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Sample records for nonselective norepinephrin reuptake

  1. Selective serotonin-norepinephrine reuptake inhibitors-induced Takotsubo cardiomyopathy

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    Rahul Vasudev

    2016-01-01

    Full Text Available Context: Takotsubo translates to "octopus pot" in Japanese. Takotsubo cardiomyopathy (TTC is characterized by a transient regional systolic dysfunction of the left ventricle. Catecholamine excess is the one most studied and favored theories explaining the pathophysiology of TTC. Case Report: We present the case of a 52-year-old Hispanic female admitted for venlafaxine-induced TTC with a review literature on all the cases of Serotonin-norepinephrine reuptake inhibitors (SNRI-associated TTC published so far. Conclusion: SNRI inhibit the reuptake of catecholamines into the presynaptic neuron, resulting in a net gain in the concentration of epinephrine and serotonin in the neuronal synapses and causing iatrogenic catecholamine excess, ultimately leading to TTC.

  2. Desvenlafaxine succinate: A new serotonin and norepinephrine reuptake inhibitor.

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    Deecher, Darlene C; Beyer, Chad E; Johnston, Grace; Bray, Jenifer; Shah, S; Abou-Gharbia, M; Andree, Terrance H

    2006-08-01

    The purpose of this study was to characterize a new chemical entity, desvenlafaxine succinate (DVS). DVS is a novel salt form of the isolated major active metabolite of venlafaxine. Competitive radioligand binding assays were performed using cells expressing either the human serotonin (5-HT) transporter (hSERT) or norepinephrine (NE) transporter (hNET) with K(i) values for DVS of 40.2 +/- 1.6 and 558.4 +/- 121.6 nM, respectively. DVS showed weak binding affinity (62% inhibition at 100 microM) at the human dopamine (DA) transporter. Inhibition of [3H]5-HT or [3H]NE uptake by DVS for the hSERT or hNET produced IC50 values of 47.3 +/- 19.4 and 531.3 +/- 113.0 nM, respectively. DVS (10 microM), examined at a large number of nontransporter targets, showed no significant activity. DVS (30 mg/kg orally) rapidly penetrated the male rat brain and hypothalamus. DVS (30 mg/kg orally) significantly increased extracellular NE levels compared with baseline in the male rat hypothalamus but had no effect on DA levels using microdialysis. To mimic chronic selective serotonin reuptake inhibitor treatment and to block the inhibitory 5-HT(1A) autoreceptors, a 5-HT(1A) antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclo hexanecarboxamide maleate salt (WAY-100635) (0.3 mg/kg s.c.), was administered with DVS (30 mg/kg orally). 5-HT increased 78% compared with baseline with no additional increase in NE or DA levels. In conclusion, DVS is a new 5-HT and NE reuptake inhibitor in vitro and in vivo that demonstrates good brain-to-plasma ratios, suggesting utility in a variety of central nervous system-related disorders.

  3. Improvement of social adaptation in depression with serotonin and norepinephrine reuptake inhibitors

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    Mike Briley

    2010-09-01

    Full Text Available Mike Briley, Chantal MoretNeuroBiz Consulting and Communication, Castres, FranceAbstract: Depression is a disabling condition resulting in significant impairment in social functioning, involving the patient’s family, friends, work colleagues, and society at large. Although both psychologic and pharmacologic treatments generally improve many depressive symptoms, they do not always result in significant improvement in social functioning. The importance of recovery of social functioning in depressed patients is now widely appreciated, and studies are beginning to include it in evaluations of therapeutic efficacy. Among the various social adjustment evaluation rating scales, the Social Adaptation Self-Evaluation Scale, a social motivation and behavior scale, has been found to be simple to use and sensitive to change. Using this scale, the selective norepinephrine reuptake inhibitor, reboxetine, has been shown to be significantly more effective in improving social functioning than the selective serotonin reuptake inhibitor, fluoxetine. These findings are consistent with the notion that improvement in social adaptation involves functions depending primarily on noradrenergic neurotransmission. This hypothesis suggests that the serotonin and norepinephrine reuptake inhibitors, venlafaxine, duloxetine, and milnacipran, could be particularly helpful in improving social functioning. Preliminary studies with the serotonin and norepinephrine reuptake inhibitors suggest that they significantly improve social functioning. Comparative studies with selective serotonin reuptake inhibitors on the effects on social functioning should be encouraged.Keywords: Social Adaptation Self-Evaluation Scale, social functioning, depression, serotonin and norepinephrine reuptake inhibitors, noradrenergic neurotransmission

  4. Contribution of depressed reuptake to the depletion of norepinephrine from rat heart and spleen during endotoxin shock

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    Pardini, B.J.; Jones, S.B.; Filkins, J.P.

    1982-01-01

    Norepinephrine content (microgram/g) was depressed in hearts and spleens of fasted male Holtzman rats treated intravenously with Salmonella enteritidis lipopolysaccharide (14-17 mg/kg). To investigate the mechanism of norepinephrine depletion during endotoxicosis, in vivo norepinephrine reuptake was evaluated in control and severely shocked rats using the incorporation of /sup 3/H-norepinephrine into hearts and spleens. Incorporation of /sup 3/H-norepinephrine into spleens of endotoxic rats was reduced 88%. In contrast, cardiac tissue incorporation of /sup 3/H-norepinephrine was not significantly impaired. In vitro analysis of total norepinephrine retained in cardiac and splenic tissue slices incubated with /sup 3/H-norepinephrine yielded results consistent with in vivo experiments: Splenic norepinephrine reuptake was significantly decreased on the order of 50% in preparations from endotoxic rats, while myocardial norepinephrine reuptake was the same in both groups. The results indicate that depression of norepinephrine reuptake is a mechanism of norepinephrine depletion in spleens but not hearts of endotoxic rats.

  5. Analytical Strategies for the Determination of Norepinephrine Reuptake Inhibitors in Pharmaceutical Formulations and Biological Fluids.

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    Saka, Cafer

    2016-01-01

    Norepinephrine reuptake inhibitors (NRIs) are a class of antidepressant drugs that act as reuptake inhibitors for the neurotransmitters norepinephrine and epinephrine. The present review provides an account of analytical methods published in recent years for the determination of NRI drugs. NRIs are atomoxetine, reboxetine, viloxazine and maprotiline. NRIs with less activity at other sites are mazindol, bupropion, tapentadol, and teniloxazine. This review focuses on the analytical methods including chromatographic, spectrophotometric, electroanalytical, and electrophoresis techniques for NRI analysis from pharmaceutical formulations and biological samples. Among all of the published methods, liquid chromatography with UV-vis or MS-MS detection is the most popular technique. The most the common sample preparation techniques in the analytical methods for NRIs include liquid-liquid extraction and solid-phase extraction. Besides the analytical methods for single components, some of the simultaneous determinations are also included in this review.

  6. Combined Norepinephrine / Serotonergic Reuptake Inhibition: Effects on Maternal Behavior, Aggression and Oxytocin in the Rat

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    Elizabeth Thomas Cox

    2011-06-01

    Full Text Available BACKGROUND: Few systematic studies exist on the effects of chronic reuptake of monoamine neurotransmitter systems during pregnancy on the regulation of maternal behavior, although many drugs act primarily through one or more of these systems. Previous studies examining fluoxetine and amfonelic acid treatment during gestation on subsequent maternal behavior in rodents indicated significant alterations in postpartum maternal care, aggression and oxytocin levels. In this study, we extended our studies to include chronic gestational treatment with desipramine or amitriptyline to examine differential effects of reuptake inhibition of norepinephrine and combined noradrenergic and serotonergic systems on maternal behavior, aggression, and oxytocin system changes. METHODS: Pregnant Sprague-Dawley rats were treated throughout gestation with saline or one of three doses of either desipramine, which has a high affinity for the norepinephrine monoamine transporter, or amitriptyline, an agent with high affinity for both the norepinephrine and serotonin monoamine transporters. Maternal behavior and postpartum aggression were assessed on postpartum days one and six respectively. Oxytocin levels were measured in relevant brain regions on postpartum day seven. Predictions were that amitriptyline would decrease maternal behavior and increase aggression relative to desipramine, particularly at higher doses. Amygdaloidal oxytocin was expected to decrease with increased aggression. RESULTS: Amitriptyline and desiprimine differentially reduced maternal behavior, and at higher doses reduced aggressive behavior. Hippocampal oxytocin levels were lower after treatment with either drug but were not correlated with specific behavioral effects. These results, in combination with previous findings following gestational treatment with other selective neurotransmitter reuptake inhibitors, highlight the diverse effects of multiple monoamine systems thought to be involved in

  7. Evaluation of the analgesic effects of ammoxetine, a novel potent serotonin and norepinephrine reuptake inhibitor

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    Zhang, Ting-Ting; Xue, Rui; Zhu, Lei; Li, Juan; Fan, Qiong-yin; Zhong, Bo-hua; Li, Yun-Feng; Ye, Cai-ying; Zhang, You-zhi

    2016-01-01

    Aim: The selective serotonin (5-HT) and norepinephrine (NE) reuptake inhibitors (SNRIs) are commonly used for the treatment of neuropathic pain and fibromyalgia. Ammoxetine ((±)-3-(benzo[d] [1,3]dioxol-4-yloxy)-N-methyl-3-(thiophen-2-yl)propan-1-amine) has been identified as a novel potent SNRI. In this study, we evaluated the acute analgesic properties of ammoxetine in different animal models of pain, and examined the involvement of monoamines in its analgesic actions. Methods: The analgesic...

  8. Levomilnacipran (Fetzima): A New Serotonin-Norepinephrine Reuptake Inhibitor for the Treatment of Major Depressive Disorder.

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    Saraceni, Megan M; Venci, Jineane V; Gandhi, Mona A

    2014-08-01

    In July 2013, the US Food and Drug Administration approved levomilnacipran extended release (ER; Fetzima), a serotonin-norepinephrine reuptake inhibitor, for the treatment of adults with major depressive disorder. Levomilnacipran is an active enantiomer of the racemic drug milnacipran that is currently approved in the United States for the treatment of fibromyalgia. This article provides an overview of the mechanism of action, pharmacokinetic properties, clinical efficacy, safety, and tolerability of levomilnacipran ER. Relevant information was identified through a search of databases using the key word levomilnacipran. Additional information was obtained from fda.gov, by a review of the reference lists of identified articles, and from posters and abstracts from scientific meetings. Levomilnacipran ER, dosed once daily, is generally well tolerated and has demonstrated favorable effects compared to placebo in clinical trials of patients with major depressive disorder. The increased potency for norepinephrine reuptake inhibition is a characteristic that may represent a novel contribution for levomilnacipran. Additional studies comparing levomilnacipran ER to other commonly prescribed antidepressants are needed to further evaluate its place in therapy.

  9. Synergistic regulation of glutamatergic transmission by serotonin and norepinephrine reuptake inhibitors in prefrontal cortical neurons.

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    Yuen, Eunice Y; Qin, Luye; Wei, Jing; Liu, Wenhua; Liu, Aiyi; Yan, Zhen

    2014-09-05

    The monoamine system in the prefrontal cortex has been implicated in various mental disorders and has been the major target of anxiolytics and antidepressants. Clinical studies show that serotonin and norepinephrine reuptake inhibitors (SNRIs) produce better therapeutic effects than single selective reuptake inhibitors, but the underlying mechanisms are largely unknown. Here, we found that low dose SNRIs, by acting on 5-HT(1A) and α2-adrenergic receptors, synergistically reduced AMPA receptor (AMPAR)-mediated excitatory postsynaptic currents and AMPAR surface expression in prefrontal cortex pyramidal neurons via a mechanism involving Rab5/dynamin-mediated endocytosis of AMPARs. The synergistic effect of SNRIs on AMPARs was blocked by inhibition of activator of G protein signaling 3, a G protein modulator that prevents reassociation of G(i) protein α subunit and prolongs the βγ-mediated signaling pathway. Moreover, the depression of AMPAR-mediated excitatory postsynaptic currents by SNRIs required p38 kinase activity, which was increased by 5-HT(1A) and α2-adrenergic receptor co-activation in an activator of G protein signaling 3-dependent manner. These results have revealed a potential mechanism for the synergy between the serotonin and norepinephrine systems in the regulation of glutamatergic transmission in cortical neurons.

  10. Plasma norepinephrine in hypertensive rats reflects α2-adrenoceptor release control only when re-uptake is inhibited

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    Torill eBerg

    2012-11-01

    Full Text Available α2 adrenoceptors (AR lower central sympathetic output and peripheral catecholamine release, thereby protecting against sympathetic hyperactivity and hypertension. Norepinephrine re-uptake transporter effectively (NET removes norepinephrine from the synapse. Overflow to plasma will therefore not reflect release. Here we tested if inhibition of re-uptake allowed presynaptic α2AR release-control to be reflected as differences in norepinephrine overflow in anesthetized hypertensive (SHR and normotensive (WKY rats. We also tested if α2AR modulated the experiment-induced epinephrine secretion, and a phenylephrine-induced, α1-adrenergic vasoconstriction. Blood pressure was recorded through a femoral artery catheter, and cardiac output by ascending aorta flow. After pre-treatment with NET inhibitor (desipramine, and/or α2AR antagonist (yohimbine, L-659,066 or agonist (clonidine, ST-91, we injected phenylephrine. Arterial blood was sampled 15 min later. Plasma catecholamine concentrations were not influenced by phenylephrine, and therefore reflected effects of pre-treatment. Desipramine and α2AR antagonist separately had little effect on norepinephrine overflow. Combined, they increased norepinephrine overflow, particularly in SHR. Clonidine, but not ST-91, reduced, and pertussis toxin increased norepinephrine overflow in SHR and epinephrine secretion in both strains. L-659,066+clonidine (central α2AR-stimulation normalized the high blood pressure, heart rate and vascular tension in SHR. α2AR antagonists reduced phenylephrine induced vasoconstriction equally in WKY and SHR. Conclusions: α2AAR inhibition increased norepinephrine overflow only when re-uptake was blocked, and then with particular efficacy in SHR, possibly due to their high sympathetic tone. α2AAR inhibited epinephrine secretion, particularly in SHR. α2AAR supported α1AR-induced vasoconstriction equally in the two strains. α2AR malfunctions were therefore not detected in SHR

  11. Improved preclinical cardiovascular therapeutic indices with long-term inhibition of norepinephrine reuptake using reboxetine

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    Fossa, Anthony A., E-mail: anthony.fossa@icardiac.com [Department of Global Safety Pharmacology, Department of Pharmacokinetics, Dynamics and Metabolism, and Neuroscience, Pfizer Global Research and Development Eastern Point Road, Groton, CT 06340 (United States); Wisialowski, Todd A. [Department of Global Safety Pharmacology, Department of Pharmacokinetics, Dynamics and Metabolism, and Neuroscience, Pfizer Global Research and Development Eastern Point Road, Groton, CT 06340 (United States); Cremers, Thomas; Hart, Marieke van der [Brains On-Line B.V., University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen (Netherlands); Tseng, Elaine; Deng, Shibing; Rollema, Hans; Wang, Ellen Q. [Department of Global Safety Pharmacology, Department of Pharmacokinetics, Dynamics and Metabolism, and Neuroscience, Pfizer Global Research and Development Eastern Point Road, Groton, CT 06340 (United States)

    2012-11-01

    Norepinephrine reuptake inhibitors (NRIs) acutely increase norepinephrine (NE) levels, but therapeutic antidepressant activity is only observed after weeks of treatment because central NE levels progressively increase during continued drug exposure. Similarly, while NRIs acutely increase blood pressure (BP) and heart rate (HR) due to enhanced sympathetic neurotransmission, chronic treatment changes the responsiveness of the central noradrenergic system and suppresses these effects via autonomic regulation. To better understand the relationship between NE increases and cardiovascular safety, we investigated acute and chronic effects of the NRI reboxetine on central NE release and on BP and HR and electrical alternans, a measure of arrhythmia liability, in guinea pigs. NE release was assessed by microdialysis in medial prefrontal cortex (mPFC) and hypothalamic paraventricular nucleus (PVN); BP and HR were measured by telemetry. Animals were treated for 28 days with 15 mg/kg/day of reboxetine or vehicle via an osmotic minipump and then challenged with acute intravenous doses of reboxetine. Animals chronically treated with reboxetine had 2-fold higher extracellular basal NE levels in mPFC and PVN compared to basal levels after chronic vehicle treatment. BP was significantly increased after the first day of treatment, and gradually returned to vehicle levels by day 21. These data indicate that chronic NRI treatment may lead to an increase in central NE levels and a concomitant reduction in BP based on exposure–response curves compared to vehicle treatment, suggesting a larger separation between preclinical estimates of efficacy vs. safety compared to acute NRI treatment. -- Highlights: ► Acute RBX produces blood pressure increases acutely that decrease with chronic RBX ► Chronic RBX increases brain NE levels, a preclinical surrogate of improved efficacy ► Short-term screening of NRI often underestimates the chronic therapeutic index ► Chronic cardiovascular

  12. Relative contributions of norepinephrine and serotonin transporters to antinociceptive synergy between monoamine reuptake inhibitors and morphine in the rat formalin model.

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    Fei Shen

    Full Text Available Multimodal analgesia is designed to optimize pain relief by coadministering drugs with distinct mechanisms of action or by combining multiple pharmacologies within a single molecule. In clinical settings, combinations of monoamine reuptake inhibitors and opioid receptor agonists have been explored and one currently available analgesic, tapentadol, functions as both a µ-opioid receptor agonist and a norepinephrine transporter inhibitor. However, it is unclear whether the combination of selective norepinephrine reuptake inhibition and µ-receptor agonism achieves an optimal antinociceptive synergy. In this study, we assessed the pharmacodynamic interactions between morphine and monoamine reuptake inhibitors that possess different affinities and selectivities for norepinephrine and serotonin transporters. Using the rat formalin model, in conjunction with measurements of ex vivo transporter occupancy, we show that neither the norepinephrine-selective inhibitor, esreboxetine, nor the serotonin-selective reuptake inhibitor, fluoxetine, produce antinociceptive synergy with morphine. Atomoxetine, a monoamine reuptake inhibitor that achieves higher levels of norepinephrine than serotonin transporter occupancy, exhibited robust antinociceptive synergy with morphine. Similarly, a fixed-dose combination of esreboxetine and fluoxetine which achieves comparable levels of transporter occupancy potentiated the antinociceptive response to morphine. By contrast, duloxetine, a monoamine reuptake inhibitor that achieves higher serotonin than norepinephrine transporter occupancy, failed to potentiate the antinociceptive response to morphine. However, when duloxetine was coadministered with the 5-HT3 receptor antagonist, ondansetron, potentiation of the antinociceptive response to morphine was revealed. These results support the notion that inhibition of both serotonin and norepinephrine transporters is required for monoamine reuptake inhibitor and opioid

  13. Dezocine exhibits antihypersensitivity activities in neuropathy through spinal μ-opioid receptor activation and norepinephrine reuptake inhibition

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    Wang, Yong-Xiang; Mao, Xiao-Fang; Li, Teng-Fei; Gong, Nian; Zhang, Ma-Zhong

    2017-01-01

    Dezocine is the number one opioid painkiller prescribed and sold in China, occupying 44% of the nation’s opioid analgesics market today and far ahead of the gold-standard morphine. We discovered the mechanisms underlying dezocine antihypersensitivity activity and assessed their implications to antihypersensitivity tolerance. Dezocine, given subcutaneously in spinal nerve-ligated neuropathic rats, time- and dose-dependently produced mechanical antiallodynia and thermal antihyperalgesia, significantly increased ipsilateral spinal norepinephrine and serotonin levels, and induced less antiallodynic tolerance than morphine. Its mechanical antiallodynia was partially (40% or 60%) and completely (100%) attenuated by spinal μ-opioid receptor (MOR) antagonism or norepinephrine depletion/α2-adrenoceptor antagonism and combined antagonism of MORs and α2-adenoceptors, respectively. In contrast, antagonism of spinal κ-opioid receptors (KORs) and δ-opioid receptors (DORs) or depletion of spinal serotonin did not significantly alter dezocine antiallodynia. In addition, dezocine-delayed antiallodynic tolerance was accelerated by spinal norepinephrine depletion/α2-adenoceptor antagonism. Thus dezocine produces antihypersensitivity activity through spinal MOR activation and norepinephrine reuptake inhibition (NRI), but apparently not through spinal KOR and DOR activation, serotonin reuptake inhibition or other mechanisms. Our findings reclassify dezocine as the first analgesic of the recently proposed MOR-NRI, and reveal its potential as an alternative to as well as concurrent use with morphine in treating pain. PMID:28230181

  14. Synthesis and carbon-11 labeling of (R)- and (S)-thionisoxetine, norepinephrine reuptake inhibitors, potential radioligands for positron emission tomography

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    Azzurra Filannino, Maria [Institute of Molecular Bioimaging and Physiology, CNR, University of Milano-Bicocca, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan (Italy); Matarrese, Mario [Institute of Molecular Bioimaging and Physiology, CNR, University of Milano-Bicocca, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan (Italy)], E-mail: matarrese.mario@hsr.it; Turolla, Elia Anna; Masiello, Valeria; Moresco, Rosa Maria; Todde, Sergio; Verza, Elisa [Institute of Molecular Bioimaging and Physiology, CNR, University of Milano-Bicocca, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan (Italy); Magni, Fulvio [University of Milano-Bicocca, DIMESAB, via Cadore 48, 20052 Monza (Italy); Cattaneo, Angela; Bachi, Angela [Institute of Molecular Bioimaging and Physiology, CNR, University of Milano-Bicocca, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan (Italy); Kienle, Marzia Galli [University of Milano-Bicocca, DIMESAB, via Cadore 48, 20052 Monza (Italy); Fazio, Ferruccio [Institute of Molecular Bioimaging and Physiology, CNR, University of Milano-Bicocca, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan (Italy)

    2007-11-15

    Standards and des-methyl precursors of (R)- and (S)-thionisoxetine, potent and selective norepinephrine reuptake inhibitors, were synthesized and radiolabeled with carbon-11. Both enantiomers of the N-methyl-3-(2-thiomethylphenoxy)-3-phenylpropanamine and the 3-(2-thiomethylphenoxy)-3-phenylpropylamine were obtained via multi-step syntheses, while the radiosyntheses were carried out using [{sup 11}C]CH{sub 3}I. The radiochemical yields were 26%, decay corrected and the specific radioactivity ranging from 2 to 3 Ci/{mu}mol. The HPLC analyses were performed using a chiral column: during the radiolabeling, no racemization occurred and the isomers were synthesized with high enantiomeric purity.

  15. Serotonin reuptake inhibition vs. norepinephrine reuptake inhibition: a double-blind differential-therapeutic study with fluvoxamine and oxaprotiline in endogenous and neurotic depressives.

