standard, followed by reversed phase separation in an Accucore® C18 column (100×2.1mm, 2.6μm). Mobile phase was composed of water and acetonitrile (gradient from 80:20 to 50:50, v/v), both containing formic acid 0.1%. The assay was validated and applied to 30 patients under FLU pharmacotherapy. The assay was linear in the range 10-750ngmL -1 . Precision assays presented CV% of 3.13-9.61 and 3.54-7.99 for FLU and NFLU, respectively, and accuracy in the range of 97.98-110.44% and 100.25-105.8%. FLU and NFLU were stable at 25 and 45°C for 7days. The assay was evaluated in 30 patients under FLU treatment. Concentrations of both compounds were higher in DBS than in plasma, and the use of the multiplying factors 0.71 and 0.68 for FLU and NFLU, respectively, allowed acceptable estimation of plasma concentrations, with median prediction bias of -0.55 to 0.55% and mean differences of 0.4 to 2.2ngmL -1 . The presented data support the clinical use of DBS for therapeutic drug monitoring of FLU. Copyright © 2017 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

  9. Stereoselective Inhibition of CYP2C19 and CYP3A4 by Fluoxetine and Its Metabolite: Implications for Risk Assessment of Multiple Time-Dependent Inhibitor Systems

    Science.gov (United States)

    Lutz, Justin D.; VandenBrink, Brooke M.; Babu, Katipudi N.; Nelson, Wendel L.; Kunze, Kent L.

    2013-01-01

    Recent guidance on drug-drug interaction (DDI) testing recommends evaluation of circulating metabolites. However, there is little consensus on how to quantitatively predict and/or assess the risk of in vivo DDIs by multiple time-dependent inhibitors (TDIs) including metabolites from in vitro data. Fluoxetine was chosen as the model drug to evaluate the role of TDI metabolites in DDI prediction because it is a TDI of both CYP3A4 and CYP2C19 with a circulating N-dealkylated inhibitory metabolite, norfluoxetine. In pooled human liver microsomes, both enantiomers of fluoxetine and norfluoxetine were TDIs of CYP2C19, (S)-norfluoxetine was the most potent inhibitor with time-dependent inhibition affinity constant (KI) of 7 μM, and apparent maximum time-dependent inhibition rate (kinact,app) of 0.059 min−1. Only (S)-fluoxetine and (R)-norfluoxetine were TDIs of CYP3A4, with (R)-norfluoxetine being the most potent (KI = 8 μM, and kinact,app = 0.011 min−1). Based on in-vitro-to-in-vivo predictions, (S)-norfluoxetine plays the most important role in in vivo CYP2C19 DDIs, whereas (R)-norfluoxetine is most important in CYP3A4 DDIs. Comparison of two multiple TDI prediction models demonstrated significant differences between them in in-vitro-to-in-vitro predictions but not in in-vitro-to-in-vivo predictions. Inclusion of all four inhibitors predicted an in vivo decrease in CYP2C19 (95%) and CYP3A4 (60–62%) activity. The results of this study suggest that adequate worst-case risk assessment for in vivo DDIs by multiple TDI systems can be achieved by incorporating time-dependent inhibition by both parent and metabolite via simple addition of the in vivo time-dependent inhibition rate/cytochrome P450 degradation rate constant (λ/kdeg) values, but quantitative DDI predictions will require a more thorough understanding of TDI mechanisms. PMID:23785064

  10. Study of the interaction between fluoxetine hydrochloride and bovine serum albumin in the imitated physiological conditions by multi-spectroscopic methods

    International Nuclear Information System (INIS)

    Katrahalli, Umesha; Jaldappagari, Seetharamappa; Kalanur, Shankara S.

    2010-01-01

    The mechanism of interaction of an antidepressant, fluoxetine hydrochloride (FLX) with bovine serum albumin (BSA) has been studied by different spectroscopic techniques under physiological conditions. FLX was found to quench the intrinsic fluorescence of protein by static quenching mechanism. The binding constant 'K' was found to be 7.06x10 3 M -1 at 296 K. The value of 'n' close to unity revealed that the BSA has a single class of binding site for FLX. Based on thermodynamic parameters, hydrogen bonding and van der Waals forces were proposed to operate between BSA and FLX. The change in conformation of protein was noticed upon its interaction with the drug. From displacement studies it was concluded that the FLX bound to protein at site I. The effects of various common metals ions on the binding were also investigated.

  11. Study of the interaction between fluoxetine hydrochloride and bovine serum albumin in the imitated physiological conditions by multi-spectroscopic methods

    Energy Technology Data Exchange (ETDEWEB)

    Katrahalli, Umesha [Department of Chemistry, Karnatak University, Dharwad 580 003 (India); Jaldappagari, Seetharamappa, E-mail: j_seetharam@rediffmail.co [Department of Chemistry, Karnatak University, Dharwad 580 003 (India); Kalanur, Shankara S. [Department of Chemistry, Karnatak University, Dharwad 580 003 (India)

    2010-02-15

    The mechanism of interaction of an antidepressant, fluoxetine hydrochloride (FLX) with bovine serum albumin (BSA) has been studied by different spectroscopic techniques under physiological conditions. FLX was found to quench the intrinsic fluorescence of protein by static quenching mechanism. The binding constant 'K' was found to be 7.06x10{sup 3} M{sup -1} at 296 K. The value of 'n' close to unity revealed that the BSA has a single class of binding site for FLX. Based on thermodynamic parameters, hydrogen bonding and van der Waals forces were proposed to operate between BSA and FLX. The change in conformation of protein was noticed upon its interaction with the drug. From displacement studies it was concluded that the FLX bound to protein at site I. The effects of various common metals ions on the binding were also investigated.

  12. Long-term effects of fluoxetine on glycemic control in obese patients with non-insulin-dependent diabetes mellitus or glucose intolerance

    DEFF Research Database (Denmark)

    Breum, Leif; Bjerre, U; Bak, J F

    1995-01-01

    differences (mean +/- SD: F, 10.1 +/- 10.0 kg; P, 9.4 +/- 11.5 kg). Fifteen patients from the F group and 14 from the P group completed the 12-month study without weight loss differences. Glycemic regulation improved along with the weight loss, but with a larger decline in plasma C-peptide and fasting glucose......Fluoxetine (F) is a specific serotonin-reuptake inhibitor that has been shown to promote weight loss and improve glycemic control in obese diabetic patients. To study its long-term metabolic effect, 40 obese patients with non-insulin -dependent diabetes mellitus (NIDDM) or impaired glucose...... tolerance (IGT) were included in a 12-month, randomized, placebo controlled study. Patients were assigned to receive either 60 mg F or placebo (P) daily in conjunction with a 5.0-MJ/d diet (> 50% carbohydrate). Both groups showed a significant weight loss, with a nadir after 6 months without group...

  13. An Examination of Fluoxetine for the Treatment of Selective Mutism Using a Nonconcurrent Multiple-Baseline Single-Case Design Across 5 Cases.

    Science.gov (United States)

    Barterian, Justin A; Sanchez, Joel M; Magen, Jed; Siroky, Allison K; Mash, Brittany L; Carlson, John S

    2018-01-01

    This study examined the utility of fluoxetine in the treatment of 5 children, aged 5 to 14 years, diagnosed with selective mutism who also demonstrated symptoms of social anxiety. A nonconcurrent, randomized, multiple-baseline, single-case design with a single-blind placebo-controlled procedure was used. Parents and the study psychiatrist completed multiple methods of assessment including Direct Behavior Ratings and questionnaires. Treatment outcomes were evaluated by calculating effect sizes for each participant as an individual and for the participants as a group. Information regarding adverse effects with an emphasis on behavioral disinhibition and ratings of parental acceptance of the intervention was gathered. All 5 children experienced improvement in social anxiety, responsive speech, and spontaneous speech with medium to large effect sizes; however, children still met criteria for selective mutism at the end of the study. Adverse events were minimal, with only 2 children experiencing brief occurrences of minor behavioral disinhibition. Parents found the treatment highly acceptable.

  14. Fluoxetine, 17-β estradiol or folic acid combined with intra-lateral septal infusions of neuropeptide Y produced antidepressant-like actions in ovariectomized rats forced to swim.

    Science.gov (United States)

    Molina-Hernández, Miguel; Téllez-Alcántara, N Patricia

    2011-12-01

    Folic acid is antidepressant, either alone or combined with several antidepressant drugs. However, the antidepressant-like actions of folic acid combined with intra-lateral septal (LSN) infusions of neuropeptide Y (NPY) in the forced swimming test (FST) have not been tested before. Thus, systemic injections of fluoxetine (20.0mg/kg, Pfluoxetine (15.0 mg/kg, P<0.05; s.c.) combined with subthreshold doses of NPY (2.5 μg/rat, P<0.05; intra-LSN) and these combinations produced antidepressant-like actions; which were canceled by BIBP 3226 (a NPY-Y1 receptor antagonist). It is concluded that folic acid produced antidepressant-like effects probably through the participation of the NPY Y1 receptors found in the lateral septal nuclei. Copyright © 2011 Elsevier Inc. All rights reserved.

  15. Effect of SSRI antidepressants on ejaculation: a double-blind, randomized, placebo-controlled study with fluoxetine, fluvoxamine, paroxetine, and sertraline.