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    Emrich, H M; Berger, M; Riemann, D; von Zerssen, D

    1987-03-01

    The antidepressive properties of the specific serotonin reuptake inhibitor fluvoxamine and the specific norepinephrine reuptake inhibitor oxaprotiline were investigated in a sequential design with the aim of evaluating the hypothesis that two distinct biochemical subtypes of depression exist. Responders were treated for 7 weeks with the compound to which they had responded. After 1 placebo week, the nonresponders were switched to the alternative compound. An evaluation of the data obtained during the 3-week treatment periods from 24 patients (37 trials) with major depression revealed a highly significant reduction of Hamilton Scores with both compounds, oxaprotiline and fluvoxamine. If the patients with major depression are subdivided into two groups, endogenous depressives and neurotic depressives, there is no significant difference between the therapeutic improvements (both compounds) achieved in the two groups. The data shows that only about 20% of the nonresponders on one compound responded to the alternative drug, whereas 90% of responders (within 3 weeks) were still responders after 7 weeks. The data are at variance with the concept of two distinct biochemical subtypes of depression (serotonergic vs. norepinephrinergic). Dexamethasone suppression tests, performed in 23 patients, gave no prognostic hint as to whether the patients reacted well to drug therapy or not.

  16. Effects of 071031B, a novel serotonin and norepinephrine reuptake inhibitor, on monoamine system in mice and rats.

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    Xue, Rui; He, Xin-Hua; Yuan, Li; Chen, Hong-Xia; Zhang, Li-Ming; Yong, Zheng; Yu, Gang; Fan, Shi-Yong; Li, Yun-Feng; Zhong, Bo-Hua; Zhang, You-Zhi

    2016-01-01

    Our previous study indicated that 071031B, a novel potential serotonin and norepinephrine reuptake inhibitor, showed robust antidepressant activity in multiple depression models, and could simultaneously inhibit 5-HT and NE reuptake in vitro. The present study was to evaluate the effects of 071031B on monoamine system in vivo, by using pharmacological models, including 5-HTP induced head-twitch test, yohimbine toxicity potentiation test, and reserpine induced hypothermia test, and determining monoamine transmitter levels in reserpine induced monoamine depletion model or chronic unpredictable stress (CUS) model. Results in pharmacological models indicated that acute administration of 071031B at 5-20 mg/kg significantly enhanced 5-HTP induced head-twitch behavior, potentiated yohimbine induced lethal rate, and reversed reserpine induced hypothermia. Further monoamine assays demonstrated that acute or chronic administration of 071031B at 10 or 20 mg/kg increased 5-HT and/or NE levels in various brain regions in reserpine or CUS induced monoamine depletion models, respectively, without effect on DA and its metabolites. Our results revealed that 071031B produces potent inhibition of 5-HT and NE reuptake in vivo.

  17. Effects of 071031B, a novel serotonin and norepinephrine reuptake inhibitor, on monoamine system in mice and rats

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    Rui Xue

    2016-01-01

    Full Text Available Our previous study indicated that 071031B, a novel potential serotonin and norepinephrine reuptake inhibitor, showed robust antidepressant activity in multiple depression models, and could simultaneously inhibit 5-HT and NE reuptake in vitro. The present study was to evaluate the effects of 071031B on monoamine system in vivo, by using pharmacological models, including 5-HTP induced head-twitch test, yohimbine toxicity potentiation test, and reserpine induced hypothermia test, and determining monoamine transmitter levels in reserpine induced monoamine depletion model or chronic unpredictable stress (CUS model. Results in pharmacological models indicated that acute administration of 071031B at 5–20 mg/kg significantly enhanced 5-HTP induced head-twitch behavior, potentiated yohimbine induced lethal rate, and reversed reserpine induced hypothermia. Further monoamine assays demonstrated that acute or chronic administration of 071031B at 10 or 20 mg/kg increased 5-HT and/or NE levels in various brain regions in reserpine or CUS induced monoamine depletion models, respectively, without effect on DA and its metabolites. Our results revealed that 071031B produces potent inhibition of 5-HT and NE reuptake in vivo.

  18. Pharmacokinetic and pharmacodynamic profiles of the novel serotonin and norepinephrine reuptake inhibitor desvenlafaxine succinate in ovariectomized Sprague-Dawley rats.

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    Alfinito, Peter D; Huselton, Christine; Chen, Xiaohong; Deecher, Darlene C

    2006-07-07

    Desvenlafaxine succinate (DVS) is a novel serotonin (5-HT) and norepinephrine (NE) reuptake inhibitor (SNRI) that is currently in clinical development for the treatment of major depressive disorder and vasomotor symptoms associated with menopause. Previous studies have documented the pharmacokinetic and pharmacodynamic profiles of DVS in male rats. Similar studies, however, have not been performed in ovariectomized (OVX) rats, a model that mimics the loss of ovarian hormones that occurs at menopause. The goal of the present study, therefore, was to characterize the pharmacokinetic and pharmacodynamic properties of DVS in OVX rats. Desvenlafaxine levels peaked in plasma, brain (total brain minus hypothalamus) and hypothalamus at concentrations of 7.0, 10.8 and 9.5 microM (assuming 1 g = 1 ml), respectively, 30 min post-dosing DVS (30 mg/kg, oral). The apparent terminal half-lives of desvenlafaxine in plasma, brain and hypothalamus were 3.0, 2.1 and 2.5 h, respectively. Based on AUC(0-last), brain to plasma and hypothalamus to plasma ratios were 1.7 and 1.3, respectively. Microdialysis experiments in the medial preoptic area of the hypothalamus showed that DVS (30 mg/kg, s.c.), in the presence of WAY-100635 (5-HT(1A) antagonist), increased 5-HT levels 225% at 1 h post-dosing. Norepinephrine levels increased 44% at 3 h post-dosing while dopamine levels were unchanged. Thus, in OVX rats, DVS has good pharmacokinetic properties, rapid brain penetration, excellent brain penetrability and selectively increases 5-HT and NE levels in the hypothalamus. This work supports the notion that DVS could have utility for treating disorders in menopausal women in which changes in 5-HT and/or NE have been implicated.

  19. Compound stimulus presentation and the norepinephrine reuptake inhibitor atomoxetine enhance long-term extinction of cocaine-seeking behavior.

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    Janak, Patricia H; Bowers, M Scott; Corbit, Laura H

    2012-03-01

    Drug abstinence is frequently compromised when addicted individuals are re-exposed to environmental stimuli previously associated with drug use. Research with human addicts and in animal models has demonstrated that extinction learning (non-reinforced cue-exposure) can reduce the capacity of such stimuli to induce relapse, yet extinction therapies have limited long-term success under real-world conditions (Bouton, 2002; O'Brien, 2008). We hypothesized that enhancing extinction would reduce the later ability of drug-predictive cues to precipitate drug-seeking behavior. We, therefore, tested whether compound stimulus presentation and pharmacological treatments that augment noradrenergic activity (atomoxetine; norepinephrine reuptake inhibitor) during extinction training would facilitate the extinction of drug-seeking behaviors, thus reducing relapse. Rats were trained that the presentation of a discrete cue signaled that a lever press response would result in cocaine reinforcement. Rats were subsequently extinguished and spontaneous recovery of drug-seeking behavior following presentation of previously drug-predictive cues was tested 4 weeks later. We find that compound stimulus presentations or pharmacologically increasing noradrenergic activity during extinction training results in less future recovery of responding, whereas propranolol treatment reduced the benefit seen with compound stimulus presentation. These data may have important implications for understanding the biological basis of extinction learning, as well as for improving the outcome of extinction-based therapies.

  20. Desvenlafaxine for major depressive disorder: incremental clinical benefits from a second-generation serotonin-norepinephrine reuptake inhibitor.

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    Nichols, Alice I; Tourian, Karen A; Tse, Susanna Y; Paul, Jeffrey

    2010-12-01

    genetic and pharmacologically-driven variations in common mechanisms involved in the disposition of antidepressant medications may contribute to variable interpatient response. This review describes the pharmacological properties underlying the safety and efficacy of desvenlafaxine, a second-generation serotonin-norepinephrine reuptake inhibitor (SNRI). literature published between January 2006 and September 2010 evaluating desvenlafaxine was reviewed. Desvenlafaxine therapy is initiated at the therapeutic dose (50 mg/day) without a need for dose titration. Desvenlafaxine metabolism and distribution are not appreciably affected by altered function of cytochrome P450 (CYP) enzymes or permeability glycoprotein (P-gp). Desvenlafaxine has clinically insignificant effects on the activity of CYP and P-gp. The efficacy of desvenlafaxine in treating major depressive disorder has been established. Adverse events are characteristic of the SNRI class. Notably, the rate of discontinuation due to adverse events with the 50 mg/day recommended therapeutic dose is comparable to that seen with placebo. incremental benefits with desvenlafaxine, derived from straight-forward dosing, a simple metabolic profile and lack of interaction with active transporter P-gp and CYP enzymes may contribute to more consistent response, good tolerability and lower incidence of drug-drug interactions with concomitant medications.

  1. High-Fat Diet-Induced Alterations in the Feeding Suppression of Low-Dose Nisoxetine, a Selective Norepinephrine Reuptake Inhibitor

    OpenAIRE

    Bello, Nicholas T.; Walters, Amy L.; Verpeut, Jessica L.; Priscila P. Cunha

    2013-01-01

    Central noradrenergic pathways are involved in feeding and cardiovascular control, physiological processes altered by obesity. The present studies determined how high-fat feeding and body weight gain alter the sensitivity to the feeding suppression and neural activation to a selective norepinephrine reuptake inhibitor, nisoxetine. Acute administration of nisoxetine (saline: 0, 3, 10, and 30 mg/kg; IP) resulted in a dose-dependent reduction in the 24 h refeeding response in male Sprague Dawley...

  2. Alleviation of thermoregulatory dysfunction with the new serotonin and norepinephrine reuptake inhibitor desvenlafaxine succinate in ovariectomized rodent models.

    Science.gov (United States)

    Deecher, Darlene C; Alfinito, Peter D; Leventhal, Liza; Cosmi, Scott; Johnston, Grace H; Merchenthaler, Istvan; Winneker, Richard

    2007-03-01

    Hot flushes and night sweats, referred to as vasomotor symptoms (VMS), are presumed to be a result of declining hormone levels and are the principal menopausal symptoms for which women seek medical treatment. To date, estrogens and/or some progestins are the most effective therapeutics for alleviating VMS; however, these therapies may not be appropriate for all women. Therefore, nonhormonal therapies are being evaluated. The present study investigated a new reuptake inhibitor, desvenlafaxine succinate (DVS), in animal models of temperature dysfunction. Both models used are based on measuring changes in tail-skin temperature (TST) in ovariectomized (OVX) rats. The first relies on naloxone-induced withdrawal in morphine-dependent (MD) OVX rats, resulting in an acute rise in TST. The second depends on an OVX-induced loss of TST decreases during the dark phase as measured by telemetry. An initial evaluation demonstrated abatement of the rise in TST with long-term administration of ethinyl estradiol or with a single oral dose of DVS (130 mg/kg) in the MD model. Further evaluation showed that orally administered DVS acutely and dose dependently (10-100 mg/kg) abated a naloxone-induced rise in TST of MD rats and alleviated OVX-induced temperature dysfunction in the telemetry model. Oral administration of DVS to OVX rats caused significant increases in serotonin and norepinephrine levels in the preoptic area of the hypothalamus, a key region of the brain involved in temperature regulation. These preclinical studies provide evidence that DVS directly impacts thermoregulatory dysfunction in OVX rats and may have utility in alleviating VMS associated with menopause.

  3. Role of prefrontal cortical calcium-independent phospholipase A2 in antinociceptive effect of the norepinephrine reuptake inhibitor antidepresssant maprotiline.

    Science.gov (United States)

    Chew, Wee-Siong; Shalini, Suku-Maran; Torta, Federico; Wenk, Markus R; Stohler, Christian; Yeo, Jin-Fei; Herr, Deron R; Ong, Wei-Yi

    2017-01-06

    The prefrontal cortex is essential for executive functions such as decision-making and planning. There is also accumulating evidence that it is important for the modulation of pain. In this study, we investigated a possible role of prefrontal cortical calcium-independent phospholipase A2 (iPLA2) in antinociception induced by the norepinephrine reuptake inhibitor (NRI) and tetracyclic (tricyclic) antidepressant, maprotiline. Intraperitoneal injections of maprotiline increased iPLA2 mRNA and protein expression in the prefrontal cortex. This treatment also reduced grooming responses to von-Frey hair stimulation of the face after facial carrageenan injection, indicating decreased sensitivity to pain. The antinociceptive effect of maprotiline was abrogated by iPLA2 antisense oligonucleotide injection to the prefrontal cortex, indicating a role of this enzyme in antinociception. In contrast, injection of iPLA2 antisense oligonucleotide to the somatosensory cortex did not reduce the antinociceptive effect of maprotiline. Lipidomic analysis of the prefrontal cortex showed decrease in phosphatidylcholine species, but increase in lysophosphatidylcholine species, indicating increased PLA2 activity, and release of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) after maprotiline treatment. Differences in sphingomyelin/ceramide were also detected. These changes were not observed in maprotiline-treated mice that received iPLA2 antisense oligonucleotide to the prefrontal cortex. Metabolites of DHA and EPA may help to strengthen a known supraspinal antinociceptive pathway from the prefrontal cortex to the periaqueductal gray. Together, results indicate a role of prefrontal cortical iPLA2 and its enzymatic products in the antinociceptive effect of maprotiline.

  4. The effects of LPM570065, a novel triple reuptake inhibitor, on extracellular serotonin, dopamine and norepinephrine levels in rats.

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    Renyu Zhang

    Full Text Available Triple reuptake inhibitors (TRIs are currently being developed as a new class of promising antidepressants that block serotonin (5-HT, dopamine (DA and norepinephrine (NE transporters, thereby increasing extracellular monoamine concentrations. The purpose of this study was to investigate the effects of LPM570065, a novel TRI and a desvenlafaxine prodrug, on extracellular 5-HT, DA and NE levels in the rat striatum after acute and chronic administration relative to desvenlafaxine, using High Performance Liquid Chromatography (HPLC and microdialysis. Acute administration was performed by providing rodents with oral solutions (0.06 mmol·kg(-1 p.o., oral suspensions (0.06 mmol·kg(-1 p.o. and intravenous solutions (0.04 mmol·kg(-1 i.v. of LPM570065 and desvenlafaxine. Oral suspensions (0.06 mmol·kg(-1·day(-1 of the two drugs were also administered for a 14-day chronic period. HPLC analysis revealed that LPM570065 rapidly penetrated the rat striatum, converted into desvenlafaxine and exhibited larger total exposure compared with the administration of desvenlafaxine. Microdialysis revealed that acute and chronic administration of oral suspension of LPM570065 increased the 5-HT, DA and NE levels more than the relative administration of desvenlafaxine. Unlike desvenlafaxine, acute administration of an intravenous LPM570065 solution did not induce the undesirable 90% decrease in extracellular 5-HT levels. In contrast to the fully dose-dependent elevation of 5-HT induced by desvenlafaxine, the acute administration of LPM570065 showed a capped increase in extracellular 5-HT levels when combined with WAY-100635. Additionally, forced swim test demonstrated that acute and chronic administration of LPM570065 reduced the immobility time more than the relative administration of desvenlafaxine. These data suggest that LPM570065 may have greater efficacy and/or a more rapid onset of antidepressant action than desvenlafaxine and also counterbalance the harmful

  5. Desvenlafaxine: a new serotonin-norepinephrine reuptake inhibitor for the treatment of adults with major depressive disorder.

    Science.gov (United States)

    Perry, Richard; Cassagnol, Manouchkathe

    2009-06-01

    Desvenlafaxine succinate, a serotonin-norepinephrine reuptake inhibitor (SNRI), was approved by the US Food and Drug Administration (FDA) in February 2008 for the treatment of adult patients with major depressive disorder (MDD). Desvenlafaxine is the third SNRI approved by the FDA for this indication. This article reviews the available information for desvenlafaxine, focusing on its pharmacodynamics, pharmacokinetics, clinical efficacy, and safety profile. A comprehensive search of MEDLINE (1950-March 2009), International Pharmaceutical Abstracts (1970-March 2009), ISI Web of Knowledge (1996-March 2009), and EMBASE (1974-March 2009) was conducted using the terms desvenlafaxine, O-desmethylvenlafaxine, and Pristiq. Reference lists of articles were reviewed for other relevant publications. Abstracts of unpublished clinical studies presented at the American Psychiatric Association annual meetings (2004-2008) were included in the review; also included were data from the FDA and the European Medicines Agency Web sites. After oral administration, desvenlafaxine reaches T(max) in 7 to 8 hours and is slowly eliminated, with t((1/2)) values of 9 to 15 hours. With once-daily dosing, steady-state plasma concentrations are achieved within 4 to 5 days. Alternate-day dosing should be implemented in patients with severe renal impairment (creatinine clearance, desvenlafaxine have been conducted but only 8 were published. These 8 clinical studies evaluated oral desvenlafaxine 50 to 400 mg/d using randomized controlled trials for the treatment of MDD in adult outpatients. Significantly greater efficacy in the reduction of depressive symptoms was found in patients taking desvenlafaxine 50 mg/d (P 50 mg/d. Preliminary data support desvenlafaxine's efficacy and tolerability in the treatment of menopause-associated vasomotor symptoms. Desvenlafaxine was generally well tolerated in clinical trials; the most common adverse events were nausea, suicidal ideation, and changes in blood

  6. Pharmacological and behavioral characterization of D-473, an orally active triple reuptake inhibitor targeting dopamine, serotonin and norepinephrine transporters.

    Directory of Open Access Journals (Sweden)

    Aloke K Dutta

    Full Text Available Major depressive disorder (MDD is a debilitating disease affecting a wide cross section of people around the world. The current therapy for depression is less than adequate and there is a considerable unmet need for more efficacious treatment. Dopamine has been shown to play a significant role in depression including production of anhedonia which has been one of the untreated symptoms in MDD. It has been hypothesized that drugs acting at all three monoamine transporters including dopamine transporter should provide more efficacious antidepressants activity. This has led to the development of triple reuptake inhibitor D-473 which is a novel pyran based molecule and interacts with all three monoamine transporters. The monoamine uptake inhibition activity in the cloned human transporters expressed in HEK-293 cells (70.4, 9.18 and 39.7 for DAT, SERT and NET, respectively indicates a serotonin preferring triple reuptake inhibition profile for this drug. The drug D-473 exhibited good brain penetration and produced efficacious activity in rat forced swim test under oral administration. The optimal efficacy dose did not produce any locomotor activation. Microdialysis experiment demonstrated that systemic administration of D-473 elevated extracellular level of the three monoamines DA, 5-HT, and NE efficaciously in the dorsal lateral striatum (DLS and the medial prefrontal cortex (mPFC area, indicating in vivo blockade of all three monoamine transporters by D-473. Thus, the current biological data from D-473 indicate potent antidepressant activity of the molecule.

  7. The effects of prolonged administration of norepinephrine reuptake inhibitors on long-term potentiation in dentate gyrus, and on tests of spatial and object recognition memory in rats.

    Science.gov (United States)

    Walling, Susan G; Milway, J Stephen; Ingram, Matthew; Lau, Catherine; Morrison, Gillian; Martin, Gerard M

    2016-02-01

    Phasic norepinephrine (NE) release events are involved in arousal, novelty detection and in plasticity processes underlying learning and memory in mammalian systems. Although the effects of phasic NE release events on plasticity and memory are prevalently documented, it is less understood what effects chronic NE reuptake inhibition and sustained increases in noradrenergic tone, might have on plasticity and cognitive processes in rodent models of learning and memory. This study investigates the effects of chronic NE reuptake inhibition on hippocampal plasticity and memory in rats. Rats were administered NE reuptake inhibitors (NRIs) desipramine (DMI; 0, 3, or 7.5mg/kg/day) or nortriptyline (NTP; 0, 10 or 20mg/kg/day) in drinking water. Long-term potentiation (LTP; 200 Hz) of the perforant path-dentate gyrus evoked potential was examined in urethane anesthetized rats after 30-32 days of DMI treatment. Short- (4-h) and long-term (24-h) spatial memory was tested in separate rats administered 0 or 7.5mg/kg/day DMI (25-30 days) using a two-trial spatial memory test. Additionally, the effects of chronically administered DMI and NTP were tested in rats using a two-trial, Object Recognition Test (ORT) at 2- and 24-h after 45 and 60 days of drug administration. Rats administered 3 or 7.5mg/kg/day DMI had attenuated LTP of the EPSP slope but not the population spike at the perforant path-dentate gyrus synapse. Short- and long-term memory for objects is differentially disrupted in rats after prolonged administration of DMI and NTP. Rats that were administered 7.5mg/kg/day DMI showed decreased memory for a two-trial spatial task when tested at 4-h. In the novel ORT, rats receiving 0 or 7.5mg/kg/day DMI showed a preference for the arm containing a Novel object when tested at both 2- and 24-h demonstrating both short- and long-term memory retention of the Familiar object. Rats that received either dose of NTP or 3mg/kg/day DMI showed impaired memory at 2-h, however this

  8. High-Fat Diet-Induced Alterations in the Feeding Suppression of Low-Dose Nisoxetine, a Selective Norepinephrine Reuptake Inhibitor

    Directory of Open Access Journals (Sweden)

    Nicholas T. Bello

    2013-01-01

    Full Text Available Central noradrenergic pathways are involved in feeding and cardiovascular control, physiological processes altered by obesity. The present studies determined how high-fat feeding and body weight gain alter the sensitivity to the feeding suppression and neural activation to a selective norepinephrine reuptake inhibitor, nisoxetine. Acute administration of nisoxetine (saline: 0, 3, 10, and 30 mg/kg; IP resulted in a dose-dependent reduction in the 24 h refeeding response in male Sprague Dawley rats maintained on standard chow. In a similar fashion, nisoxetine resulted in reductions in blood pressure and a compensatory increase in heart rate. From these studies, the 3 mg/kg dose was subthreshold. In a separate experiment, however, 10 wk exposure to a high-fat diet (60% fat resulted in weight gain and significant feeding suppression following administration of nisoxetine (3 mg/kg compared with animals fed a control diet (10% fat. Nisoxetine (3 mg/kg also resulted in greater neural activation, as measured by c-Fos immunohistochemistry, in the arcuate nucleus of the hypothalamus in animals exposed to the high-fat diet. Such data indicate acute nisoxetine doses that suppress food intake can impact cardiovascular measures. It also suggests that the feeding suppression to a low-dose nisoxetine is enhanced as a result of high-fat diet and weight gain.

  9. High-fat diet-induced alterations in the feeding suppression of low-dose nisoxetine, a selective norepinephrine reuptake inhibitor.

    Science.gov (United States)

    Bello, Nicholas T; Walters, Amy L; Verpeut, Jessica L; Cunha, Priscila P

    2013-01-01

    Central noradrenergic pathways are involved in feeding and cardiovascular control, physiological processes altered by obesity. The present studies determined how high-fat feeding and body weight gain alter the sensitivity to the feeding suppression and neural activation to a selective norepinephrine reuptake inhibitor, nisoxetine. Acute administration of nisoxetine (saline: 0, 3, 10, and 30 mg/kg; i.p.) resulted in a dose-dependent reduction in the 24 h refeeding response in male Sprague Dawley rats maintained on standard chow. In a similar fashion, nisoxetine resulted in reductions in blood pressure and a compensatory increase in heart rate. From these studies, the 3 mg/kg dose was subthreshold. In a separate experiment, however, 10 wk exposure to a high-fat diet (60% fat) resulted in weight gain and significant feeding suppression following administration of nisoxetine (3 mg/kg) compared with animals fed a control diet (10% fat). Nisoxetine (3 mg/kg) also resulted in greater neural activation, as measured by c-Fos immunohistochemistry, in the arcuate nucleus of the hypothalamus in animals exposed to the high-fat diet. Such data indicate acute nisoxetine doses that suppress food intake can impact cardiovascular measures. It also suggests that the feeding suppression to a low-dose nisoxetine is enhanced as a result of high-fat diet and weight gain.

  10. Randomized controlled trials of serotonin-norepinephrine reuptake inhibitor in treating major depressive disorder in children and adolescents: a meta-analysis of efficacy and acceptability

    Directory of Open Access Journals (Sweden)

    Y. Xu

    2016-01-01

    Full Text Available New generation antidepressant therapies, including serotonin-norepinephrine reuptake inhibitor (SNRIs, were introduced in the late 1980s; however, few comprehensive studies have compared the benefits and risks of various contemporary treatments for major depressive disorder (MDD in young patients. A comprehensive literature search of PubMed, Cochrane, Embase, Web of Science, and PsycINFO databases was conducted from 1970 to January 2015. Only clinical trials that randomly assigned one SNRI or placebo to patients aged 7 to 18 years who met the diagnostic criteria for major depressive disorder were included. Treatment success, dropout rate, and suicidal ideation/attempt outcomes were measured. Primary efficacy was determined by pooling the risk ratios (RRs of treatment response and remission. Acceptability was determined by pooling the RRs of dropouts for all reasons and for adverse effects as well as suicide-risk outcomes. Five trials with a total of 973 patients were included. SNRIs were not significantly more effective than placebo for treatment response but were for remission. The comparison of patients taking SNRIs that dropped out for all reasons and those taking placebo did not reach statistical significance. Significantly more patients taking SNRIs dropped out for adverse effects than those taking placebo. No significant difference was found in suicide-related risk outcomes. SNRI therapy does not display a superior efficacy and is not better tolerated compared to placebo in these young patients. However, duloxetine has a potential beneficial effect for depression in young populations, showing a need for further research.

  11. Dissociation of the role of the prelimbic cortex in interval timing and resource allocation: beneficial effect of norepinephrine and dopamine reuptake inhibitor nomifensine on anxiety-inducing distraction

    Directory of Open Access Journals (Sweden)

    Alexander R Matthews

    2012-12-01

    Full Text Available Emotional distracters impair cognitive function. Emotional processing is dysregulated in affective disorders such as depression, phobias, schizophrenia, and PTSD. Among the processes impaired by emotional distracters, and whose dysregulation is documented in affective disorders, is the ability to time in the seconds-to-minutes range, i.e. interval timing. Presentation of task-irrelevant distracters during a timing task results in a delay in responding suggesting a failure to maintain subjective time in working memory, possibly due to attentional and working memory resources being diverted away from timing, as proposed by the Relative Time-Sharing model. We investigated the role of the prelimbic cortex in the detrimental effect of anxiety-inducing task-irrelevant distracters on the cognitive ability to keep track of time, using local infusions of norepinephrine and dopamine reuptake inhibitor nomifensine in a modified peak-interval procedure with neutral and anxiety-inducing distracters. Given that some antidepressants have beneficial effects on attention and working memory, e.g., decreasing emotional response to negative events, we hypothesized that nomifensine would improve maintenance of information in working memory in trials with distracters, resulting in a decrease of the disruptive effect of emotional events on the timekeeping abilities. Our results revealed a dissociation of the effects of nomifensine infusion in prelimbic cortex between interval timing and resource allocation, and between neutral and anxiety-inducing distraction. Nomifensine was effective only during trials with distracters, but not during trials without distracters. Nomifensine reduced the detrimental effect of the distracters only when the distracters were anxiety-inducing, but not when they were neutral. Results are discussed in relation to the brain circuits involved in Relative Time-Sharing of resources, and the pharmacological management of affective disorders.

  12. Spinal-supraspinal and intrinsic μ-opioid receptor agonist-norepinephrine reuptake inhibitor (MOR-NRI) synergy of tapentadol in diabetic heat hyperalgesia in mice.

    Science.gov (United States)

    Christoph, Thomas; Schröder, Wolfgang; Tallarida, Ronald J; De Vry, Jean; Tzschentke, Thomas M

    2013-12-01

    Tapentadol is a μ-opioid receptor (MOR) agonist and norepinephrine reuptake inhibitor (NRI) with established efficacy in neuropathic pain in patients and intrinsic synergistic interaction of both mechanisms as demonstrated in rodents. In diabetic mice, we analyzed the central antihyperalgesic activity, the occurrence of site-site interaction, as well as the spinal contribution of opioid and noradrenergic mechanisms in a hotplate test. Tapentadol (0.1-3.16 µg/animal) showed full efficacy after intrathecal as well as after intracerebroventricular administration (ED50 0.42 µg/animal i.t., 0.18 µg/animal i.c.v.). Combined administration of equianalgesic doses revealed spinal-supraspinal synergy (ED50 0.053 µg/animal i.t. + i.c.v.). Morphine (0.001-10 µg/animal) also showed central efficacy and synergy (ED50 0.547 µg/animal i.t., 0.004 µg/animal i.c.v., 0.014 µg/animal i.t. + i.c.v.). Supraspinal potencies of tapentadol and morphine correlated with the 50-fold difference in their MOR affinities. In contrast, spinal potencies of both drugs were similar and correlated with their relative systemic potencies (ED50 0.27 mg/kg i.p. tapentadol, 1.1 mg/kg i.p. morphine). Spinal administration of the opioid antagonist naloxone or the α2-adrenoceptor antagonist yohimbine before systemic administration of equianalgesic doses of tapentadol (1 mg/kg i.p.) or morphine (3.16 mg/kg i.p.) revealed pronounced influence on opioidergic and noradrenergic pathways for both compounds. Tapentadol was more sensitive toward both antagonists than was morphine, with median effective dose values of 0.75 and 1.72 ng/animal i.t. naloxone and 1.56 and 2.04 ng/animal i.t. yohimbine, respectively. It is suggested that the antihyperalgesic action of systemically administered tapentadol is based on opioid spinal-supraspinal synergy, as well as intrinsic spinally mediated MOR-NRI synergy.

  13. Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs)

    Science.gov (United States)

    Diseases and Conditions Depression (major depressive disorder) Antidepressant SNRIs help relieve depression symptoms, such as irritability and sadness, but some are also used for anxiety disorders and nerve pain. Here's how they work and ...

  14. (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl): a novel mu-opioid receptor agonist/norepinephrine reuptake inhibitor with broad-spectrum analgesic properties.

    Science.gov (United States)

    Tzschentke, Thomas M; Christoph, Thomas; Kögel, Babette; Schiene, Klaus; Hennies, Hagen-Heinrich; Englberger, Werner; Haurand, Michael; Jahnel, Ulrich; Cremers, Thomas I F H; Friderichs, Elmar; De Vry, Jean

    2007-10-01

    (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl) is a novel micro-opioid receptor (MOR) agonist (Ki = 0.1 microM; relative efficacy compared with morphine 88% in a [35S]guanosine 5'-3-O-(thio)triphosphate binding assay) and NE reuptake inhibitor (Ki = 0.5 microM for synaptosomal reuptake inhibition). In vivo intracerebral microdialysis showed that tapentadol, in contrast to morphine, produces large increases in extracellular levels of NE (+450% at 10 mg/kg i.p.). Tapentadol exhibited analgesic effects in a wide range of animal models of acute and chronic pain [hot plate, tail-flick, writhing, Randall-Selitto, mustard oil colitis, chronic constriction injury (CCI), and spinal nerve ligation (SNL)], with ED50 values ranging from 8.2 to 13 mg/kg after i.p. administration in rats. Despite a 50-fold lower binding affinity to MOR, the analgesic potency of tapentadol was only two to three times lower than that of morphine, suggesting that the dual mode of action of tapentadol may result in an opiate-sparing effect. A role of NE in the analgesic efficacy of tapentadol was directly demonstrated in the SNL model, where the analgesic effect of tapentadol was strongly reduced by the alpha2-adrenoceptor antagonist yohimbine but only moderately attenuated by the MOR antagonist naloxone, whereas the opposite was seen for morphine. Tolerance development to the analgesic effect of tapentadol in the CCI model was twice as slow as that of morphine. It is suggested that the broad analgesic profile of tapentadol and its relative resistance to tolerance development may be due to a dual mode of action consisting of both MOR activation and NE reuptake inhibition.

  15. Efeito da ropivacaína na recaptação neuronal de noradrenalina em músculo liso Efecto de la ropivacaína en la recaptación neuronal de noradrenalina en un músculo liso Effect of ropivacaine on neuronal norepinephrine reuptake in smooth muscle

    Directory of Open Access Journals (Sweden)

    Carlos Alberto de Souza Martins

    2005-10-01

    .mL-1 potentiated (150% and 25%, respectively norepinephrine-induced contractions, while higher concentrations (50 or 100 µg.mL-1 have not changed responses to norepinephrine. CONCLUSIONS: Ropivacaine blocks neuronal norepinephrine reuptake by sympathetic nerve terminals.

  16. Selective serotonin reuptake inhibitor exposure.

    Science.gov (United States)

    Fitzgerald, Kevin T; Bronstein, Alvin C

    2013-02-01

    Many antidepressants inhibit serotonin or norepinephrine reuptake or both to achieve their clinical effect. The selective serotonin reuptake inhibitor class of antidepressants (SSRIs) includes citalopram, escitalopram (active enantiomer of citalopram), fluoxetine, fluvoxamine, paroxetine, and sertraline. The SSRIs are as effective as tricyclic antidepressants in treatment of major depression with less significant side effects. As a result, they have become the largest class of medications prescribed to humans for depression. They are also used to treat obsessive-compulsive disorder, panic disorders, alcoholism, obesity, migraines, and chronic pain. An SSRI (fluoxetine) has been approved for veterinary use in treatment of canine separation anxiety. SSRIs act specifically on synaptic serotonin concentrations by blocking its reuptake in the presynapse and increasing levels in the presynaptic membrane. Clinical signs of SSRI overdose result from excessive amounts of serotonin in the central nervous system. These signs include nausea, vomiting, mydriasis, hypersalivation, and hyperthermia. Clinical signs are dose dependent and higher dosages may result in the serotonin syndrome that manifests itself as ataxia, tremors, muscle rigidity, hyperthermia, diarrhea, and seizures. Current studies reveal no increase in appearance of any specific clinical signs of serotonin toxicity with regard to any SSRI medication. In people, citalopram has been reported to have an increased risk of electrocardiographic abnormalities. Diagnosis of SSRI poisoning is based on history, clinical signs, and response to therapy. No single clinical test is currently available to confirm SSRI toxicosis. The goals of treatment in this intoxication are to support the animal, prevent further absorption of the drug, support the central nervous system, control hyperthermia, and halt any seizure activity. The relative safety of the SSRIs in overdose despite the occurrence of serotonin syndrome makes them

  17. An association study between the norepinephrine transporter gene and depression

    DEFF Research Database (Denmark)

    Buttenschøn, Henriette N; Jacobsen, Iben S; Grynderup, Matias B;

    2013-01-01

    A2 for solute carrier 6 family member 2). The gene is responsible for the reuptake of norepinephrine and dopamine into presynaptic nerve terminals and the norepinephrine system appears to play an important role in depression. We therefore analyzed genetic variants within SLC6A2 for association......A potential approach for identification of candidate genes for depression is characterization of chromosomal rearrangements. Through analysis of a chromosome translocation in an individual with recurrent depression, we identified a potential candidate gene: the norepinephrine transporter (NET; SLC6...... with depression in 408 affected and 559 control individuals from Denmark. After quality control of the genotypes, 31 of 45 single nucleotide polymorphisms (SNPs) were left for analyses. One SNP showed a nominal association with depression but did not survive correction for multiple testing. The results from our...

  18. Design, synthesis, and biological activities of 1-aryl-1,4-diazepan-2-one derivatives as novel triple reuptake inhibitors.

    Science.gov (United States)

    Honda, Eiji; Ishichi, Yuji; Kimura, Eiji; Yoshikawa, Masato; Kanzaki, Naoyuki; Nakagawa, Hideyuki; Terao, Yasuko; Suzuki, Atsuko; Kawai, Takayuki; Arakawa, Yuuichi; Ohta, Hiroyuki; Terauchi, Jun

    2014-08-15

    A novel series of triple reuptake inhibitors were explored by ligand-based drug design. A cyclic structure was designed from cyclopropane derivative 5 using the core structure of reported monoamine reuptake inhibitors, leading to the formation of the 1-aryl-1,4-diazepan-2-one derivative 23j-S. Compound 23j-S was shown to act as a potent TRI with an excellent ADME-Tox profile. Oral administration of 23j-S significantly enhanced norepinephrine, dopamine, and serotonin levels in the mouse prefrontal cortex and showed significant antidepressant-like activity in tail suspension tests in mouse.

  19. Selective serotonin reuptake inhibitor antidepressants potentiate methylphenidate (Ritalin)-induced gene regulation in the adolescent striatum.

    Science.gov (United States)

    Van Waes, Vincent; Beverley, Joel; Marinelli, Michela; Steiner, Heinz

    2010-08-01

    The psychostimulant methylphenidate (Ritalin) is used in conjunction with selective serotonin reuptake inhibitors (SSRIs) in the treatment of medical conditions such as attention-deficit hyperactivity disorder with anxiety/depression comorbidity and major depression. Co-exposure also occurs in patients on SSRIs who use psychostimulant 'cognitive enhancers'. Methylphenidate is a dopamine/norepinephrine reuptake inhibitor that produces altered gene expression in the forebrain; these effects partly mimic gene regulation by cocaine (dopamine/norepinephrine/serotonin reuptake inhibitor). We investigated whether the addition of SSRIs (fluoxetine or citalopram; 5 mg/kg) modified gene regulation by methylphenidate (2-5 mg/kg) in the striatum and cortex of adolescent rats. Our results show that SSRIs potentiate methylphenidate-induced expression of the transcription factor genes zif268 and c-fos in the striatum, rendering these molecular changes more cocaine-like. Present throughout most of the striatum, this potentiation was most robust in its sensorimotor parts. The methylphenidate + SSRI combination also enhanced behavioral stereotypies, consistent with dysfunction in sensorimotor striatal circuits. In so far as such gene regulation is implicated in psychostimulant addiction, our findings suggest that SSRIs may enhance the addiction potential of methylphenidate.

  20. KCl stimulation increases norepinephrine transporter function in PC12 cells.

    Science.gov (United States)

    Mandela, Prashant; Ordway, Gregory A

    2006-09-01

    The norepinephrine transporter (NET) plays a pivotal role in terminating noradrenergic signaling and conserving norepinephrine (NE) through the process of re-uptake. Recent evidence suggests a close association between NE release and regulation of NET function. The present study evaluated the relationship between release and uptake, and the cellular mechanisms that govern these processes. KCl stimulation of PC12 cells robustly increased [3H]NE uptake via the NET and simultaneously increased [3H]NE release. KCl-stimulated increases in uptake and release were dependent on Ca2+. Treatment of cells with phorbol-12-myristate-13-acetate (PMA) or okadaic acid decreased [3H]NE uptake but did not block KCl-stimulated increases in [3H]NE uptake. In contrast, PMA increased [3H]NE release and augmented KCl-stimulated release, while okadaic acid had no effects on release. Inhibition of Ca2+-activated signaling cascades with KN93 (a Ca2+ calmodulin-dependent kinase inhibitor), or ML7 and ML9 (myosin light chain kinase inhibitors), reduced [3H]NE uptake and blocked KCl-stimulated increases in uptake. In contrast, KN93, ML7 and ML9 had no effect on KCl-stimulated [3H]NE release. KCl-stimulated increases in [3H]NE uptake were independent of transporter trafficking to the plasma membrane. While increases in both NE release and uptake mediated by KCl stimulation require Ca2+, different intracellular mechanisms mediate these two events.

  1. Stereoselective Actions of Methylenedioxypyrovalerone (MDPV) To Inhibit Dopamine and Norepinephrine Transporters and Facilitate Intracranial Self-Stimulation in Rats

    OpenAIRE

    Kolanos, R; Partilla, J. S.; Baumann, M. H.; Hutsell, B. A.; Banks, M. L.; Negus, S. S.; Glennon, R. A.

    2015-01-01

    The designer stimulant methylenedioxypyrovalerone (MDPV) is a potent reuptake inhibitor at transporters for dopamine (DAT) and norepinephrine (NET) that produces a constellation of abuse-related behavioral effects. MDPV possesses a chiral center, and the abused formulation of the drug is a racemic mixture, but no data are available on the pharmacology of its isomers. Here, the individual optical isomers of MDPV were prepared and examined with respect to their neurochemical actions on neurotra...

  2. Modulation of muscarinic system with serotonin-norepinephrine reuptake inhibitor antidepressant attenuates depression in mice

    Directory of Open Access Journals (Sweden)

    Paramdeep Singh

    2015-01-01

    Full Text Available Objective: Several studies suggest that muscarinic receptor antagonist scopolamine is a rapidly acting antidepressant for the treatment-resistant depression. Therefore, this study was carried out to investigate the possibility of synergistic potential of scopolamine with antidepressants for the treatment of depression without memory impairment in mice. Materials and Methods: Antidepressants such as citalopram, duloxetine, fluvoxamine, and venlafaxine at their median effective dose that is 12.5, 42.8, 17.5, 15.7 mg/kg p.o., respectively, were evaluated in combination with scopolamine 0.2 mg/kg intraperitoneally for the synergistic potential for ameliorating depression in Swiss albino mice. A battery of tests including forced swim test (FST and tail suspension test (TST were performed in all the groups comprising vehicle control, scopolamine, antidepressants per se, and the combinations of antidepressants with scopolamine. This was followed by the locomotor activity and memory tests. Results: Behavioral studies indicated that only antidepressant venlafaxine with scopolamine resulted in 95.5% and 93.6% reduction in immobility time compared to the vehicle control in FST and TST, respectively. This is significant (P < 0.0001 synergistic hyper-additive antidepressive-like effect compared to scopolamine per se and venlafaxine per se treatment effects in antidepressant paradigms. All the data were evaluated using the one-way analysis of variance followed by individual comparisons using Tukey′s post-hoc test. Control open field studies demonstrated no significant increase in general locomotion after co-administration of the compounds. Step down avoidance paradigm confirmed that scopolamine at the selected dose has no cognition deficit in any mice. Conclusions: The dose of scopolamine selected for synergistic potential has no detrimental effect on memory. The present results suggest the concoction of scopolamine with venlafaxine for enhanced synergistic antidepressive effects with the reduction of dose.

  3. DOPA, norepinephrine, and dopamine in rat tissues

    DEFF Research Database (Denmark)

    Eldrup, E; Richter, Erik; Christensen, N J

    1989-01-01

    We studied the effect of unilateral sympathectomy on rat quadriceps and gastrocnemius muscle concentrations of endogenous dihydroxyphenylalanine (DOPA), dopamine (DA), and norepinephrine (NE) and assessed the relationships between these catecholamines in several rat tissues. Catecholamines were...

  4. An open-label, randomized positron emission tomography (PET) study in healthy male volunteers consisiting of Part A and Part B. Part A: Clinical validation of norepinephrine transporter (NET) PET ligand, (S,S)-[11C]O-methylreboxetine ([11C]MRB) using different doses of oral atomoxetine as NET reuptake inhibitor. Part B: Evaluation of NET occupancy, as measured by [11C]MRB, with multiple dosing regimens of orally administered GSK372475.

    Energy Technology Data Exchange (ETDEWEB)

    Fowler, Joanna

    2007-08-31

    Results from human studies with the PET radiotracer (S,S)-[(11)C]O-methyl reboxetine ([(11)C](S,S)-MRB), a ligand targeting the norepinephrine transporter (NET), are reported. Quantification methods were determined from test/retest studies, and sensitivity to pharmacological blockade was tested with different doses of atomoxetine (ATX), a drug that binds to the NET with high affinity (K(i)=2-5 nM). METHODS: Twenty-four male subjects were divided into different groups for serial 90-min PET studies with [(11)C](S,S)-MRB to assess reproducibility and the effect of blocking with different doses of ATX (25, 50 and 100 mg, po). Region-of-interest uptake data and arterial plasma input were analyzed for the distribution volume (DV). Images were normalized to a template, and average parametric images for each group were formed. RESULTS: [(11)C](S,S)-MRB uptake was highest in the thalamus (THL) and the midbrain (MBR) [containing the locus coeruleus (LC)] and lowest for the caudate nucleus (CDT). The CDT, a region with low NET, showed the smallest change on ATX treatment and was used as a reference region for the DV ratio (DVR). The baseline average DVR was 1.48 for both the THL and MBR with lower values for other regions [cerebellum (CB), 1.09; cingulate gyrus (CNG) 1.07]. However, more accurate information about relative densities came from the blocking studies. MBR exhibited greater blocking than THL, indicating a transporter density approximately 40% greater than THL. No relationship was found between DVR change and plasma ATX level. Although the higher dose tended to induce a greater decrease than the lower dose for MBR (average decrease for 25 mg=24+/-7%; 100 mg=31+/-11%), these differences were not significant. The different blocking between MBR (average decrease=28+/- 10%) and THL (average decrease=17+/-10%) given the same baseline DVR indicates that the CDT is not a good measure for non-NET binding in both regions. Threshold analysis of the difference between the

  5. LeuT-Desipramine Structure Reveals How Antidepressants Block Neurotransmitter Reuptake

    Energy Technology Data Exchange (ETDEWEB)

    Zhou,Z.; Zhen, J.; Karpowich, N.; Goetz, R.; Law, C.; Reith, M.; Wang, D.