    Science.gov (United States)

    Waldinger, M D; Hengeveld, M W; Zwinderman, A H; Olivier, B

    1998-08-01

    Depression is a common cause of sexual dysfunction, but also antidepressant medication is often associated with sexual side effects. This article includes two related studies. The first double-blind, placebo-controlled study was conducted in men with lifelong rapid ejaculation and aimed to assess putative differences between the major selective serotonin reuptake inhibitors (SSRIs) (fluoxetine, fluvoxamine, paroxetine, and sertraline) with regard to their ejaculation-delaying effect. Sixty men with an intravaginal ejaculation latency time (IELT) of 1 minute or less were randomly assigned to receive fluoxetine 20 mg/day, fluvoxamine 100 mg/day, paroxetine 20 mg/day, sertraline 50 mg/day, or placebo for 6 weeks. During the 1-month baseline and 6-week treatment periods, the men measured their IELT at home using a stopwatch. The trial was completed by 51 men. During the 6-week treatment period, the geometric mean IELT in the placebo group was constant at approximately 20 seconds. Analysis of variance revealed a between-groups difference in the evolution of IELT delay (p = 0.0004); in the paroxetine, fluoxetine, and sertraline groups there was a gradual increase to about 110 seconds, whereas in the fluvoxamine group, IELT was increased to only approximately 40 seconds. The paroxetine, fluoxetine, and sertraline groups differed significantly (p IELT IELT > 1 minute) to investigate whether data about SSRI-induced delayed ejaculation in men with rapid ejaculation may be extrapolated to men with less-rapid ejaculation. After measurement of IELT at home (using a stopwatch) during a 1-month baseline assessment, 32 men with an IELT of 1 minute or less (group 1) or more than 1 minute (group 2) were randomly assigned to receive paroxetine 20 mg/day or placebo for 6 weeks in a double-blind manner. Patients continued to measure their IELTs at home during the 6 weeks of the study. At baseline, 24 patients consistently had IELTs of one minute or less (group 1), and eight patients

  16. Chronic fluoxetine treatment in middle-aged rats induces changes in the expression of plasticity-related molecules and in neurogenesis

    Directory of Open Access Journals (Sweden)

    Guirado Ramon

    2012-01-01

    Full Text Available Abstract Background Antidepressants promote neuronal structural plasticity in young-adult rodents, but little is known of their effects on older animals. The polysialylated form of the neural cell adhesion molecule (PSA-NCAM may mediate these structural changes through its anti-adhesive properties. PSA-NCAM is expressed in immature neurons and in a subpopulation of mature interneurons and its expression is modulated by antidepressants in the telencephalon of young-adult rodents. Results We have analyzed the effects of 14 days of fluoxetine treatment on the density of puncta expressing PSA-NCAM and different presynaptic markers in the medial prefrontal cortex, hippocampus and amygdala of middle-aged (8 months old rats. The density of puncta expressing PSA-NCAM increased in the dorsal cingulate cortex, as well as in different hippocampal and amygdaloid regions. In these later regions there were also increases in the density of puncta expressing glutamic acid decarboxylase 65/67 (GAD6, synaptophysin (SYN, PSA-NCAM/SYN and PSA-NCAM/GAD6, but a decrease of those expressing vesicular glutamate transporter 1 (VGluT1. Since there is controversy on the effects of antidepressants on neurogenesis during aging, we analyzed the number of proliferating cells expressing Ki67 and that of immature neurons expressing doublecortin or PSA-NCAM. No significant changes were found in the subgranular zone, but the number of proliferating cells decreased in the subventricular zone. Conclusions These results indicate that the effects of fluoxetine in middle-aged rats are different to those previously described in young-adult animals, being more restricted in the mPFC and even following an opposite direction in the amygdala or the subventricular zone.

  17. Pramipexole but not imipramine or fluoxetine reverses the "depressive-like" behaviour in a rat model of preclinical stages of Parkinson's disease.

    Science.gov (United States)

    Berghauzen-Maciejewska, Klemencja; Kuter, Katarzyna; Kolasiewicz, Wacław; Głowacka, Urszula; Dziubina, Anna; Ossowska, Krystyna; Wardas, Jadwiga