    2007-01-01

    Tricyclic antidepressants exert their pharmacological effect -- inhibiting the reuptake of serotonin, norepinephrine, and dopamine -- by directly blocking neurotransmitter transporters (SERT, NET, and DAT, respectively) in the presynaptic membrane. The drug-binding site and the mechanism of this inhibition are poorly understood. We determined the crystal structure at 2.9 angstroms of the bacterial leucine transporter (LeuT), a homolog of SERT, NET, and DAT, in complex with leucine and the antidepressant desipramine. Desipramine binds at the inner end of the extracellular cavity of the transporter and is held in place by a hairpin loop and by a salt bridge. This binding site is separated from the leucine-binding site by the extracellular gate of the transporter. By directly locking the gate, desipramine prevents conformational changes and blocks substrate transport. Mutagenesis experiments on human SERT and DAT indicate that both the desipramine-binding site and its inhibition mechanism are probably conserved in the human neurotransmitter transporters.

  6. LeuT-desipramine structure reveals how antidepressants block neurotransmitter reuptake.

    Science.gov (United States)

    Zhou, Zheng; Zhen, Juan; Karpowich, Nathan K; Goetz, Regina M; Law, Christopher J; Reith, Maarten E A; Wang, Da-Neng

    2007-09-07

    Tricyclic antidepressants exert their pharmacological effect-inhibiting the reuptake of serotonin, norepinephrine, and dopamine-by directly blocking neurotransmitter transporters (SERT, NET, and DAT, respectively) in the presynaptic membrane. The drug-binding site and the mechanism of this inhibition are poorly understood. We determined the crystal structure at 2.9 angstroms of the bacterial leucine transporter (LeuT), a homolog of SERT, NET, and DAT, in complex with leucine and the antidepressant desipramine. Desipramine binds at the inner end of the extracellular cavity of the transporter and is held in place by a hairpin loop and by a salt bridge. This binding site is separated from the leucine-binding site by the extracellular gate of the transporter. By directly locking the gate, desipramine prevents conformational changes and blocks substrate transport. Mutagenesis experiments on human SERT and DAT indicate that both the desipramine-binding site and its inhibition mechanism are probably conserved in the human neurotransmitter transporters.

  7. Binge-Like Eating Attenuates Nisoxetine Feeding Suppression, Stress Activation, and Brain Norepinephrine Activity

    Science.gov (United States)

    Bello, Nicholas T.; Yeh, Chung-Yang; Verpeut, Jessica L.; Walters, Amy L.

    2014-01-01

    Stress is often associated with binge eating. A critical component of the control of stress is the central norepinephrine system. We investigated how dietary-induced binge eating alters central norepinephrine and related behaviors. Young male Sprague Dawley rats received calorie deprivation (24 h) and /or intermittent sweetened fat (vegetable shortening with sucrose; 30 min) twice a week for 10 weeks. The groups were Restrict Binge (calorie deprivation/sweetened fat), Binge (sweetened fat), Restrict (calorie deprivation), and Naive (no calorie deprivation/no sweetened fat). Dietary-induced binge eating was demonstrated by Restrict Binge and Binge, which showed an escalation in 30-min intake over time. Feeding suppression following nisoxetine (3 mg/kg; IP), a selective norepinephrine reuptake inhibitor, was not evident in Restrict Binge (Restrict Binge: 107±13, Binge: 52±9, Restrict: 80±8, Naive: 59±13% of saline injection at 1 h). In subsequent experiments with Restrict Binge and Naive, Restrict Binge had reduced corticosterone (Restrict Binge: 266±25; Naive: 494±36 ng/ml) and less feeding suppression (Restrict Binge: 81±12, Naive: 50±11% of non-restraint intake at 30 min) following restraint stress (1 h). Dietary-induced binge eating in Restrict Binge was not altered by a dorsal noradrenergic bundle lesion caused by N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4), but frontal cortex norepinephrine was positively correlated with the average 30-min intake post-lesion (0.69; p<0.01). In a separate set of animals, single-unit in vivo electrophysiological recording of locus coeruleus–norepinephrine neural activity demonstrated reduced sensory-evoked response as a consequence of the Restrict Binge schedule (Restrict Binge: 8.1±0.67, Naive: 11.9±1.09 Hz). These results, which suggest that a consequence of dietary-induced binge eating is to attenuate the responsiveness of the brain norepinephrine system, will further our understanding of how highly

  8. Binge-like eating attenuates nisoxetine feeding suppression, stress activation, and brain norepinephrine activity.

    Directory of Open Access Journals (Sweden)

    Nicholas T Bello

    Full Text Available Stress is often associated with binge eating. A critical component of the control of stress is the central norepinephrine system. We investigated how dietary-induced binge eating alters central norepinephrine and related behaviors. Young male Sprague Dawley rats received calorie deprivation (24 h and /or intermittent sweetened fat (vegetable shortening with sucrose; 30 min twice a week for 10 weeks. The groups were Restrict Binge (calorie deprivation/sweetened fat, Binge (sweetened fat, Restrict (calorie deprivation, and Naive (no calorie deprivation/no sweetened fat. Dietary-induced binge eating was demonstrated by Restrict Binge and Binge, which showed an escalation in 30-min intake over time. Feeding suppression following nisoxetine (3 mg/kg; IP, a selective norepinephrine reuptake inhibitor, was not evident in Restrict Binge (Restrict Binge: 107±13, Binge: 52±9, Restrict: 80±8, Naive: 59±13% of saline injection at 1 h. In subsequent experiments with Restrict Binge and Naive, Restrict Binge had reduced corticosterone (Restrict Binge: 266±25; Naive: 494±36 ng/ml and less feeding suppression (Restrict Binge: 81±12, Naive: 50±11% of non-restraint intake at 30 min following restraint stress (1 h. Dietary-induced binge eating in Restrict Binge was not altered by a dorsal noradrenergic bundle lesion caused by N-(2-chloroethyl-N-ethyl-2-bromobenzylamine (DSP4, but frontal cortex norepinephrine was positively correlated with the average 30-min intake post-lesion (0.69; p<0.01. In a separate set of animals, single-unit in vivo electrophysiological recording of locus coeruleus-norepinephrine neural activity demonstrated reduced sensory-evoked response as a consequence of the Restrict Binge schedule (Restrict Binge: 8.1±0.67, Naive: 11.9±1.09 Hz. These results, which suggest that a consequence of dietary-induced binge eating is to attenuate the responsiveness of the brain norepinephrine system, will further our understanding of how highly

  9. Selective and nonselective inhibition of competitors in picture naming.

    Science.gov (United States)

    Shao, Zeshu; Meyer, Antje S; Roelofs, Ardi

    2013-11-01

    The present study examined the relation between nonselective inhibition and selective inhibition in picture naming performance. Nonselective inhibition refers to the ability to suppress any unwanted response, whereas selective inhibition refers to the ability to suppress specific competing responses. The degree of competition in picture naming was manipulated by presenting targets along with distractor words that could be semantically related (e.g., a picture of a dog combined with the word cat) or unrelated (tree) to the picture name. The mean naming response time (RT) was longer in the related than in the unrelated condition, reflecting semantic interference. Delta plot analyses showed that participants with small mean semantic interference effects employed selective inhibition more effectively than did participants with larger semantic interference effects. The participants were also tested on the stop-signal task, which taps nonselective inhibition. Their performance on this task was correlated with their mean naming RT but, importantly, not with the selective inhibition indexed by the delta plot analyses and the magnitude of the semantic interference effect. These results indicate that nonselective inhibition ability and selective inhibition of competitors in picture naming are separable to some extent.

  10. The Effect of Diet Mixing on a Nonselective Herbivore.

    Directory of Open Access Journals (Sweden)

    Sophie Groendahl

    Full Text Available The balanced-diet hypothesis states that a diverse prey community is beneficial to consumers due to resource complementarity among the prey species. Nonselective consumer species cannot differentiate between prey items and are therefore not able to actively regulate their diet intake. We thus wanted to test whether the balanced-diet hypothesis is applicable to nonselective consumers. We conducted a laboratory experiment in which a nonselective model grazer, the freshwater gastropod Lymnaea stagnalis, was fed benthic green algae as single species or as a multi-species mixture and quantified the snails' somatic growth rates and shell lengths over a seven-week period. Gastropods fed the mixed diet were found to exhibit a higher somatic growth rate than the average of the snails fed single prey species. However, growth on the multi-species mixture did not exceed the growth rate obtained on the best single prey species. Similar results were obtained regarding the animals' shell height increase over time. The mixed diet did not provide the highest growth rate, which confirms our hypothesis. We thus suggest that the balanced-diet hypothesis is less relevant for non-selective generalist consumers, which needs to be considered in estimates of secondary production.

  11. Non-Selective Lexical Access in Different-Script Bilinguals

    Science.gov (United States)

    Moon, Jihye; Jiang, Nan

    2012-01-01

    Lexical access in bilinguals is known to be largely non-selective. However, most studies in this area have involved bilinguals whose two languages share the same script. This study aimed to examine bilingual lexical access among bilinguals whose two languages have distinct scripts. Korean-English bilinguals were tested in a phoneme monitoring task…

  12. Serotonin reuptake inhibitors and cardiovascular disease

    OpenAIRE

    Belcher, P.R.; Drake-Holland, A.J.; Noble, M.

    2005-01-01

    Selective serotonin re-uptake inhibiting drugs (SSRIs) are widely used for endogenous depression. In addition to depleting the nerve terminals of serotonin they also lower blood platelet serotonin levels. Platelet aggregation is a major component of acute coronary syndromes, including sudden death, and also of limb ischaemia. Platelet-released serotonin causes constriction of diseased blood vessels. The recent literature has revealed a number of reports of association between the treatment of...

  13. Cocaine synergism with alpha agonists in rat aorta: computational analysis reveals an action beyond reuptake inhibition*

    Science.gov (United States)

    Lamarre, Neil S.; Raffa, Robert B.; Tallarida, Ronald J.

    2012-01-01

    BACKGROUND Cocaine has long been known to increase blood pressure, but the degree and mechanism of vasoconstricting action remain poorly understood. Here we examine the interaction between cocaine and alpha-adrenoceptor agonists, with the action of reuptake inhibition minimized. METHODS Cocaine was administered to isolated rings of rat thoracic aorta, alone and in combination with three different adrenoceptor agonists: phenylephrine, methoxamine, and norepinephrine. Synergy analysis begins with the predicted additive effect of the combination of two agonists, based upon dose equivalence theory. This case where one agonist (cocaine) has no effect when administered alone requires only a t-test to demonstrate that a departure from additivity has occurred. RESULTS At doses where cocaine alone produced no vasoconstriction, it potentiated the vasoconstriction produced by all three alpha agonists, a clear indication of synergism between cocaine and these agents. Higher doses of cocaine in combination with alpha adrenoceptor agents gave an inverted-U shaped (hormetic) dose-effect curve, i.e., dose-related relaxation at higher doses. The hormetic dose-effect relation was analyzed using computational methodology based on dose equivalence to derive the unknown second component of action that causes relaxation. CONCLUSIONS Cocaine exhibits both vasoconstricting and vasorelaxant effects. This relaxing component, possibly related to activation of myosin light chain phosphatase, was quantified as a dose-effect curve. Most important is the synergism between cocaine and alpha-adrenoceptor stimulation which cannot be explained as an action due to reuptake inhibition, and has not been previously described. PMID:23270987

  14. Hydroxytyrosol increases norepinephrine transporter function in pheochromocytoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Luzon-Toro, Berta [Institute of Parasitology and Biomedicine ' Lopez-Neyra' , Spanish National Research Council (CSIC), 18100 Granada (Spain); Geerlings, Arjan [Puleva Biotech, 18004 Granada (Spain); Hilfiker, Sabine [Institute of Parasitology and Biomedicine ' Lopez-Neyra' , Spanish National Research Council (CSIC), 18100 Granada (Spain)], E-mail: sabine.hilfiker@ipb.csic.es

    2008-10-15

    Introduction: The norepinephrine transporter is responsible for the intracellular uptake of {sup 131}I- iodometaiodobenzylguanidine ({sup 131}I-MIBG), which is used for the diagnostic localization and treatment of pheochromocytomas as well as other tumors such as neuroblastomas and carcinoids. This agent is variably delivered into tumor cells by the norepinephrine transporter, but few studies have shown treatments that work to increase norepinephrine transporter activity. The objective of the present study was to test the possible beneficial effects of hydroxytyrosol in enhancing norepinephrine transporter function, which may have implications for its combined use with {sup 131}I-MIBG in the diagnosis and treatment of pheochromocytomas. Methods: Rat pheochromocytoma PC12 cells were labeled with [{sup 3}H]-norepinephrine in the presence or absence of different concentrations of hydroxytyrosol, a naturally occurring compound with strong antioxidant properties, followed by measurements of uptake and release of radiolabeled norepinephrine. Results: Hydroxytyrosol pronouncedly increased norepinephrine transporter activity, with the rapid onset excluding effects on norepinephrine transporter expression levels. Concomitant with increased norepinephrine transporter activity, hydroxytyrosol caused a decrease of both spontaneous and evoked norepinephrine release, indicating that it affects pre-existing plasma membrane-associated norepinephrine transporter, rather than the incorporation of novel norepinephrine transporter molecules into the plasma membrane. Conclusion: Hydroxytyrosol potently enhances norepinephrine transporter activity in pheochromocytoma PC12 cells, suggesting that combinatorial therapy employing hydroxytyrosol may improve the effectiveness of {sup 131}I-MIBG as a diagnosis and treatment modality.

  15. Norepinephrine kinetics during insulin-induced hypoglycemia

    DEFF Research Database (Denmark)

    Hilsted, J; Christensen, N J; Larsen, S

    1985-01-01

    Norepinephrine (NE) kinetics (plasma appearance rate, clearance, and forearm extraction) were measured during insulin-induced hypoglycemia in six healthy subjects. NE clearance did not change during hypoglycemia, indicating that the increase in plasma NE during hypoglycemia is due to an increased...

  16. Disposition and metabolism of [14C]-levomilnacipran, a serotonin and norepinephrine reuptake inhibitor, in humans, monkeys, and rats

    Directory of Open Access Journals (Sweden)

    Brunner V

    2015-06-01

    Full Text Available Valérie Brunner,1 Bernadette Maynadier,2 Laishun Chen,3 Louise Roques,2 Isabelle Hude,2 Sébastien Séguier,2 Laurence Barthe,1 Philippe Hermann11Pierre Fabre Médicament, Centre de R&D, Toulouse, 2Centre Experimental PreClinque, Campans, France; 3Forest Research Institute Inc., an affiliate of Actavis Inc., Jersey City, NJ, USAAbstract: Levomilnacipran is approved in the US for the treatment of major depressive disorder in adults. We characterized the metabolic profile of levomilnacipran in humans, monkeys, and rats after oral administration of [14C]-levomilnacipran. In vitro binding of levomilnacipran to human plasma proteins was also studied. Unchanged levomilnacipran was the major circulating compound after dosing in all species. Within 12 hours of dosing in humans, levomilnacipran accounted for 52.9% of total plasma radioactivity; the circulating metabolites N-desethyl levomilnacipran N-carbamoyl glucuronide, N-desethyl levomilnacipran, and levomilnacipran N-carbamoyl glucuronide accounted for 11.3%, 7.5%, and 5.6%, respectively. Similar results were seen in monkeys. N-Desethyl levomilnacipran and p-hydroxy levomilnacipran were the main circulating metabolites in rats. Mass balance results indicated that renal excretion was the major route of elimination with 58.4%, 35.5%, and 40.2% of total radioactivity being excreted as unchanged levomilnacipran in humans, monkeys, and rats, respectively. N-Desethyl levomilnacipran was detected in human, monkey, and rat urine (18.2%, 12.4%, and 7.9% of administered dose, respectively. Human and monkey urine contained measurable quantities of levomilnacipran glucuronide (3.8% and 4.1% of administered dose, respectively and N-desethyl levomilnacipran glucuronide (3.2% and 2.3% of administered dose, respectively; these metabolites were not detected in rat urine. The metabolites p-hydroxy levomilnacipran and p-hydroxy levomilnacipran glucuronide were detected in human urine (≤1.2% of administered dose, and p-hydroxy levomilnacipran glucuronide was found in rat urine (4% of administered dose. None of the metabolites were pharmacologically active. Levomilnacipran was widely distributed with low plasma protein binding (22%.Keywords: FETZIMA, metabolites, mass balance, excretion, tissue distribution

  17. Non-Selective SiGe Graphic Epitaxial by MBE

    Institute of Scientific and Technical Information of China (English)

    Qian Zhou; Chun Han; Jing-Chun Li

    2007-01-01

    To handle the thermal budget in SiGe BiCMOS process, a nonselective graphic epitaxial technology using molecular beam epitaxial (MBE) has been developed. SEM, AFM, XRD, and dislocation density measurements are carried out. The SiGe film's RMS roughness is 0.45nm, and dislocation density is 0.3×103cm2~1.2×103cm2. No dislocation accumulation exists on the boundary of the windows; this indicates the high quality of the SiGe film. The experiment results show that the technology presented in this paper meets the fabrication requirements of SiGe BiCMOS.

  18. Nonselective and polarization effects in time-resolved optogalvanic spectroscopy

    Science.gov (United States)

    Zhechev, D.; Steflekova, V.

    2016-02-01

    Three interfering effects in optogalvanic (OG) spectroscopy are identified in a hollow cathode discharge (HCD) - OG detector. The laser beam is found to generate two nonselective processes, namely photoelectron emission (PE) from the cathode surface with a sub-breakdown bias applied, and nonresonant space ionization. The convolution of these galvanic contributions was determined experimentally as an instrumental function and a deconvolution procedure to determine the actual OG signal was developed. Specific plasma conductance is detected dependent on the polarization of the laser beam irradiating. Linearly/circularly polarized light beam is found to induce OG signals differ in amplitude (and their shape parameters in the time-resolved OG signals (TROGS)). The phenomena coherence and specific conductance are found to be in causal relationship. The additional conductance due to coherent states of atoms manifests itself as an intrinsic instrumental property of OG detector.

  19. Selective serotonin reuptake inhibitorprescribing before, during and after pregnancy

    DEFF Research Database (Denmark)

    Charlton, Ra; Jordan, S; Pierini, A;

    2015-01-01

    OBJECTIVE: To explore the prescribing patterns of selective serotonin reuptake inhibitors (SSRIs) before, during and after pregnancy in six European population-based databases. DESIGN: Descriptive drug utilisation study. SETTING: Six electronic healthcare databases in Denmark, the Netherlands...

  20. Isolating the Norepinephrine Pathway Comparing Lithium in Bipolar Patients to SSRIs in Depressive Patients

    Directory of Open Access Journals (Sweden)

    Andy R. Eugene

    2015-07-01

    Full Text Available Introduction: The purpose of this investigatory neuroimaging analysis was done to better understand the pharmacodynamics of Lithium by isolating the norepinephrine pathway in the brain. To accomplish this, we compared patients with Bipolar Disorder treated with Lithium to patients diagnosed with Major Depression or Depressive Disorder who are treated with Selective Serotonin Reuptake Inhibitors (SSRIs.Methodology: We used Standardized Low Resolution Brain Electrotomography to calculate the whole brain, voxel-by-voxel, unpaired t-tests Statistical non-Parametric Maps. For our first electrophysiological neuroimaging investigation, we compared 46 patients (average age = 34 ± 16.5 diagnosed with Bipolar Affective Disorder to three patient groups all diagnosed with Major Depression or Depressive Episode. The first is with 48 patients diagnosed with Major Depression or Depressive Episode (average age = 49 ± 12.9, the second to 16 male depressive patients (average age = 45 ± 15.1, and the final comparison to 32 depressive females (average age = 50 ± 11.7.Results: The results of sLORETA three-dimensional statistical non-parametric maps illustrated that Lithium influenced an increase in neurotransmission in the right Superior TemporalGyrus (t=1.403, p=0.00780, Fusiform Gyrus (t=1.26, and Parahippocampal Gyrus (t=1.29.Moreover, an increased in neuronal function was found was also identified at the Cingulate Gyrus(t=1.06, p=0.01200.Conclusion: We are proposing a translational clinical biological marker for patients diagnosed with Bipolar Disorder to guide physicians during the course of Lithium therapy and have identified neuroanatomical structures influenced by norepinephrine.

  1. Synthesis and in vivo evaluation of novel radiotracers for the in vivo imaging of the norepinephrine transporter

    Energy Technology Data Exchange (ETDEWEB)

    Wilson, Alan A. E-mail: aaw@camhpet.on.ca; Patrick Johnson, David; Mozley, David; Hussey, Doug; Ginovart, Nathalie; Nobrega, Jose; Garcia, Armando; Meyer, Jeffery; Houle, Sylvain

    2003-02-01

    The (R,R) and (S,S) enantiomers of 2-[(2-methoxyphenoxy)phenylmethyl]morpholine (MeNER) have been radiolabelled with carbon-11 in good yield and at high specific activity. These radiotracers are close analogues of reboxetine, a potent and selective ligand for the norepinephrine transporter (NET). They were examined as potential ligands for imaging NET in vivo by positron emission tomography (PET). The in vivo brain distribution of both [{sup 11}C]-labeled enantiomers were evaluated in rats. Following tail-vein injection of the (R,R)-enantiomer regional brain uptake and washout of radioactivity was homogeneous at all time points examined (5-60 min). In contrast, administration of the (S,S)-enantiomer produced a heterogeneous distribution of radioactivity in brain with highest uptake in the hypothalamus, a NET rich region, and lowest uptake in the striatum, a brain region devoid of NET. Hypothalamus to striatum ratios of 2.5 to one were achieved at 60 min post injection of (S,S)-[{sup 11}C]-MeNER. Pre-injection of the norepinephrine reuptake inhibitors, reboxetine or desipramine, reduced hypothalamus to striatum ratios to near unity while reuptake inhibitors of dopamine and serotonin had no significant effect on binding. In vitro autoradiography studies (rat brain slices) with (S,S)-[{sup 11}C]-MeNER produced a regional distribution pattern that was consistent with the reported distribution of NET. (S,S)-[{sup 11}C]-MeNER has the potential to be the first successful PET ligand to image NET.

  2. Norepinephrine transporter variant A457P knock-in mice display key features of human postural orthostatic tachycardia syndrome

    Directory of Open Access Journals (Sweden)

    Jana K. Shirey-Rice

    2013-07-01

    Postural orthostatic tachycardia syndrome (POTS is a common autonomic disorder of largely unknown etiology that presents with sustained tachycardia on standing, syncope and elevated norepinephrine spillover. Some individuals with POTS experience anxiety, depression and cognitive dysfunction. Previously, we identified a mutation, A457P, in the norepinephrine (NE; also known as noradrenaline transporter (NET; encoded by SLC6A2 in POTS patients. NET is expressed at presynaptic sites in NE neurons and plays a crucial role in regulating NE signaling and homeostasis through NE reuptake into noradrenergic nerve terminals. Our in vitro studies demonstrate that A457P reduces both NET surface trafficking and NE transport and exerts a dominant-negative impact on wild-type NET proteins. Here we report the generation and characterization of NET A457P mice, demonstrating the ability of A457P to drive the POTS phenotype and behaviors that are consistent with reported comorbidities. Mice carrying one A457P allele (NET+/P exhibited reduced brain and sympathetic NE transport levels compared with wild-type (NET+/+ mice, whereas transport activity in mice carrying two A457P alleles (NETP/P was nearly abolished. NET+/P and NETP/P mice exhibited elevations in plasma and urine NE levels, reduced 3,4-dihydroxyphenylglycol (DHPG, and reduced DHPG:NE ratios, consistent with a decrease in sympathetic nerve terminal NE reuptake. Radiotelemetry in unanesthetized mice revealed tachycardia in NET+/P mice without a change in blood pressure or baroreceptor sensitivity, consistent with studies of human NET A457P carriers. NET+/P mice also demonstrated behavioral changes consistent with CNS NET dysfunction. Our findings support that NET dysfunction is sufficient to produce a POTS phenotype and introduces the first genetic model suitable for more detailed mechanistic studies of the disorder and its comorbidities.

  3. Norepinephrine transporter variant A457P knock-in mice display key features of human postural orthostatic tachycardia syndrome.

    Science.gov (United States)

    Shirey-Rice, Jana K; Klar, Rebecca; Fentress, Hugh M; Redmon, Sarah N; Sabb, Tiffany R; Krueger, Jessica J; Wallace, Nathan M; Appalsamy, Martin; Finney, Charlene; Lonce, Suzanna; Diedrich, André; Hahn, Maureen K

    2013-07-01

    Postural orthostatic tachycardia syndrome (POTS) is a common autonomic disorder of largely unknown etiology that presents with sustained tachycardia on standing, syncope and elevated norepinephrine spillover. Some individuals with POTS experience anxiety, depression and cognitive dysfunction. Previously, we identified a mutation, A457P, in the norepinephrine (NE; also known as noradrenaline) transporter (NET; encoded by SLC6A2) in POTS patients. NET is expressed at presynaptic sites in NE neurons and plays a crucial role in regulating NE signaling and homeostasis through NE reuptake into noradrenergic nerve terminals. Our in vitro studies demonstrate that A457P reduces both NET surface trafficking and NE transport and exerts a dominant-negative impact on wild-type NET proteins. Here we report the generation and characterization of NET A457P mice, demonstrating the ability of A457P to drive the POTS phenotype and behaviors that are consistent with reported comorbidities. Mice carrying one A457P allele (NET(+/P)) exhibited reduced brain and sympathetic NE transport levels compared with wild-type (NET(+/+)) mice, whereas transport activity in mice carrying two A457P alleles (NET(P/P)) was nearly abolished. NET(+/P) and NET(P/P) mice exhibited elevations in plasma and urine NE levels, reduced 3,4-dihydroxyphenylglycol (DHPG), and reduced DHPG:NE ratios, consistent with a decrease in sympathetic nerve terminal NE reuptake. Radiotelemetry in unanesthetized mice revealed tachycardia in NET(+/P) mice without a change in blood pressure or baroreceptor sensitivity, consistent with studies of human NET A457P carriers. NET(+/P) mice also demonstrated behavioral changes consistent with CNS NET dysfunction. Our findings support that NET dysfunction is sufficient to produce a POTS phenotype and introduces the first genetic model suitable for more detailed mechanistic studies of the disorder and its comorbidities.

  4. In vivo assessment of [{sup 11}C]MRB as a prospective PET ligand for imaging the norepinephrine transporter

    Energy Technology Data Exchange (ETDEWEB)

    Severance, Alin J. [New York State Psychiatric Institute, Division of Brain Imaging, Department of Neuroscience, New York, NY (United States); Milak, Matthew S.; Dileep Kumar, J.S.; Arango, Victoria; Parsey, Ramin V. [Columbia University College of Physicians and Surgeons, Department of Psychiatry, New York, NY (United States); New York State Psychiatric Institute, Division of Brain Imaging, Department of Neuroscience, New York, NY (United States); Prabhakaran, Jaya; Majo, Vattoly J. [Columbia University College of Physicians and Surgeons, Department of Psychiatry, New York, NY (United States); Simpson, Norman R.; Van Heertum, Ronald L. [Columbia University College of Physicians and Surgeons, Department of Radiology, New York, NY (United States); Mann, J.J. [Columbia University College of Physicians and Surgeons, Department of Psychiatry, New York, NY (United States); Columbia University College of Physicians and Surgeons, Department of Radiology, New York, NY (United States); New York State Psychiatric Institute, Division of Brain Imaging, Department of Neuroscience, New York, NY (United States)

    2007-05-15

    Antagonism of norepinephrine reuptake is now an important pharmacological strategy in the treatment of anxiety and depressive disorders, and many antidepressants have substantial potential occupancy of the norepinephrine transporter (NET) at recommended dosages. Despite the importance of understanding this transporter's role in psychiatric disease and treatment, a suitable radioligand for studying NET has been slow to emerge. (S,S)-Methylreboxetine (MRB) is among the more promising ligands recently adapted for positron emission tomography (PET), and the present study aimed to evaluate its potential for use in higher primates. Affinities for various brain targets were determined in vitro. PET studies were conducted in baboon under both test-retest and blocking conditions using 1 mg/kg nisoxetine. MRB has sixfold higher affinity for NET than the serotonin transporter, and negligible affinity for other sites. PET studies in baboons showed little regional heterogeneity in binding and were minimally affected by pretreatment with the NET antagonist nisoxetine. Despite improvement over previous ligands for imaging NET in vivo, the low signal to noise ratio indicates [{sup 11}C]MRB lacks sensitivity and reliability as a PET radiotracer in humans. (orig.)

  5. Stereoselective Actions of Methylenedioxypyrovalerone (MDPV) To Inhibit Dopamine and Norepinephrine Transporters and Facilitate Intracranial Self-Stimulation in Rats.

    Science.gov (United States)

    Kolanos, R; Partilla, J S; Baumann, M H; Hutsell, B A; Banks, M L; Negus, S S; Glennon, R A

    2015-05-20

    The designer stimulant methylenedioxypyrovalerone (MDPV) is a potent reuptake inhibitor at transporters for dopamine (DAT) and norepinephrine (NET) that produces a constellation of abuse-related behavioral effects. MDPV possesses a chiral center, and the abused formulation of the drug is a racemic mixture, but no data are available on the pharmacology of its isomers. Here, the individual optical isomers of MDPV were prepared and examined with respect to their neurochemical actions on neurotransmitter reuptake and behavioral effects in an assay of intracranial self-stimulation (ICSS) in rats. In assays of DAT uptake inhibition, S(+)MDPV (EC50 = 2.13 nM) was more potent than either (±)MDPV (EC50 = 4.85 nM) or R(-)MDPV (EC50 = 382.80 nM); the three drugs were less potent at NET uptake inhibition, with the same rank order of potency. Neither racemic MDPV nor its optical isomers inhibited the reuptake of serotonin at concentrations up to 10 μM. S(+)MDPV produced an abuse-related and dose-dependent facilitation of ICSS, and the potency of S(+)MDPV (significant facilitation at doses ≥ 0.1 mg/kg) was greater than that of the racemate (significant facilitation at doses ≥ 0.32 mg/kg). R(-)MDPV failed to alter ICSS at doses up to 100 times greater than the lowest effective dose of S(+)MDPV. The results indicate that abuse-related neurochemical and behavioral effects of racemic MDPV reside primarily with its S(+) isomer.

  6. Primary repair of colon injuries: clinical study of nonselective approach

    Directory of Open Access Journals (Sweden)

    Krivokapic Zoran V

    2010-12-01

    Full Text Available Abstract Background This study was designed to determine the role of primary repair and to investigate the possibility of expanding indications for primary repair of colon injuries using nonselective approach. Methods Two groups of patients were analyzed. Retrospective (RS group included 30 patients managed by primary repair or two stage surgical procedure according to criteria published by Stone (S/F and Flint (Fl. In this group 18 patients were managed by primary repair. Prospective (PR group included 33 patients with primary repair as a first choice procedure. In this group, primary repair was performed in 30 cases. Results Groups were comparable regarding age, sex, and indexes of trauma severity. Time between injury and surgery was shorter in PR group, (1.3 vs. 3.1 hours. Stab wounds were more frequent in PR group (9:2, and iatrogenic lesions in RS group (6:2. Associated injuries were similar, as well as segmental distribution of colon injuries. S/F criteria and Flint grading were similar. In RS group 15 primary repairs were successful, while in two cases relaparotomy and colostomy was performed due to anastomotic leakage. One patient died. In PR group, 25 primary repairs were successful, with 2 immediate and 3 postoperative (7-10 days deaths, with no evidence of anastomotic leakage. Conclusions Results of this study justify more liberal use of primary repair in early management of colon injuries. Trial registration Current Controlled Trials ISRCTN94682396

  7. Ibudilast: a non-selective phosphodiesterase inhibitor in brain disorders

    Directory of Open Access Journals (Sweden)

    Joanna Schwenkgrub

    2017-03-01

    Full Text Available Ibudilast (IBD is a non-selective (3, 4, 10, 11 phosphodiesterase (PDE inhibitor, used mainly as a bronchodilator for the treatment of bronchial asthma. PDE play a central role in cellular function (e.g. differentiation, synaptic plasticity and inflammatory response by metabolizing cyclic nucleotides. The results from preclinical and clinical studies indicate that IBD has a broader range of action through suppression of pro-inflammatory cytokines (IL-6, IL-1β, TNF-α, toll-like receptor 4 blockade (TLR-4, inhibition of a macrophage migration inhibitory factor (MIF, up-regulation the anti-inflammatory cytokine (IL-10, and promotion of neurotrophic factors (GDNF, NGF, NT-4. Recent data indicate that the efficacy of IBD appears to be independent from PDE inhibition activity and rather linked to glial activity attenuation. Additional advantages of IBD, such as crossing the blood–brain barrier, good tolerance and activity by oral administration, makes it a promising therapeutic candidate for treating neuroinflammatory conditions, where the currently available treatment remains unsatisfying due to poor tolerability and/or sub-optimal efficacy. IBD has no direct receptor affinity with exemption of some undefined effect on adenosine receptors that makes the drug devoid of its receptors-mediated adverse effects. Current article provides an overview of the pharmacology of IBD with a focus on preclinical and clinical data supporting its potential neuroprotective benefits for neurological conditions, including multiple sclerosis, neuropathic pain, medication overuse headache, stroke, opioid, alcohol and methamphetamine abuse.

  8. Serotonin and noradrenaline reuptake inhibitors improve micturition control in mice.

    Directory of Open Access Journals (Sweden)

    Marco Redaelli

    Full Text Available Poor micturition control may cause profound distress, because proper voiding is mandatory for an active social life. Micturition results from the subtle interplay of central and peripheral components. It involves the coordination of autonomic and neuromuscular activity at the brainstem level, under the executive control of the prefrontal cortex. We tested the hypothesis that administration of molecules acting as reuptake inhibitors of serotonin, noradrenaline or both may exert a strong effect on the control of urine release, in a mouse model of overactive bladder. Mice were injected with cyclophosphamide (40 mg/kg, to increase micturition acts. Mice were then given one of four molecules: the serotonin reuptake inhibitor imipramine, its metabolite desipramine that acts on noradrenaline reuptake, the serotonin and noradrenaline reuptake inhibitor duloxetine or its active metabolite 4-hydroxy-duloxetine. Cyclophosphamide increased urine release without inducing overt toxicity or inflammation, except for increase in urothelium thickness. All the antidepressants were able to decrease the cyclophosphamide effects, as apparent from longer latency to the first micturition act, decreased number of urine spots and volume of released urine. These results suggest that serotonin and noradrenaline reuptake inhibitors exert a strong and effective modulatory effect on the control of urine release and prompt to additional studies on their central effects on brain areas involved in the social and behavioral control of micturition.

  9. Boosting Norepinephrine Transmission Triggers Flexible Reconfiguration of Brain Networks at Rest.

    Science.gov (United States)

    Guedj, Carole; Monfardini, Elisabetta; Reynaud, Amélie J; Farnè, Alessandro; Meunier, Martine; Hadj-Bouziane, Fadila

    2016-09-06

    The locus coeruleus-norepinephrine (LC-NE) system is thought to act as a reset signal allowing brain network reorganization in response to salient information in the environment. However, no direct evidence of NE-dependent whole-brain reorganization has ever been described. We used resting-state functional magnetic resonance imaging in monkeys to investigate the impact of NE-reuptake inhibition on whole-brain connectivity patterns. We found that boosting NE transmission changes functional connectivity between and within resting-state networks. It modulated the functional connectivity pattern of a brainstem network including the LC region and interactions between associative and sensory-motor networks as well as within sensory-motor networks. Among the observed changes, those involving the fronto-parietal attention network exhibited a unique pattern of uncoupling with other sensory-motor networks and correlation switching from negative to positive with the brainstem network that included the LC nucleus. These findings provide the first empirical evidence of NE-dependent large-scale brain network reorganization and further demonstrate that the fronto-parietal attention network represents a central feature within this reorganization. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  10. Norepinephrine-induced diuresis in chronically ethanol-treated rats

    Energy Technology Data Exchange (ETDEWEB)

    Pohorecky, L.A. (Rutgers Univ., Piscataway, NJ (USA))

    1989-01-01

    Previous research from this laboratory indicated that noradrenergic mechanisms might mediate ethanol diuresis. Experiments described here examined changes in sensitivity of noradrenergic mechanisms in animals chronically treated with ethanol. Norepinephrine hydrochloride (0-12 ug intracerebroventricularly) produced dose-dependent diuresis in control and ethanol treated rats on the first day of treatment. Tolerance to ethanol diuresis was present after 10 day of ethanol treatment. Lack of responsiveness to norepinephrine-induced diuresis was evident only on the 20th day of treatment in both the ethanol and dextrin-maltose groups of rats. These results indicate a temporal dissociation between the tolerance to ethanol-induced and norepinephrine-induced diuresis and suggest that norepinephrine may not play a primary role in the development of tolerance to the diuretic action of ethanol.

  11. Continuous infusion of tracer norepinephrine may miscalculate unidirectional nerve uptake of norepinephrine in humans

    DEFF Research Database (Denmark)

    Henriksen, Jens Henrik; Christensen, N J; Ring-Larsen, H

    1989-01-01

    In order to evaluate uptake kinetics of norepinephrine (NE) in different tissues, a catheterization study was performed in control subjects (n = 6) and patients with enhanced sympathetic nervous activity (cirrhosis, n = 12) during constant intravenous infusion of L[3H]norepinephrine ([3H]NE) for 75...... minutes. In spite of a higher NE spillover from kidneys in patients compared with controls (82 vs. 49 ng/min, p less than 0.01), renal extraction ratios of [3H]NE were similar in the two groups (0.33 vs. 0.32, NS), and no significant change was observed during the time of infusion. In contrast, liver......-intestine extraction ratios of [3H]NE decreased significantly and equally with infusion time in patients (from 0.57 to 0.44, p less than 0.01) and controls (from 0.59 to 0.46, p less than 0.01). This was observed despite the fact that spillover of NE from this vascular bed was observed only in patients with cirrhosis...

  12. Safety of the nonselective NSAID nabumetone : focus on gastrointestinal tolerability.

    Science.gov (United States)

    Bannwarth, Bernard

    2008-01-01

    Although effective in the treatment of pain associated with rheumatic conditions such as osteoarthritis and rheumatoid arthritis, long-term use of NSAIDs is primarily limited by their association with upper gastrointestinal (GI) toxicity. Adverse effects range from dyspepsia and abdominal pain to ulceration and bleeding. GI damage elicited by NSAIDs arises as the result of biochemically induced topical irritant effects and by topical and systemic pharmacological suppression of gastroprotective prostaglandins. Variation in the physicochemical properties and pharmacological profiles among the individual NSAIDs translate into inter-agent differences regarding propensity to cause adverse GI effects. Nabumetone is a nonselective NSAID that offers distinct advantages over other agents in this class with regard to GI tolerability. Its non-acidic nature and pro-drug formulation, together with the lack of biliary secretion of its active metabolite, 6-methoxy-2-naphthylacetic acid, are thought to contribute to the improved GI tolerability of this drug. In head-to-head trials with other NSAIDs, nabumetone has demonstrated significant benefits regarding the incidence of GI events and more serious perforations, ulcers and bleeds (PUBs). Pooled data from eight postmarketing, randomized, controlled trials demonstrated a lower cumulative frequency of PUBs with nabumetone (0.03%; 95% CI 0.0, 0.08) versus comparator NSAIDs (1.4%; 95% CI 0.5, 2.4). Large-scale database studies also indicate that risk of serious GI complications is lower with nabumetone than comparator NSAIDs. Limited comparative data suggest that nabumetone offers a GI tolerability profile similar to that of cyclo-oxygenase-2 selective NSAIDs (coxibs). Although adverse cardiovascular outcomes appear to be a class effect of the coxibs, conventional NSAIDs may also have the potential for causing atherothrombotic complications. However, based on available data, nabumetone does not appear to be associated with increased

  13. Selective serotonin reuptake inhibitors for fibromyalgia syndrome

    Directory of Open Access Journals (Sweden)

    Brian Walitt

    Full Text Available ABSTRACT BACKGROUND: Fibromyalgia is a clinically well-defined chronic condition with a biopsychosocial aetiology. Fibromyalgia is characterized by chronic widespread musculoskeletal pain, sleep problems, cognitive dysfunction, and fatigue. Patients often report high disability levels and poor quality of life. Since there is no specific treatment that alters the pathogenesis of fibromyalgia, drug therapy focuses on pain reduction and improvement of other aversive symptoms. OBJECTIVES: To assess the benefits and harms of selective serotonin reuptake inhibitors (SSRIs in the treatment of fibromyalgia. METHODS: Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 5, MEDLINE (1966 to June 2014, EMBASE (1946 to June 2014, and the reference lists of reviewed articles. Selection criteria: We selected all randomized, double-blind trials of SSRIs used for the treatment of fibromyalgia symptoms in adult participants. We considered the following SSRIs in this review: citalopram, fluoxetine, escitalopram, fluvoxamine, paroxetine, and sertraline. Data collection and analysis: Three authors extracted the data of all included studies and assessed the risks of bias of the studies. We resolved discrepancies by discussion. MAIN RESULTS: The quality of evidence was very low for each outcome. We downgraded the quality of evidence to very low due to concerns about risk of bias and studies with few participants. We included seven placebo-controlled studies, two with citalopram, three with fluoxetine and two with paroxetine, with a median study duration of eight weeks (4 to 16 weeks and 383 participants, who were pooled together. All studies had one or more sources of potential major bias. There was a small (10% difference in patients who reported a 30% pain reduction between SSRIs (56/172 (32.6% and placebo (39/171 (22.8% risk difference (RD 0.10, 95% confidence interval (CI 0.01 to 0.20; number needed to treat for an

  14. Selective serotonin reuptake inhibitors for fibromyalgia syndrome

    Science.gov (United States)

    Walitt, Brian; Urrútia, Gerard; Nishishinya, María Betina; Cantrell, Sarah E; Häuser, Winfried

    2016-01-01

    Background Fibromyalgia is a clinically well-defined chronic condition with a biopsychosocial aetiology. Fibromyalgia is characterized by chronic widespread musculoskeletal pain, sleep problems, cognitive dysfunction, and fatigue. Patients often report high disability levels and poor quality of life. Since there is no specific treatment that alters the pathogenesis of fibromyalgia, drug therapy focuses on pain reduction and improvement of other aversive symptoms. Objectives The objective was to assess the benefits and harms of selective serotonin reuptake inhibitors (SSRIs) in the treatment of fibromyalgia. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 5), MEDLINE (1966 to June 2014), EMBASE (1946 to June 2014), and the reference lists of reviewed articles. Selection criteria We selected all randomized, double-blind trials of SSRIs used for the treatment of fibromyalgia symptoms in adult participants. We considered the following SSRIs in this review: citalopram, fluoxetine, escitalopram, fluvoxamine, paroxetine, and sertraline. Data collection and analysis Three authors extracted the data of all included studies and assessed the risks of bias of the studies. We resolved discrepancies by discussion. Main results The quality of evidence was very low for each outcome. We downgraded the quality of evidence to very low due to concerns about risk of bias and studies with few participants. We included seven placebo-controlled studies, two with citalopram, three with fluoxetine and two with paroxetine, with a median study duration of eight weeks (4 to 16 weeks) and 383 participants, who were pooled together. All studies had one or more sources of potential major bias. There was a small (10%) difference in patients who reported a 30% pain reduction between SSRIs (56/172 (32.6%)) and placebo (39/171 (22.8%)) risk difference (RD) 0.10, 95% confidence interval (CI) 0.01 to 0.20; number needed to treat for an additional

  15. Use of selective serotonin reuptake inhibitors reduces fertility in men

    DEFF Research Database (Denmark)

    Nørr, L; Bennedsen, Birgit; Fedder, Jens

    2016-01-01

    Clinical review of the present data on the effects of selective serotonin reuptake inhibitors (SSRIs) on male fertility was the objective of the study. PubMed and Scopus were searched for publications in English or Danish and reviewed. Human trials, animal studies and in vitro studies were included...