    2014-09-01

    Depression is a frequent comorbid disorder in Parkinson's disease and may antedate its motor symptoms. However, mechanisms underlying Parkinson's disease-associated depression are unknown and its current medication is insufficient. The aim of the present study was to compare antidepressant-like effects of imipramine, fluoxetine and pramipexole in a model of preclinical stages of Parkinson's disease in rats. 6-Hydroxydopamine was bilaterally injected into the ventrolateral region of the caudate-putamen in rats. This treatment induced moderate decreases in the levels of dopamine and its metabolites in the caudate-putamen, nucleus accumbens and frontal cortex and reduced the density of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra pars compacta and ventral tegmental area. The lesion increased immobility measured in the forced swimming test without influencing locomotor activity. Chronic (13 days) administration of pramipexole (1mg/kg sc/twice a day) reversed prolongation of the immobility time in lesioned animals but did not stimulate their locomotion. Chronic pramipexole activated dopaminergic transmission in the brain structures which might contribute to its effectiveness in the forced swimming test. In contrast, the 13-day administration of imipramine (10mg/kg ip/day) and fluoxetine (10mg/kg ip/day) did not shorten the immobility time in lesioned rats but reduced their locomotion. The present study indicates that already a moderate lesion of dopaminergic neurons induces "depressive-like" behaviour in animals which is reversed by chronic administration of the antiparkinsonian drug, pramipexole. Copyright © 2014 Elsevier B.V. All rights reserved.

  18. Genetic background contributes to the co-morbidity of anxiety and depression with audiogenic seizure propensity and responses to fluoxetine treatment.

    Science.gov (United States)

    Sarkisova, Karine Yu; Fedotova, Irina B; Surina, Natalia M; Nikolaev, Georgy M; Perepelkina, Olga V; Kostina, Zoya A; Poletaeva, Inga I

    2017-03-01

    Anxiety and depression are the most frequent comorbidities of different types of convulsive and non-convulsive epilepsies. Increased anxiety and depression-like phenotype have been described in the genetic absence epilepsy models as well as in models of limbic epilepsy and acquired seizure models, suggesting a neurobiological connection. However, whether anxiety and/or depression are comorbid to audiogenic epilepsy remains unclear. The aim of this study was to investigate whether anxiety or depression-like behavior can be found in rat strains with different susceptibility to audiogenic seizures (AS) and whether chronic fluoxetine treatment affects this co-morbidity. Behavior in the elevated plus-maze and the forced swimming test was studied in four strains: Wistar rats non-susceptible to AS; Krushinsky-Molodkina (KM) strain, selectively bred for AS propensity from outbred Wistar rats; and a selection lines bred for maximal AS expression (strain "4") and for a lack of AS (strain "0") from KM×Wistar F2 hybrids. Effects of chronic antidepressant treatment on AS and behavior were also evaluated. Anxiety and depression levels were higher in KM rats (with AS) compared with Wistar rats (without AS), indicating the comorbidity with AS. However, in strains "4" and "0" with contrasting AS expression, but with a genetic background close to KM rats, anxiety and depression were not as divergent as in KMs versus Wistars. Fluoxetine treatment exerted an antidepressant effect in all rat strains irrespective of its effect on AS. Genetic background contributes substantively to the co-morbidity of anxiety and depression with AS propensity. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Influence of the brain sexual differentiation process on despair and antidepressant-like effect of fluoxetine in the rat forced swim test.

    Science.gov (United States)

    Gómez, M L; Martínez-Mota, L; Estrada-Camarena, E; Fernández-Guasti, A

    2014-03-07

    Sex differences exist in the depressive disorder prevalence and response to treatment. Several studies suggest that females respond better than males to the action of selective serotonin reuptake inhibitors (SSRIs), suggesting that gonadal hormones modulate mood and the response to these drugs. Sexual steroid hormones exert organizational actions (perennial and on early development) and activational effects (transient and on differentiated tissues). The aim of this study was to analyze sex differences in the forced swim test (FST) in animals without treatment and after fluoxetine (FLX, 0, 2.5, 5.0 and 10.0mg/kg). Initially, we compared male and female adult rats under control conditions or after altering their sexual differentiation process (at day 5 postnatally, PN, 60μg of testosterone propionate to females and male castration to induce or preclude masculinization, respectively). To further analyze if the sex differences depend on organizational or activational steroid hormone action we tested the same animals before and after adult gonadectomy. To prevent variations depending upon the estrous cycle, control and masculinized females were tested in estrus. Control females showed lower immobility and required lower doses of FLX (5mg/kg), to show an antidepressant-like effect, than males (10mg/kg), even after adult gonadectomy. In control males adult orchidectomy prevented FLX's action. Neonatally masculinized females exhibited analogous levels of immobility than control ones; before ovariectomy they responded to FLX similar to controls, but after the surgery they did not respond to fluoxetine. Neonatally orchidectomized males exhibited similar immobility values and response to FLX than control females. The findings suggest that the sex difference in despair depends on the hormones organizational effects and, in males, the response to FLX relies on organizational and activational actions. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

  20. Early deprivation leads to long-term reductions in motivation for reward and 5-HT1A binding and both effects are reversed by fluoxetine.

    Science.gov (United States)

    Leventopoulos, Michail; Russig, Holger; Feldon, Joram; Pryce, Christopher R; Opacka-Juffry, Jolanta

    2009-03-01

    Early life stress is a risk factor in aetiology of depression. In rats, earl