  16. Selective serotonin reuptake inhibitors as a novel class of immunosuppressants

    NARCIS (Netherlands)

    Gobin, Veerle; Van Steendam, Katleen; Denys, D.; Deforce, Dieter

    2014-01-01

    In the past decades, selective serotonin reuptake inhibitors (SSRIs) have been shown to exert several immunological effects, such as reduced lymphocyte proliferation, alteration of cytokine secretion and induction of apoptosis. Based on these effects, SSRIs were proposed as drugs for the treatment o

  17. Sex differences in hypothalamic-mediated tonic norepinephrine release for thermal hyperalgesia in rats.

    Science.gov (United States)

    Wagner, M; Banerjee, T; Jeong, Y; Holden, J E

    2016-06-02

    Neuropathic pain is treated using serotonin norepinephrine reuptake inhibitors with mixed results. Pain facilitation mediated by α1-adrenoceptors may be involved, but whether norepinephrine (NE) is tonically released is unclear. The aim of this study was to determine whether NE is tonically released from A7 cells following chronic constriction injury (CCI), and if the lateral hypothalamus (LH) plays a role in this release in male and female rats with nociceptive and neuropathic pain types. Neuropathic groups received left CCI while nociceptive groups remained naïve to injury. Fourteen days later, rats were given intrathecal infusion of either the α1-adrenoceptor antagonist WB4101, the α2-adrenoceptor antagonist yohimbine (74 μg), or normal saline for control. Paw withdrawal latency (PWL) from a thermal stimulus was measured. The generalized estimated equation method was used for statistical analysis. Nociceptive rats given WB4101 had a PWL significantly longer than saline control (7.89 ± 0.63 vs. 5.87 ± 0.52 s), while the PWL of neuropathic rats given WB4101 was 13.20 ± 0.52 s compared to 6.78 ± 0.52 s for the saline control rats. Yohimbine had no significant effect. Microinjection of cobalt chloride (CoCl) in the A7 catecholamine cell group to prevent synaptic transmission blocked the effect of WB4101 in all groups, supporting the notion that spinally descending A7 cells tonically release NE that contributes to α1-mediated nociceptive facilitation. Microinjection of CoCl into the left LH blocked the effect of WB4101 in nociceptive and neuropathic male rats, but had no effect in female rats of either pain type, suggesting differential innervation. These findings indicate that tonic release of NE acts at pronociceptive α1-adrenoceptors, that this effect is greater in rats with nerve damage, and that, while NE comes primarily from the A7 cell group, LH innervation of the A7 cell group is different between the sexes.

  18. Norepinephrine Regulates Condylar Bone Loss via Comorbid Factors.

    Science.gov (United States)

    Jiao, K; Niu, L; Xu, X; Liu, Y; Li, X; Tay, F R; Wang, M

    2015-06-01

    Degenerative changes of condylar subchondral bone occur frequently in temporomandibular disorders. Although psychologic stresses and occlusal abnormalities have been implicated in temporomandibular disorder, it is not known if these risks represent synergistic comorbid factors that are involved in condylar subchondral bone degradation that is regulated by the sympathetic nervous system. In the present study, chronic immobilization stress (CIS), chemical sympathectomy, and unilateral anterior crossbite (UAC) were sequentially applied in a murine model. Norepinephrine contents in the subjects' serum and condylar subchondral bone were detected by ELISA; bone and cartilage remodeling parameters and related gene expression in the subchondral bone were examined. Subchondral bone loss and increased subchondral bone norepinephrine level were observed in the CIS and UAC groups. These groups exhibited decreased bone mineral density, volume fraction, and bone formation rate; decreased expressions of osterix, collagen I, and osteocalcin; but increased trabecular separation, osteoclast number and surface, and RANKL expression. Combined CIS + UAC produced more severe subchondral bone loss, higher bone norepinephrine level, and decreased chondrocyte density and cartilage thickness when compared to CIS or UAC alone. Sympathectomy simultaneously prevented subchondral bone loss and decreased bone norepinephrine level in all experimental subgroups when compared to the vehicle-treated counterparts. Norepinephrine also decreased mRNA expression of osterix, collagen I, and osteocalcin by mesenchymal stem cells at 7 and 14 d of stimulation and increased the expression of RANKL and RANKL/OPG ratio by mesenchymal stem cells at 2 h. In conclusion, CIS and UAC synergistically promote condylar subchondral bone loss and cartilage degradation; such processes are partially regulated by norepinephrine within subchondral bone.

  19. Dextroamphetamine (but Not Atomoxetine Induces Reanimation from General Anesthesia: Implications for the Roles of Dopamine and Norepinephrine in Active Emergence.

    Directory of Open Access Journals (Sweden)

    Jonathan D Kenny

    Full Text Available Methylphenidate induces reanimation (active emergence from general anesthesia in rodents, and recent evidence suggests that dopaminergic neurotransmission is important in producing this effect. Dextroamphetamine causes the direct release of dopamine and norepinephrine, whereas atomoxetine is a selective reuptake inhibitor for norepinephrine. Like methylphenidate, both drugs are prescribed to treat Attention Deficit Hyperactivity Disorder. In this study, we tested the efficacy of dextroamphetamine and atomoxetine for inducing reanimation from general anesthesia in rats. Emergence from general anesthesia was defined by return of righting. During continuous sevoflurane anesthesia, dextroamphetamine dose-dependently induced behavioral arousal and restored righting, but atomoxetine did not (n = 6 each. When the D1 dopamine receptor antagonist SCH-23390 was administered prior to dextroamphetamine under the same conditions, righting was not restored (n = 6. After a single dose of propofol (8 mg/kg i.v., the mean emergence times for rats that received normal saline (vehicle and dextroamphetamine (1 mg/kg i.v. were 641 sec and 404 sec, respectively (n = 8 each. The difference was statistically significant. Although atomoxetine reduced mean emergence time to 566 sec (n = 8, this decrease was not statistically significant. Spectral analysis of electroencephalogram recordings revealed that dextroamphetamine and atomoxetine both induced a shift in peak power from δ (0.1-4 Hz to θ (4-8 Hz during continuous sevoflurane general anesthesia, which was not observed when animals were pre-treated with SCH-23390. In summary, dextroamphetamine induces reanimation from general anesthesia in rodents, but atomoxetine does not induce an arousal response under the same experimental conditions. This supports the hypothesis that dopaminergic stimulation during general anesthesia produces a robust behavioral arousal response. In contrast, selective noradrenergic stimulation

  20. Cutaneous vasoconstriction affects near-infrared spectroscopy determined cerebral oxygen saturation during administration of norepinephrine

    DEFF Research Database (Denmark)

    Sørensen, Niels Henrik Breiner; Secher, Niels H; Siebenmann, Christoph

    2012-01-01

    Perioperative optimization of spatially resolved near-infrared spectroscopy determined cerebral frontal lobe oxygenation (scO2) may reduce postoperative morbidity. Norepinephrine is routinely administered to maintain cerebral perfusion pressure and, thereby, cerebral blood flow, but norepinephrine...

  1. Norepinephrine transporter blocker atomoxetine increases salivary alpha amylase

    NARCIS (Netherlands)

    Warren, C.M.; van den Brink, R.L.; Nieuwenhuis, S.; Bosch, J.A.

    It has been suggested that central norepinephrine (NE) activity may be inferred from increases in salivary alpha-amylase (SAA), but data in favor of this proposition are limited. We administered 40mg of atomoxetine, a selective NE transporter blocker that increases central NE levels, to 24 healthy

  2. Selective serotonin reuptake inhibitor (SSRI antidepressants, prolactin and breast cancer

    Directory of Open Access Journals (Sweden)

    Janet eAshbury

    2012-12-01

    Full Text Available Selective serotonin reuptake inhibitors (SSRIs are a widely prescribed class of anti-depressants. Laboratory and epidemiologic evidence suggests that a prolactin-mediated mechanism secondary to increased serotonin levels at neuronal synapses could lead to a potentially carcinogenic effect of SSRIs. In this population-based case-control study, we evaluated the association between SSRI use and breast cancer risk as a function of their relative degree of inhibition of serotonin reuptake as a proxy for their impact on prolactin levels. Cases were 2,129 women with primary invasive breast cancer diagnosed from 2003-2007, and controls were 21,297 women randomly selected from the population registry. Detailed information for each SSRI prescription dispensed was compiled using the Saskatchewan prescription database. Logistic regression was used to evaluate the impact of use of high and lower inhibitors of serotonin reuptake and duration of use, as well as to assess the effect of individual high inhibitors on the risk of breast cancer. Exclusive users of high or lower inhibitors of serotonin reuptake were not at increased risk for breast cancer compared with nonusers of SSRIs (OR = 1.01, CI = 0.88-1.17 and OR = 0.91, CI = 0.67-1.25 respectively, regardless of their duration of use or menopausal status. While we cannot rule out the possibility of a clinically important risk increase (OR = 1.83, CI = 0.99-3.40 for long-term users of sertraline (≥24 prescriptions, given the small number of exposed cases (n=12, the borderline statistical significance and the wide confidence interval, these results need to be interpreted cautiously. In this large population-based case-control study, we found no conclusive evidence of breast cancer risk associated with the use of SSRIs even after assessing the degree of serotonin reuptake inhibition and duration of use. Our results do not support the serotonin-mediated pathway for the prolactin-breast cancer hypothesis.

  3. Can non-selective beta-blockers prevent hepatocellular carcinoma in patients with cirrhosis?

    DEFF Research Database (Denmark)

    Thiele, Maja; Wiest, Reiner; Gluud, Lise Lotte

    2013-01-01

    Hepatocellular carcinoma is the main liver-related cause of death in patients with compensated cirrhosis. The early phases are asymptomatic and the prognosis is poor, which makes prevention essential. We propose that non-selective beta-blockers decrease the incidence and growth of hepatocellular...... carcinoma via a reduction of the inflammatory load from the gut to the liver and inhibition of angiogenesis. Due to their effect on the portal pressure, non-selective beta-blockers are used for prevention of esophageal variceal bleeding. Recently, non-hemodynamic effects of beta-blockers have received...... reduce hepatic inflammation. Blockage of β-adrenoceptors also decrease angiogenesis by inhibition of vascular endothelial growth factors. Because gut-derived inflammation and neo-angiogenesis are important in hepatic carcinogenesis, non-selective beta-blockers can potentially reduce the development...

  4. Norepinephrine inhibits the migratory activity of pancreatic cancer cells.

    Science.gov (United States)

    Stock, Anna-Maria; Powe, Desmond G; Hahn, Stephan A; Troost, Gabriele; Niggemann, Bernd; Zänker, Kurt S; Entschladen, Frank

    2013-07-15

    We have shown previously that norepinephrine induces migratory activity of tumour cells from breast, colon and prostate tissue via activation of beta-2 adrenergic receptors. Consequently, this effect can be inhibited pharmacologically by clinically established beta-blockers. Tumour cell migration is a prerequisite for metastasis formation, and accordingly we and others have shown that breast cancer patients, which take beta-blockers due to hypertension, have reduced metastasis formation and increased survival probability as compared to patients without hypertension or using other anti-hypertensive medication. Unlike the aforementioned tumour cells, pancreatic cancer cells show a reduced migratory activity upon norepinephrine treatment. By means of our three-dimensional, collagen-based cell migration assay, we have investigated the signal transduction pathways involved in this phenomenon. We have found that this conflicting effect of norepinephrine on pancreatic cancer cells is due to an imbalanced activation of the two pathways that usually mediate a pro-migratory effect of norepinephrine in other tumour cell types. Firstly, the inhibitory effect results from activation of a pathway which causes a strong increase of the secondary cell signalling molecule, cAMP. In addition, activation of phospholipase C gamma and the downstream protein kinase C alpha were shown to be already activated in pancreatic cancer cells and cannot be further activated by norepinephrine. We hypothesize that this constitutive activation of the phospholipase C gamma pathway is due to a cross-talk with receptor tyrosine kinase signalling, and this might also deliver an explanation for the unusual high spontaneous migratory activity of pancreatic cancer cells. Copyright © 2013 Elsevier Inc. All rights reserved.

  5. Presynaptic α₂-adrenoceptors control the inhibitory action of presynaptic CB₁ cannabinoid receptors on prefrontocortical norepinephrine release in the rat.

    Science.gov (United States)

    Richter, Hardy; Teixeira, Filipe M; Ferreira, Samira G; Kittel, Ágnes; Köfalvi, Attila; Sperlágh, Beáta

    2012-10-01

    Endocannabinoids play a crucial neuromodulator role in both physiological and pathological states in various brain regions including the prefrontal cortex (PFC). We examined, whether presynaptic cannabinoid receptors are involved in the modulation of basal and electrical field stimulation-evoked [³H]norepinephrine ([³H]NE) release from rat PFC slices. WIN55,212-2, a nonselective CB₁ receptor (CB₁R) agonist, inhibited the electrical stimulation-evoked efflux of [³H]NE in a concentration-dependent fashion, which was antagonized by the CB₁R antagonist/inverse agonist, AM251 (1 μM). Idazoxan, a selective α₂-adrenoceptor antagonist, augmented the evoked [³H]NE release. In the presence of idazoxan, the effect of WIN55,212-2 was exacerbated or attenuated, depending on the applied concentration and stimulation frequency. Moreover their combined, but not individual application elicited a depressive-like phenomenon in the forced-swim test. These data were bolstered with fluorescent and confocal microscopy analysis, which revealed that CB₁R immunoreactivity co-localized with dopamine-β-hydroxylase positive (i.e. noradrenergic) fibers and the inhibitory α(2A) adrenergic autoreceptors (α(2A)R) in the PFC. Furthermore, idazoxan triggered a decrease in CB₁R density in the PFC, suggesting that high extracellular level of norepinephrine downregulates CB₁Rs.

  6. Non-selective β-blockers do not affect mortality in cirrhosis patients with ascites

    DEFF Research Database (Denmark)

    Bossen, Lars; Krag, Aleksander; Vilstrup, Hendrik

    2016-01-01

    The safety of non-selective β-blockers (NSBBs) in advanced cirrhosis has been questioned. We used data from three satavaptan trials to examine whether NSBBs increase mortality in cirrhosis patients with ascites. The trials were conducted in 2006-2008 and included 1198 cirrhosis patients with asci...

  7. Non-selective beta-blockers decrease thrombotic events in patients with heart failure

    NARCIS (Netherlands)

    De Peuter, Olav R.; Souverein, Patrick C.; Klungel, Olaf H.; Lip, Gregory Y.; Buller, Harry R.; De Boer, Anthonius; Kamphuisen, Pieter W.

    2010-01-01

    Background: Beta-blockers are often prescribed to patients with heart failure (HF) without distinctions between types of beta-blockers. The 2002 COMET study showed superiority of carvedilol (a non-selective beta-blocker) over metoprolol (selective beta-blocker) on mortality and cardiovascular events

  8. Memory Outcomes Following Selective versus Nonselective Temporal Lobe Removal: A Systematic Review

    Science.gov (United States)

    Girgis, Fady

    2012-01-01

    The surgical removal of brain tissue for the treatment of temporal lobe epilepsy can be either nonselective, as with an anterior temporal lobectomy (ATL), or selective, as with a selective amygdalohippocampectomy (SAH). Although seizure outcomes are similar with both procedures, cognitive and memory outcomes remain a matter of debate. This study…

  9. Nonselective Harvesting of a Prey-Predator Fishery with Gompertz Law of Growth

    Science.gov (United States)

    Purohit, D.; Chaudhuri, K. S.

    2002-01-01

    This paper develops a mathematical model for the nonselective harvesting of a prey-predator system in which both the prey and the predator obey the Gompertz law of growth and some prey avoid predation by hiding. The steady states of the system are determined, and the dynamical behaviour of both species is examined. The possibility of existence of…

  10. Serotonin synthesis, release and reuptake in terminals: a mathematical model

    Directory of Open Access Journals (Sweden)

    Best Janet

    2010-08-01

    Full Text Available Abstract Background Serotonin is a neurotransmitter that has been linked to a wide variety of behaviors including feeding and body-weight regulation, social hierarchies, aggression and suicidality, obsessive compulsive disorder, alcoholism, anxiety, and affective disorders. Full understanding of serotonergic systems in the central nervous system involves genomics, neurochemistry, electrophysiology, and behavior. Though associations have been found between functions at these different levels, in most cases the causal mechanisms are unknown. The scientific issues are daunting but important for human health because of the use of selective serotonin reuptake inhibitors and other pharmacological agents to treat disorders in the serotonergic signaling system. Methods We construct a mathematical model of serotonin synthesis, release, and reuptake in a single serotonergic neuron terminal. The model includes the effects of autoreceptors, the transport of tryptophan into the terminal, and the metabolism of serotonin, as well as the dependence of release on the firing rate. The model is based on real physiology determined experimentally and is compared to experimental data. Results We compare the variations in serotonin and dopamine synthesis due to meals and find that dopamine synthesis is insensitive to the availability of tyrosine but serotonin synthesis is sensitive to the availability of tryptophan. We conduct in silico experiments on the clearance of extracellular serotonin, normally and in the presence of fluoxetine, and compare to experimental data. We study the effects of various polymorphisms in the genes for the serotonin transporter and for tryptophan hydroxylase on synthesis, release, and reuptake. We find that, because of the homeostatic feedback mechanisms of the autoreceptors, the polymorphisms have smaller effects than one expects. We compute the expected steady concentrations of serotonin transporter knockout mice and compare to

  11. [Selective serotonine reuptake inhibitors (SSRI) in the treatment of paraphilia].

    Science.gov (United States)

    Kraus, C; Strohm, K; Hill, A; Habermann, N; Berner, W; Briken, P

    2007-06-01

    For about 15 years selective serotonine reuptake inhibitors (SSRI) have been used in the treatment of paraphilias. In an open, uncontrolled, retrospective study, which was the first in the German speaking countries we investigated 16 male outpatients, who have been treated for different paraphilias with SSRI and psychotherapy. There was a marked reduction in paraphilic symptoms. Despite high rates of sexual side effects most patients reported a high overall treatment satisfaction. SSRI are an important addition in pharmacological treatment of paraphilic patients, especially with a risk of so called "hands-off" delinquency.

  12. Norepinephrine as a Potential Aggravator of Symptomatic Cerebral Vasospasm: Two Cases and Argument for Milrinone Therapy

    Directory of Open Access Journals (Sweden)

    F. A. Zeiler

    2014-01-01

    Full Text Available Background. During hypertensive therapy for post-subarachnoid hemorrhage (SAH symptomatic vasospasm, norepinephrine is commonly used to reach target blood pressures. Concerns over aggravation of vasospasm with norepinephrine exist. Objective. To describe norepinephrine temporally related deterioration in neurological examination of two post-SAH patients in vasospasm. Methods. We retrospectively reviewed two charts of patients with delayed cerebral ischemia (DCI post-SAH who deteriorated with norepinephrine infusions. Results. We identified two patients with DCI post-SAH who deteriorated during hypertensive therapy with norepinephrine. The first, a 43-year-old male presented to hospital with DCI, failed MABP directed therapy with rapid deterioration in exam with high dose norepinephrine and MABP of 140–150 mm Hg. His exam improved on continuous milrinone and discontinuation of norepinephrine. The second, a 39-year-old female who developed DCI on postbleed day 8 responded to milrinone therapy upfront. During further deterioration and after angioplasty, norepinephrine was utilized to drive MABP to 130–140 mm Hg. Progressive deterioration in examination occurred after angioplasty as norepinephrine doses escalated. After discontinuation of norepinephrine and continuation of milrinone, function dramatically returned but not to baseline. Conclusions. The potential exists for worsening of DCI post-SAH with hypertensive therapy directed by norepinephrine. A potential role exists for vasodilation and inotropic directed therapy with milrinone in the setting of DCI post-SAH.

  13. [Adrenergic innervation and norepinephrine content in postnatal rat uterus].

    Science.gov (United States)

    Itoh, M

    1983-03-01

    Using fluorescent histochemical method and high performance liquid chromatography with electrochemical detector, we investigated adrenergic innervation and norepinephrine content in the rat uterus in the process of the growth. The adrenergic nerve terminals in the rat uterus developed with age and reached to adult level at 7 weeks of age after birth, although the short adrenergic ganglionic cells and small intense fluorescent cells were present even at birth. Norepinephrine content per organ also increased with age and reached to adult level at 10 weeks of age after birth, while NE content per gram wet tissue weight had a peak in 3-day-old rat uterus. These morphological and biochemical data revealed that the sympathetic nervous system in rat uterus matures in 7 to 10 weeks after birth, while the short adrenergic nervous system is accomplished in earlier stage. The maturation of adrenergic innervation in the uterus was considerably later than in the other organs of rat and developed with the sexual maturation.

  14. Norepinephrine and octopamine: linking stress and immune function across phyla

    Directory of Open Access Journals (Sweden)

    SA Adamo

    2008-02-01

    Full Text Available In species from three widely divergent phyla (Arthropoda, Mollusca and Chordata tyrosine derivatives (norepinephrine or octopamine mediate a response to acute stress. Part of this response is a change in immune function that results in a decrease in resistance to pathogens. This decrease in disease resistance appears maladaptive. However, if the connections between norepinephrine/octopamine and immune function were maladaptive, they should have been selected against. None of the four commonly proposed adaptive explanations for acute stress-induced changes in immune function fit the available data for species from all three phyla. However, this result is probably due to the lack of information about acute stress-induced immunosuppression in invertebrates and a lack of ecologically valid studies in vertebrates. Understanding why immune function and disease resistance changes during acute stress will require greater comparative study.

  15. Beta blockers, norepinephrine, and cancer: an epidemiological viewpoint

    OpenAIRE

    2012-01-01

    Paul J FitzgeraldThe Zanvyl Krieger Mind/Brain Institute, Solomon H Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, MD, USAAbstract: There is growing evidence that the neurotransmitter norepinephrine (NE) and its sister molecule epinephrine (EPI) (adrenaline) affect some types of cancer. Several recent epidemiological studies have shown that chronic use of beta blocking drugs (which antagonize NE/EPI receptors) results in lower recurrence, progression, or mortality of ...

  16. Teratogenic effects of mescaline, epinephrine, and norepinephrine in the hamster.

    Science.gov (United States)

    Hirsch, K S; Fritz, H I

    1981-06-01

    Mescaline was administered orally at doses of 16 and 32 mg/kg on the seventh through tenth days of gestation to pregnant cream-strain hamsters. This treatment resulted in a dose-dependent effect on reproductive success and skeletal ossification. The effect of mescaline on reproductive success included an increased number of resorptions resulting in a decreased litter size. The 32 mg/kg dose of mescaline caused 48.8% resorptions, while 16 mg/kg and control animals had 12.0% and 6.4% resorptions, respectively. Litter size was decreased from 12.0 pups in controls to 10.3 (16 mg/kg) and 6.5 (32 mg/kg) pups per litter in treated groups. No gross abnormalities were observed at necropsy; there was, however, a dose-dependent increased delay in the ossification of the skull, sternum, and metatarsals. Both epinephrine and norepinephrine caused a decrease in reproductive success when administered at 500 micrograms/kg. Epinephrine appeared to cause a trend toward preimplantation wastage as indicated by an increased corpora lutea to implantation site ratio (from 1.3-1.9). Norepinephrine, however, caused an increased number of resorptions (29.1% in controls). Both norepinephrine and epinephrine produced similar delays in ossification.

  17. Mechanisms of immune regulation by norepinephrine and cholera toxin

    Energy Technology Data Exchange (ETDEWEB)

    Campbell, K.S.

    1988-01-01

    Norepinephrine has previously been demonstrated by this laboratory to potentiate the in vitro T-dependent antibody response through the stimulation of {beta}-adrenergic receptors. The role of {beta}-adrenergic receptor subtypes in norepinephrine-induced potentiation of the antibody responses was examined with selective {beta}-adrenergic antagonists. The antagonists were metoprolol ({beta}{sub 1}-selective), ICI 118-551 ({beta}{sub 2}-selective), and propranolol ({beta}-non-selective). Both propranolol and ICI 118-551 blocked norepinephrine-induced potentiation of the antibody response, but metoprolol was ineffective. Receptor binding competition of antagonists with the radioligant, ({sup 3}H)CGP-12177 was examined and results were analyzed with the computer program, LIGAND. Competition by ICI 118-551 identified 75% {beta}{sub 2}- and 25% {beta}{sub 1}-adrenergic receptors on splenic mononuclear cells. Enriched T lymphocytes exhibited 75% {beta}{sub 2}-adrenergic receptors, while enriched B lymphocytes contained 90% {beta}{sub 2}-adrenergic receptors as identified by ICI 118-551. Greater than twice as many total receptors were identified on B lymphocytes than T lymphocytes. A T cell lymphoma contained about 60% {beta}{sub 2}-receptors, while 100% were {beta}{sub 2} receptors on a B cell lymphoma, as assessed by ICI 118-551. Results support a heterogeneous {beta}-adrenergic receptor population on T lymphocytes and a more homogeneous {beta}{sub 2}-population on B lymphocytes.

  18. Fractal analysis of striatal dopamine re-uptake sites

    Energy Technology Data Exchange (ETDEWEB)

    Kuikka, J.T.; Bergstroem, K.A. [Department of Clinical Physiology, Kuopio University Hospital, Kuopio (Finland); Tiihonen, J.; Raesaenen, P. [Department of Forensic Psychiatry, University of Kuopio and Niuvanniemi Hospital, Kuopio (Finland); Karhu, J. [Department of Clinical Neurophysiology, Kuopio University Hospital, Kuopio (Finland)

    1997-09-01

    Spatial variation in regional blood flow, metabolism and receptor density within the brain and in other organs is measurable even with a low spatial resolution technique such as emission tomography. It has been previously shown that the observed variance increases with increasing number of subregions in the organ/tissue studied. This resolution-dependent variance can be described by fractal analysis. We studied striatal dopamine re-uptake sites in 39 healthy volunteers with high-resolution single-photon emission tomography using iodine-123 labelled 2{beta}-carbomethoxy-3{beta}-(4-iodophenyl)tropane ([{sup 123}I]{beta}-CIT). The mean fractal dimension was 1.15{+-}0.07. The results indicate that regional striatal dopamine re-uptake sites involve considerable spatial heterogeneity which is higher than the uniform density (dimension=1.00) but much lower than complete randomness (dimension=1.50). There was a gender difference, with females having a higher heterogeneity in both the left and the right striatum. In addition, we found striatal asymmetry (left-to-right heterogeneity ratio of 1.19{+-}0.15; P<0.001), suggesting functional hemispheric lateralization consistent with the control of motor behaviour and integrative functions. (orig.). With 5 figs., 1 tab.

  19. Research progress in monoamine transporters and monoamine transmitter reuptake inhibitors%单胺转运蛋白与单胺重摄取抑制剂研究进展

    Institute of Scientific and Technical Information of China (English)

    张亭亭; 薛瑞; 李云峰; 洪浩; 张有志

    2013-01-01

    Presynaptic membrane serotonin transporters ( SERT ) and norepinephrine transporter ( NET ), which are important neurotransmitter transporters, are responsible for reuptake of released serotonin ( 5-HT ) and norepinephrine ( NE ), respectively. The major function of these transporters is to terminate monoamine transmission by mediating uptake of neurotransmitters from extracellular space into neurons and glial cells. Drugs that inhibit the activity of monoamine transporters produce increased neurotransmitter levels in the synaptic cleft, leading to their therapeutic use in depression. As SERT and NET are pharmacological targets for most antidepressants, understanding about the molecular pharmacology of these transporters, including their localization and function, molecular structure and regulation, as well as drug binding sites and mechanism of action, is important to new antidepressant development.%5-羟色胺转运蛋白(serotonin transporter,SERT)和去甲肾上腺素转运蛋白(norepinephrine transporter,NET)是单胺类神经递质转运体,其功能是将释放到突触间隙的5-羟色胺(serotonin,5-HT)和去甲肾上腺素(norepinephrine,NE)分别转运入突触前神经细胞,以终止相应的突触信号传递.SERT、NET抑制剂可阻断5-HT和NE的重摄取,提高突触间隙单胺递质水平,从而发挥抗抑郁效应.SERT、NET作为主流抗抑郁药物的作用靶标,了解其分布与功能、分子结构和活性调节因素,以及单胺重摄取抑制剂的作用机制对抗抑郁药物研发及应用具有重要意义.

  20. Neuronal monoamine reuptake inhibitors enhance in vitro susceptibility to chloroquine in resistant Plasmodium falciparum.

    OpenAIRE

    Coutaux, A F; Mooney, J. J.; Wirth, D. F.

    1994-01-01

    Chloroquine resistance in Plasmodium falciparum was reversed in vitro by the neuronal monoamine reuptake inhibitors and antidepressants desipramine, sertraline, fluoxetine, and norfluoxetine but not by carbamazepine, an antiseizure and mood-stabilizing tricyclic drug resembling desipramine which only weakly inhibits neuronal monoamine reuptake. These findings have important clinical implications for drug combination therapy.

  1. Hopf Bifurcation Analysis of a Predator-Prey Biological Economic System with Nonselective Harvesting

    OpenAIRE

    Biwen Li; Zhenwei Li; Boshan Chen; Gan Wang

    2015-01-01

    A modified predator-prey biological economic system with nonselective harvesting is investigated. An important mathematical feature of the system is that the economic profit on the predator-prey system is investigated from an economic perspective. By using the local parameterization method and Hopf bifurcation theorem, we analyze the Hopf bifurcation of the proposed system. In addition, the modified model enriches the database for the predator-prey biological economic system. Finally, numeric...

  2. Reaching Hard-to-Reach Individuals: Nonselective Versus Targeted Outbreak Response Vaccination for Measles

    OpenAIRE

    2013-01-01

    Current mass vaccination campaigns in measles outbreak response are nonselective with respect to the immune status of individuals. However, the heterogeneity in immunity, due to previous vaccination coverage or infection, may lead to potential bias of such campaigns toward those with previous high access to vaccination and may result in a lower-than-expected effective impact. During the 2010 measles outbreak in Malawi, only 3 of the 8 districts where vaccination occurred achieved a measureabl...

  3. [Galactorrhoea and the use of selective serotonin reuptake inhibitors].

    Science.gov (United States)

    Wessels-van Middendorp, A M; Timmerman, L

    2006-01-01

    The subject of this case study is a female patient who was treated with a selective serotonin reuptake inhibitor (SSRI), citalopram, because of a depressive episode. She developed symptoms of galactorrhea; there was a time relationship between suspension of the treatment with citalopram and a reduction of the galactorrhea symptoms. The consulting internist assumed that the symptoms were due to hyperprolactinemia arising from under-supplementation of thyroid hormone and resultant hypothyroidism. Psychiatrists usually see galactorrhea in patients who are taking antipsychotics. However, few psychiatrists know that galactorrhea can also be caused by SSRIs. When a patient has symptoms of bilateral galactorrhea and has used an SSRI and when hyperprolactinemia has been found in laboratory tests it is probably advisable to stop the SSRI medication. The article mentions what additional research is needed.

  4. Altered reward circuitry in the norepinephrine transporter knockout mouse.

    Directory of Open Access Journals (Sweden)

    Joseph J Gallagher

    Full Text Available Synaptic levels of the monoamine neurotransmitters dopamine, serotonin, and norepinephrine are modulated by their respective plasma membrane transporters, albeit with a few exceptions. Monoamine transporters remove monoamines from the synaptic cleft and thus influence the degree and duration of signaling. Abnormal concentrations of these neuronal transmitters are implicated in a number of neurological and psychiatric disorders, including addiction, depression, and attention deficit/hyperactivity disorder. This work concentrates on the norepinephrine transporter (NET, using a battery of in vivo magnetic resonance imaging techniques and histological correlates to probe the effects of genetic deletion of the norepinephrine transporter on brain metabolism, anatomy and functional connectivity. MRS recorded in the striatum of NET knockout mice indicated a lower concentration of NAA that correlates with histological observations of subtle dysmorphisms in the striatum and internal capsule. As with DAT and SERT knockout mice, we detected minimal structural alterations in NET knockout mice by tensor-based morphometric analysis. In contrast, longitudinal imaging after stereotaxic prefrontal cortical injection of manganese, an established neuronal circuitry tracer, revealed that the reward circuit in the NET knockout mouse is biased toward anterior portions of the brain. This is similar to previous results observed for the dopamine transporter (DAT knockout mouse, but dissimilar from work with serotonin transporter (SERT knockout mice where Mn(2+ tracings extended to more posterior structures than in wildtype animals. These observations correlate with behavioral studies indicating that SERT knockout mice display anxiety-like phenotypes, while NET knockouts and to a lesser extent DAT knockout mice display antidepressant-like phenotypic features. Thus, the mainly anterior activity detected with manganese-enhanced MRI in the DAT and NET knockout mice is likely

  5. Neuromodulatory influence of norepinephrine during developmental experience-dependent plasticity.

    Science.gov (United States)

    Golovin, Randall M; Ward, Nicholas J

    2016-07-01

    Critical periods represent phases of development during which neuronal circuits and their responses can be readily shaped by stimuli. Experience-dependent plasticity that occurs within these critical periods can be influenced in many ways; however, Shepard et al. (J Neurosci 35: 2432-2437, 2015) recently singled out norepinephrine as an essential driver of this plasticity within the auditory cortex. This work provides novel insight into the mechanisms of critical period plasticity and challenges previous conceptions that a functional redundancy exists between noradrenergic and cholinergic influences on cortical plasticity.

  6. Comparison of the neurobiological effects of attribution retraining group therapy with those of selective serotonin reuptake inhibitors

    Directory of Open Access Journals (Sweden)

    C. Wang

    Full Text Available The aim of this study was to compare the effectiveness of attribution retraining group therapy (ARGT with selective serotonin reuptake inhibitors (SSRIs in the treatment of major depressive disorder (MDD, generalized anxiety disorder (GAD, and obsessive-compulsive disorder (OCD. Subjects were sequentially recruited and randomized into two groups, one receiving ARGT (n = 63 and the other SSRIs (n = 66 for 8 weeks. Fifty-four ARGT outpatients with MDD (n = 19, GAD (n = 19, and OCD (n = 16 and 55 SSRI outpatients with MDD (n = 19, GAD (n = 19, and OCD (n = 17 completed the study. All subjects were assessed using the Hamilton Depression Scale and Hamilton Anxiety Scale before and after treatment. The 10-item Yale-Brown Obsessive Compulsive Scale was employed only for OCD subjects. Plasma levels of serotonin, norepinephrine, cortisol, and adrenocorticotropic hormone were also measured at baseline and 8 weeks after completion of treatment. Symptom scores were significantly reduced (P < 0.001 in both the ARGT and SSRI groups at the end of treatment. However, MDD, GAD and OCD patients in the ARGT group had significantly lower plasma cortisol concentrations compared to baseline (P < 0.05, whereas MDD and OCD patients receiving SSRIs showed significantly increased plasma levels of serotonin (P < 0.05. These findings suggest that ARGT may modulate plasma cortisol levels and affect the hypothalamus-pituitary-adrenal axis as opposed to SSRIs, which may up-regulate plasma serotonin levels via a different pathway to produce an overall improvement in the clinical condition of the patients.

  7. Comparison of the neurobiological effects of attribution retraining group therapy with those of selective serotonin reuptake inhibitors

    Directory of Open Access Journals (Sweden)

    C. Wang

    2013-03-01

    Full Text Available The aim of this study was to compare the effectiveness of attribution retraining group therapy (ARGT with selective serotonin reuptake inhibitors (SSRIs in the treatment of major depressive disorder (MDD, generalized anxiety disorder (GAD, and obsessive-compulsive disorder (OCD. Subjects were sequentially recruited and randomized into two groups, one receiving ARGT (n = 63 and the other SSRIs (n = 66 for 8 weeks. Fifty-four ARGT outpatients with MDD (n = 19, GAD (n = 19, and OCD (n = 16 and 55 SSRI outpatients with MDD (n = 19, GAD (n = 19, and OCD (n = 17 completed the study. All subjects were assessed using the Hamilton Depression Scale and Hamilton Anxiety Scale before and after treatment. The 10-item Yale-Brown Obsessive Compulsive Scale was employed only for OCD subjects. Plasma levels of serotonin, norepinephrine, cortisol, and adrenocorticotropic hormone were also measured at baseline and 8 weeks after completion of treatment. Symptom scores were significantly reduced (P < 0.001 in both the ARGT and SSRI groups at the end of treatment. However, MDD, GAD and OCD patients in the ARGT group had significantly lower plasma cortisol concentrations compared to baseline (P < 0.05, whereas MDD and OCD patients receiving SSRIs showed significantly increased plasma levels of serotonin (P < 0.05. These findings suggest that ARGT may modulate plasma cortisol levels and affect the hypothalamus-pituitary-adrenal axis as opposed to SSRIs, which may up-regulate plasma serotonin levels via a different pathway to produce an overall improvement in the clinical condition of the patients.

  8. The novel trisubstituted pyran derivative D-142 has triple monoamine reuptake inhibitory activity and exerts potent antidepressant-like activity in rodents

    Science.gov (United States)

    Dutta, Aloke K.; Gopishetty, Bhaskar; Gogoi, Sanjib; Ali, Solav; Zhen, Juan; Reith, Maarten

    2011-01-01

    Major depression disorder is a significant health problem with 10-20% of all adults suffering from this disease. The underlying causes of depression are still unclear and 15% of depressed patients are resistant to all known therapies. Monoamine therapies have so far been the most successful approach for treating depression. Triple monoamine reuptake inhibitors have recently been implicated in generation of potent antidepressant activity while possibly exhibiting a low side-effect profile in addition to treating anhedonia. The additional, previously under-appreciated involvement of dopaminergic systems in depression prompted our efforts to develop novel asymmetric trisubstituted and disubstituted pyran derivatives as triple reuptake inhibitors. One of the lead compounds, D-142, exhibited uptake inhibition (Ki) values of 29.3 nM, 14.7 nM and 37.4 nM for norepinephrine, serotonin and dopamine transporters, respectively. Its affinity for serotonin transporter was comparable to fluoxetine , a well known SSRI. In the rat forced swimming test, compound D-142 exhibited potent antidepressant activity in the dose range tested (2.5, 5 and 10 mg/kg) and was far more efficacious than the reference compound imipramine. In the mouse tail suspension test, compound D-142 reduced immobility in a dose (2.5, 5 and 10 mg/kg) dependent manner, indicating a potent antidepressant effect. In locomotor activity tests, compound D-142 did not exhibit any stimulation in the same dose ranges. In the extended CNS receptors screening assay this molecule exhibited little or no non-specific interaction in the CNS, indicating high specificity for monoamine transporters. These results advance D-142 as a potential potent antidepressant. PMID:21963455

  9. Efficacy outcomes from 3 clinical trials of edivoxetine as adjunctive treatment for patients with major depressive disorder who are partial responders to selective serotonin reuptake inhibitor treatment.

    Science.gov (United States)

    Ball, Susan G; Ferguson, Margaret B; Martinez, James M; Pangallo, Beth A; Nery, E Serap Monkul; Dellva, Mary Anne; Sparks, JonDavid; Zhang, Qi; Liu, Peng; Bangs, Mark; Goldberger, Celine

    2016-05-01

    Three studies examined whether edivoxetine (a highly selective norepinephrine reuptake inhibitor) had efficacy as adjunctive therapy for patients with major depressive disorder (DSM-IV-TR) who were partial responders to selective serotonin reuptake inhibitor (SSRI) treatment of at least 6 weeks' duration. Studies were 8-week randomized, placebo-controlled trials with a 3-week double-blind placebo lead-in phase, conducted from December 16, 2010, to October 21, 2013. Patients entered the double-blind adjunctive treatment phase if they met randomization criteria (Depression Rating Scale [MADRS] and MADRS total score ≥ 14); patients not randomized remained on adjunctive placebo. Study 1 compared fixed-dose edivoxetine (12 or 18 mg daily) + SSRI (N = 231 and N = 230, respectively) with placebo + SSRI (N = 240); study 2 compared flexible-dose edivoxetine (12-18 mg daily) + SSRI (N = 232) and fixed-dose edivoxetine (6 mg daily) + SSRI (N = 226) with placebo + SSRI (N = 231); and study 3 compared flexible-dose edivoxetine (12-18 mg daily) + SSRI (N = 230) with placebo + SSRI (N = 219). The primary outcome was mean change from randomization baseline to week 8 in MADRS total score, analyzed using repeated measures analysis. Each trial failed to meet the primary and most of the secondary objectives. The least-squares mean changes in MADRS total score were as follows-study 1: -8.5 (edivoxetine 12 mg + SSRI), -8.7 (edivoxetine 18 mg + SSRI), and -7.8 (placebo + SSRI); study 2: -9.4 (edivoxetine 12-18 mg + SSRI), -9.6 (edivoxetine 6 mg + SSRI), and -9.4 (placebo + SSRI); and study 3: -8.7 (edivoxetine 12-18 mg + SSRI) and -8.5 (placebo + SSRI). Adjunctive edivoxetine treatment for patients with major depressive disorder who were partial responders to SSRIs did not significantly improve efficacy outcomes. ClinicalTrials.gov identifiers: NCT01173601, NCT01187407, NCT01185340. © Copyright 2016 Physicians Postgraduate Press, Inc.

  10. Maitotoxin activates a nonselective cation channel and stimulates Ca2+ entry in MDCK renal epithelial cells.

    Science.gov (United States)

    Dietl, P; Völkl, H

    1994-02-01

    We examined the mechanisms of maitotoxin (MTX), a water-soluble polyether from the marine dinoflagellate Gambierdiscus toxicus, in stimulation of Ca2+ entry into Mardin-Darby canine kidney cells. In the presence of bath Ca2+, MTX (3 nM) caused an elevation of the intracellular calcium concentration ([Ca2+]i), which was partially inhibited by SK&F 96365 (25 microM) or La3+ (100 microM). A stimulation of Ca(2+)-dependent K+ channels in cell-attached membrane patches coincided with this rise in [Ca2+]i and was also partially inhibited by SK&F 96365. Before the rise in [Ca2+]i, a nonselective cation current (Ins), studied by the whole-cell patch-clamp technique, was irreversibly activated. Ins poorly discriminated between Na+, K+, and Cs+, was unaffected by replacement of Cl- with gluconate-, and was not voltage gated. MTX-induced Ins was partially blocked by La3+ ions (100 microM) but not by SK&F 96365 (25 microM) or nifedipine (10 microM). SK&F 96365 by itself induced a small but significant stimulation of Ins and a rise in [Ca2+]i. The activation of Ins by MTX was instantaneous and depended on the presence of extracellular Ca2+ ions. In the absence of other cations, the inward current of Ins was dependent on the bath Ca2+ concentration. Cell-attached and excised single-channel measurements revealed that MTX activated a SK&F 96365-insensitive, approximately 40-pS, nonselective cation channel from the outside. We conclude that the initial action of MTX is the stimulation of a nonselective cation channel, which requires the presence of extracellular Ca2+ ions. The subsequent rise in [Ca2+]i is at least in part caused by another, SK&F 96365-sensitive, Ca2+ entry pathway, which may be activated as a result of or independently of Ins.

  11. How to sell successfully a perfume in the non-selective market?

    OpenAIRE

    Ramalho, Maria Rita Pinto Coelho de Magalhães

    2009-01-01

    A Work Project, presented as part of the requirements for the Award of a Masters Degree in Management from the NOVA – School of Business and Economics This document presents a market research on the positioning of perfumes in the non selective market. This project’s main goal had been to analyze the challenge of “successfully selling a perfume in the non-selective market” in order to propose potential solutions. To address this marketing problem, an exploratory research had been c...

  12. 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)

  13. Norepinephrine stimulates progesterone production in highly estrogenic bovine granulosa cells cultured under serum-free, chemically defined conditions

    Directory of Open Access Journals (Sweden)

    Piccinato Carla A

    2012-11-01

    Full Text Available Abstract Background Since noradrenergic innervation was described in the ovarian follicle, the actions of the intraovarian catecholaminergic system have been the focus of a variety of studies. We aimed to determine the gonadotropin-independent effects of the catecholamine norepinephrine (NE in the steroid hormone profile of a serum-free granulosa cell (GC culture system in the context of follicular development and dominance. Methods Primary bovine GCs were cultivated in a serum-free, chemically defined culture system supplemented with 0.1% polyvinyl alcohol. The culture features were assessed by hormone measurements and ultrastructural characteristics of GCs. Results GCs produced increasing amounts of estradiol and pregnenolone for 144h and maintained ultrastructural features of healthy steroidogenic cells. Progesterone production was also detected, although it significantly increased only after 96h of culture. There was a highly significant positive correlation between estradiol and pregnenolone production in high E2-producing cultures. The effects of NE were further evaluated in a dose–response study. The highest tested concentration of NE (10 (−7 M resulted in a significant increase in progesterone production, but not in estradiol or pregnenolone production. The specificity of NE effects on progesterone productio n was further investigated by incubating GCs with propranolol (10 (−8 M, a non-selective beta-adrenergic antagonist. Conclusions The present culture system represents a robust model to study the impact of intrafollicular factors, such as catecholamines, in ovarian steroidogenesis and follicular development. The results of noradrenergic effects in the steroidogenesis of GC have implications on physiological follicular fate and on certain pathological ovarian conditions such as cyst formation and anovulation.

  14. The brain norepinephrine system, stress and cardiovascular vulnerability.

    Science.gov (United States)

    Wood, Susan K; Valentino, Rita J

    2017-03-01

    Chronic exposure to psychosocial stress has adverse effects on cardiovascular health, however the stress-sensitive neurocircuitry involved remains to be elucidated. The anatomical and physiological characteristics of the locus coeruleus (LC)-norepinephrine (NE) system position it to contribute to stress-induced cardiovascular disease. This review focuses on cardiovascular dysfunction produced by social stress and a major theme highlighted is that differences in coping strategy determine individual differences in social stress-induced cardiovascular vulnerability. The establishment of different coping strategies and cardiovascular vulnerability during repeated social stress has recently been shown to parallel a unique plasticity in LC afferent regulation, resulting in either excitatory or inhibitory input to the LC. This contrasting regulation of the LC would translate to differences in cardiovascular regulation and may serve as the basis for individual differences in the cardiopathological consequences of social stress. The advances described suggest new directions for developing treatments and/or strategies for decreasing stress-induced cardiovascular vulnerability.

  15. Guidelines for Homology Modeling of Dopamine, Norepinephrine, and Serotonin Transporters.

    Science.gov (United States)

    Haddad, Yazan; Heger, Zbynek; Adam, Vojtech

    2016-11-16

    The human dopamine, norepinephrine, and serotonin transporters (hDAT, hNET, and hSERT) are carriers of neurotransmitters and targets for many drugs. Pioneering works in the past three years to elucidate experimental models of the Drosophila dDAT and human hSERT structures will rapidly impact the field of neuroscience. Here, we evaluated automated homology-based human models of these transporters, employing systematic physics-based, knowledge-based, and empirical-based check. Modeling guidelines were conveyed with attention to the central binding site (S1), secondary binding site (S2), and the extracellular loops EL2 and EL4. Application of new experimental models (dDAT and hSERT) will improve the accuracy of homology models, previously utilizing prokaryotic leucine transporter (LeuT) structure, and provide better predictions of ligand interactions, which is required for understanding of cellular mechanisms and for development of novel therapeutics.

  16. Norepinephrine spillover from skeletal muscle during exercise in humans

    DEFF Research Database (Denmark)

    Savard, G K; Richter, Erik; Strange, S

    1989-01-01

    The purpose of this study was to determine the effect of increasing muscle mass involvement in dynamic exercise on both sympathetic nervous activation and local hemodynamic variables of individual active and inactive skeletal muscle groups. Six male subjects performed 15-min bouts of one...... in both legs. Arterial and venous plasma concentrations of norepinephrine (NE) and epinephrine were analyzed, and the calculated NE spillover was used as an index of sympathetic nervous activity to the limb. NE spillover increased gradually both in the resting, and to a larger extent in the exercising...... legs, with a steeper rise occurring approximately 70% VO2max. These increases were not associated with any significant changes in leg blood flow or leg vascular conductance at the exercise intensities examined. These results suggest that, as the total active muscle mass increases, the rise...

  17. Modification of proteins by norepinephrine is important for vascular contraction

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    Kyle B Johnson

    2010-10-01

    Full Text Available Norepinephrine (NE is thought to mediate its effects through G-protein coupled receptors. However, previous studies have shown that norepinephrine and another primary amine, serotonin, also have the ability to exert effects in a receptor-independent manner. We hypothesized that the enzyme transglutaminase II (TG II has the ability modify proteins with NE and that this modification is physiologically relevant. As our model we used rat aortic and vena cava tissues, two tissues that depend on NE to modulate vascular tone. Immunohistochemical and immunocytochemical staining showed that NE and TG II are present in smooth muscle cells of these tissues. Western analysis shows aorta and vena cava homogenate proteins are recognized by an anti-NE antibody. NE and α-actin colocalize in cultured aorta and vena cava smooth muscle cells. Freshly dissociated smooth muscle cells from these vessels were able to take up NE-biotin. In isolated tissue baths, inhibition of TG II with cystamine (0.5 mM completely abolished NE-induced contraction in the aorta but only attenuated the receptor-independent contractant KCl (max contraction to 100 mM KCl in cystamine treated = 88.8 ± 7.5% of vehicle treated, p<0.05. In the vena cava, contraction to NE was abolished with 0.1 mM cystamine and KCl contraction was attenuated (max contraction to 100 mM KCl in cystamine treated = 54.8 ± 21.2% of vehicle treated, p<0.05. Taken together, these results show that vascular smooth muscle cells take up and utilize NE for the modification of proteins, and that this modification may play an important role in vascular contraction.

  18. Reaching hard-to-reach individuals: Nonselective versus targeted outbreak response vaccination for measles.

    Science.gov (United States)

    Minetti, Andrea; Hurtado, Northan; Grais, Rebecca F; Ferrari, Matthew

    2014-01-15

    Current mass vaccination campaigns in measles outbreak response are nonselective with respect to the immune status of individuals. However, the heterogeneity in immunity, due to previous vaccination coverage or infection, may lead to potential bias of such campaigns toward those with previous high access to vaccination and may result in a lower-than-expected effective impact. During the 2010 measles outbreak in Malawi, only 3 of the 8 districts where vaccination occurred achieved a measureable effective campaign impact (i.e., a reduction in measles cases in the targeted age groups greater than that observed in nonvaccinated districts). Simulation models suggest that selective campaigns targeting hard-to-reach individuals are of greater benefit, particularly in highly vaccinated populations, even for low target coverage and with late implementation. However, the choice between targeted and nonselective campaigns should be context specific, achieving a reasonable balance of feasibility, cost, and expected impact. In addition, it is critical to develop operational strategies to identify and target hard-to-reach individuals.

  19. Persistent sexual dysfunction after discontinuation of selective serotonin reuptake inhibitors.

    Science.gov (United States)

    Csoka, Antonei B; Csoka, A; Bahrick, Audrey; Mehtonen, Olli-Pekka

    2008-01-01

    Sexual dysfunctions such as low libido, anorgasmia, genital anesthesia, and erectile dysfunction are very common in patients taking selective serotonin reuptake inhibitors (SSRIs). It has been assumed that these side effects always resolve after discontinuing treatment, but recently, four cases were presented in which sexual function did not return to baseline. Here, we describe three more cases. Case #1: A 29-year-old with apparently permanent erectile dysfunction after taking fluoxetine 20 mg once daily for a 4-month period in 1996. Case #2: A 44-year-old male with persistent loss of libido, genital anesthesia, ejaculatory anhedonia, and erectile dysfunction after taking 20-mg once daily citalopram for 18 months. Case #3: A 28-year-old male with persistent loss of libido, genital anesthesia, and ejaculatory anhedonia since taking several different SSRIs over a 2-year period from 2003-2005. No psychological issues related to sexuality were found in any of the three cases, and all common causes of sexual dysfunction such as decreased testosterone, increased prolactin or diabetes were ruled out. Erectile capacity is temporarily restored for Case #1 with injectable alprostadil, and for Case #2 with oral sildenafil, but their other symptoms remain. Case #3 has had some reversal of symptoms with extended-release methylphenidate, although it is not yet known if these prosexual effects will persist when the drug is discontinued. SSRIs can cause long-term effects on all aspects of the sexual response cycle that may persist after they are discontinued. Mechanistic hypotheses including persistent endocrine and epigenetic gene expression alterations were briefly discussed.

  20. Early Onset of Selective Serotonin Reuptake Inhibitor Antidepressant Action

    Science.gov (United States)

    Taylor, Matthew J.; Freemantle, Nick; Geddes, John R.; Bhagwagar, Zubin

    2008-01-01

    Context: Selective serotonin reuptake inhibitors (SSRIs) are often described as having a delayed onset of effect in the treatment of depression. However, some trials have reported clinical improvement as early as the first week of treatment. Objective: To test the alternative hypotheses of delayed vs early onset of antidepressant action with SSRIs in patients with unipolar depression. Data Sources: Trials identified by searching CENTRAL, The Cochrane Collaboration database of controlled trials (2005), and the reference lists of identified trials and other systematic reviews. Study Selection: Randomized controlled trials of SSRIs vs placebo for the treatment of unipolar depression in adults that reported outcomes for at least 2 time points in the first 4 weeks of treatment (50 trials from >500 citations identified). Trials were excluded if limited to participants older than 65 years or specific comorbidities. Data Extraction: Data were extracted on trial design, participant characteristics, and outcomes by a single reviewer. Data Synthesis: Pooled estimates of treatment effect on depressive symptom rating scales were calculated for weeks 1 through 6 of treatment. In the primary analysis, the pattern of response seen was tested against alternative models of onset of response. The primary analysis incorporated data from 28 randomized controlled trials (n=5872). A model of early treatment response best fit the experimental data. Treatment with SSRIs rather than placebo was associated with clinical improvement by the end of the first week of use. A secondary analysis indicated an increased chance of achieving a 50% reduction in Hamilton Depression Rating Scale scores by 1 week (relative risk, 1.64; 95% confidence interval, 1.2-2.25) with SSRI treatment compared with placebo. Conclusions: Treatment with SSRIs is associated with symptomatic improvement in depression by the end of the first week of use, and the improvement continues at a decreasing rate for at least 6

  1. Selective serotonin reuptake inhibitors in the treatment of premature ejaculation

    Institute of Scientific and Technical Information of China (English)

    WANG Wei-fu; CHANG Le; Suks Minhas; David J Ralph

    2007-01-01

    Objective To review and assess the update studies regarding se lective serotonin reuptake inhibitors (SSRIs) in the treatment of premature ejaculation (PE) and then provide practical recommendations and possible mechanisms concerning state of the art knowledge for the use of SSRIs in alleviating PE.Data sources Using the Medline, 48 articles published from January 1st, 1996 to August 1st, 2006 concerning the use of SSRIs and their possible mechanisms in alleviating PE were found and reviewed.Study selection PE, rapid ejaculation, early ejaculation and SSRIs were employed as the keywords, and relevant articles about the use of SSRIs and their possible mechanisms in the treatment of PE were selected.Results Many kinds of SSRIs, such as fluoxetine, sertraline, paroxetine and citalopram, have widely been employed to treat PE. However, their effects are moderate and there is no a universal agreement about the kind, dose, protocol and duration. Dapoxetine, as the first prescription treatment of PE, may change this bottle-neck situation. SSRIs are suggested to be used in young men with lifelong PE, and acquired PE when etiological factors are removed but PE still exists. Phosphodiesterase 5 inhibitors (PDE5-Is) are suggested to be employed alone or combined with SSRIs when SSRIs fail to treat PE or sexual dysfunction associated with SSRIs occurs. The protocol of taking drugs on demand based on taking them daily for a suitable period is proposed to be chosen firstly. The possible mechanisms include increasing serotonergic neurotransmission and activating 5-hydroxytryptamine 2C (5-HT2C) receptors, then switching the ejaculatory threshold to a higher level, decreasing the penile sensitivity and their own effect of antidepression.Conclusion The efficacies of the current SSRIs are moderate in the treatment of PE and they have not been approved by the FDA, therefore new SSRI like dapoxetine needs to be further evaluated.

  2. Enhanced responsiveness to selective serotonin reuptake inhibitors during lactation.

    Directory of Open Access Journals (Sweden)

    Nicholas J Jury

    Full Text Available The physiology of mood regulation in the postpartum is poorly understood despite the fact that postpartum depression (PPD is a common pathology. Serotonergic mechanisms and their dysfunction are widely presumed to be involved, which has led us to investigate whether lactation induces changes in central or peripheral serotonin (5-HT systems and related affective behaviors. Brain sections from lactating (day 10 postpartum and age-matched nulliparous (non-pregnant C57BL/6J mice were processed for 5-HT immunohistochemistry. The total number of 5-HT immunostained cells and optical density were measured. Lactating mice exhibited lower immunoreactive 5-HT and intensity in the dorsal raphe nucleus when compared with nulliparous controls. Serum 5-HT was quantified from lactating and nulliparous mice using radioimmunoassay. Serum 5-HT concentrations were higher in lactating mice than in nulliparous controls. Affective behavior was assessed in lactating and non-lactating females ten days postpartum, as well as in nulliparous controls using the forced swim test (FST and marble burying task (MBT. Animals were treated for the preceding five days with a selective serotonin reuptake inhibitor (SSRI, citalopram, 5mg/kg/day or vehicle. Lactating mice exhibited a lower baseline immobility time during the FST and buried fewer marbles during the MBT as compared to nulliparous controls. Citalopram treatment changed these behaviors in lactating mice with further reductions in immobility during the FST and decreased marble burying. In contrast, the same regimen of citalopram treatment had no effect on these behaviors in either non-lactating postpartum or nulliparous females. Our findings demonstrate changes in both central and peripheral 5-HT systems associated with lactation, independent of pregnancy. They also demonstrate a significant interaction of lactation and responsiveness to SSRI treatment, which has important implications in the treatment of PPD. Although

  3. Antidepressants are selective serotonin neuronal reuptake inhibitors: 40-year history

    Directory of Open Access Journals (Sweden)

    D. S. Danilov

    2015-01-01

    Full Text Available The paper presents historical prerequisites for designing antidepressants from a group of selective serotonin neuronal reuptake inhibitors (SSRIs: to determine a lower serotonin concentration in the different tissues of depressed patients; to establish a higher serotonin concentration in the treatment of depressed patients with tricyclic antidepressants, and to formulate the serotonergic theory of depression. It also provides a consecutive account of the history of clinical introduction of individual SSRI representatives, such as fluoxetine, zimelidine, fluvoxamine, indalpine, citalopram, sertraline, paroxetine, and escitalopram. There are data from the history of studying the mechanism of SSRI action: from the theory of the importance of an increase in the concentration of serotonin in the synaptic cleft to the current understanding of complex successive intracellular rearrangements at the level of the postsynaptic neuron. The history of studying the efficacy of SSRIs in treating depression is considered in detail. Emphasis is laid on the reasons for a paradoxical difference in the evaluations of the efficiency of therapy with SSRIs versus other groups of antidepressants at different developmental stages of psychopharmacology. The role of marketing technologies in disseminating the data on the efficacy of this or that group of antidepressants is described. The practical significance of differences in individual SSRI representatives (the potency of serotonin uptake inhibition; the degree of selectivity and activity against the serotonergic system; the likelihood of an unfavorable pharmacokinetic interaction with other drugs; the half-life of elimination; the quickness of achieving a therapeutic dose is analyzed. Whether it is possible and reasonable to differentially choose different SSRI representatives in the treatment of depressions at the present stage is discussed. The authors state their belief that researches should be continued to

  4. Cardiopulmonary effects of dobutamine and norepinephrine infusion in healthy anesthetized alpacas.

    Science.gov (United States)

    Vincent, Caitlin J; Hawley, Alexander T; Rozanski, Elizabeth A; Lascola, Kara M; Bedenice, Daniela

    2009-10-01

    To characterize the cardiopulmonary effects of dobutamine and norepinephrine infusion in isoflurane-anesthetized healthy alpacas. 8 adult alpacas. Initial baseline cardiovascular, respiratory, and metabolic variables were obtained 30 minutes after induction of isoflurane anesthesia in 8 alpacas (3 females and 5 sexually intact males). Four treatments (dobutamine at 4 and 8 microg/kg/min and norepinephrine at 0.3 and 1 microg/kg/min) were administered in random order via constant rate infusion over 15 minutes, followed by repeat measurements of cardiopulmonary values and a 20-minute washout period. Subsequent baseline and posttreatment measurements were similarly repeated until both drugs and dosages were administered to each animal. Baseline data in awake alpacas were obtained 18 to 24 hours following recovery from anesthesia. Both dobutamine and norepinephrine significantly increased cardiac index and arterial blood pressure from baseline values. Similar increases in hemoglobin concentration, oxygen content, and oxygen delivery were observed following administration of each drug at either dosage. Only dobutamine, however, reduced relative oxygen consumption while improving overall tissue oxygenation. Furthermore, heart rate was selectively enhanced by dobutamine and systemic vascular resistance by norepinephrine. Norepinephrine infusion resulted in dose-dependent changes in cardiopulmonary variables. Results indicated that both dobutamine and norepinephrine were appropriate choices to improve cardiac index, mean arterial pressure, and overall oxygen delivery in alpacas with isoflurane-induced hypotension. Careful titration by use of low infusion rates of dobutamine and norepinephrine is recommended to avoid potential arrhythmogenic effects and excessive vasoconstriction, respectively.

  5. Changes in postnatal norepinephrine alter alpha-2 adrenergic receptor development.

    Science.gov (United States)

    Sanders, J D; Happe, H K; Bylund, D B; Murrin, L C

    2011-09-29

    Alpha-2 adrenergic receptors (A2AR) regulate multiple brain functions and are enriched in developing brain. Studies demonstrate norepinephrine (NE) plays a role in regulating brain maturation, suggesting it is important in A2AR development. To investigate this we employed models of NE absence and excess during brain development. For decreases in NE we used N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP4), a specific noradrenergic neurotoxin. Increased noradrenergic terminal density was produced by methylazoxymethanol acetate (MAM) treatment. A2AR density was assayed with [(3)H]RX821002 autoradiography. DSP4 lesions on postnatal day (PND) 3 produce A2AR decreases in many regions by PND 5. A2AR recover to control levels by PND 15 and 25 and there is no further change in total receptor density. We also assayed A2AR in brains lesioned with DSP4 on PND 13, 23, 33 and 43 and harvested 22 days post-lesion. A2AR levels remain similar to control at each of these time points. We examined A2AR functionality and high affinity state with epinephrine-stimulated [(35)S]GTPγS and [(125)I]p-iodoclonidine autoradiography, respectively. On PND 25, control animals and animals lesioned with DSP4 on PND 3 have similar levels of [(35)S]GTPγS incorporation and no change in high affinity state. This is in contrast to increases in A2AR high affinity state produced by DSP4 lesions of mature brain. We next investigated A2AR response to increases in norepinephrine levels produced by MAM. In contrast to DSP4 lesions, increasing NE results in a large increase in A2AR. Animals treated with MAM on gestational day 14 had cortical [(3)H]RX821002 binding 100-200% greater than controls on PND 25, 35, 45, 55 and 65. These data indicate that NE regulation of A2AR differs in developing and mature brain and support the idea that NE regulates A2AR development and this has long term effects on A2AR function.

  6. Reducing cardiovascular risk factors in non-selected outpatients with schizophrenia

    DEFF Research Database (Denmark)

    Hansen, Mette Vinther; Hjorth, Peter; Kristiansen, Christina Blanner;

    2016-01-01

    glucose, serum lipids, and information on smoking and alcohol were obtained. Results: On average, small significant increases in body mass index (BMI) and waist circumferences were observed while small non-significant improvements in other cardiovascular risk factors were seen. Patients with high baseline......Objectives: Cardiovascular diseases are the most common causes of premature death in patients with schizophrenia. We aimed at reducing cardiovascular risk factors in non-selected outpatients with schizophrenia using methods proven effective in short-term trials. Furthermore, we examined whether any...... motivated to participate in the interventions, and it was difficult to monitor the recommended metabolic risk measures in the patient group. Future research should focus on simple strategies in health promotion that can be integrated into routine care....

  7. Autosomal mutants of proton-exposed kidney cells display frequent loss of heterozygosity on nonselected chromosomes.

    Science.gov (United States)

    Grygoryev, Dmytro; Dan, Cristian; Gauny, Stacey; Eckelmann, Bradley; Ohlrich, Anna P; Connolly, Marissa; Lasarev, Michael; Grossi, Gianfranco; Kronenberg, Amy; Turker, Mitchell S

    2014-05-01

    High-energy protons found in the space environment can induce mutations and cancer, which are inextricably linked. We hypothesized that some mutants isolated from proton-exposed kidneys arose through a genome-wide incident that causes loss of heterozygosity (LOH)-generating mutations on multiple chromosomes (termed here genomic LOH). To test this hypothesis, we examined 11 pairs of nonselected chromosomes for LOH events in mutant cells isolated from the kidneys of mice exposed to 4 or 5 Gy of 1 GeV protons. The mutant kidney cells were selected for loss of expression of the chromosome 8-encoded Aprt gene. Genomic LOH events were also assessed in Aprt mutants isolated from isogenic cultured kidney epithelial cells exposed to 5 Gy of protons in vitro. Control groups were spontaneous Aprt mutants and clones isolated without selection from the proton-exposed kidneys or cultures. The in vivo results showed significant increases in genomic LOH events in the Aprt mutants from proton-exposed kidneys when compared with spontaneous Aprt mutants and when compared with nonmutant (i.e., nonselected) clones from the proton-exposed kidneys. A bias for LOH events affecting chromosome 14 was observed in the proton-induced Aprt mutants, though LOH for this chromosome did not confer increased radiation resistance. Genomic LOH events were observed in Aprt mutants isolated from proton-exposed cultured kidney cells; however the incidence was fivefold lower than in Aprt mutants isolated from exposed intact kidneys, suggesting a more permissive environment in the intact organ and/or the evolution of kidney clones prior to their isolation from the tissue. We conclude that proton exposure creates a subset of viable cells with LOH events on multiple chromosomes, that these cells form and persist in vivo, and that they can be isolated from an intact tissue by selection for a mutation on a single chromosome.

  8. Nonselective Blocking of the Sympathetic Nervous System Decreases Detrusor Overactivity in Spontaneously Hypertensive Rats

    Directory of Open Access Journals (Sweden)

    Chang-Shin Park

    2012-04-01

    Full Text Available The involuntary dual control systems of the autonomic nervous system (ANS in the bladder of awake spontaneously hypertensive rats (SHRs were investigated through simultaneous registrations of intravesical and intraabdominal pressures to observe detrusor overactivity (DO objectively as a core symptom of an overactive bladder. SHRs (n = 6 showed the features of overactive bladder syndrome during urodynamic study, especially DO during the filling phase. After injection of the nonselective sympathetic blocking agent labetalol, DO disappeared in 3 of 6 SHRs (50%. DO frequency decreased from 0.98 ± 0.22 min−1 to 0.28 ± 0.19 min−1 (p < 0.01, and DO pressure decreased from 3.82 ± 0.57 cm H2O to 1.90 ± 0.86 cm H2O (p < 0.05. This suggests that the DO originating from the overactive parasympathetic nervous system is attenuated by the nonselective blocking of the sympathetic nervous system. The detailed mechanism behind this result is still not known, but parasympathetic overactivity seems to require overactive sympathetic nervous system activity in a kind of balance between these two systems. These findings are consistent with recent clinical findings suggesting that patients with idiopathic overactive bladder may have ANS dysfunction, particularly a sympathetic dysfunction. The search for newer and better drugs than the current anticholinergic drugs as the mainstay for overactive bladder will be fueled by our research on these sympathetic mechanisms. Further studies of this principle are required.

  9. An Overview of the CNS-Pharmacodynamic Profiles of Nonselective and Selective GABA Agonists

    Directory of Open Access Journals (Sweden)

    Xia Chen

    2012-01-01

    Full Text Available Various 2,3 subtype selective partial GABA-A agonists are in development to treat anxiety disorders. These compounds are expected to be anxiolytic with fewer undesirable side effects, compared to nonselective GABA-A agonists like benzodiazepines. Several 2,3 subtype selective and nonselective GABA-A agonists have been examined in healthy volunteers, using a battery addressing different brain domains. Data from five placebo-controlled double-blind studies were pooled. Lorazepam 2 mg was the comparator in three studies. Three 2,3-selective GABAA agonists (i.e., TPA023, TPACMP2, SL65.1498, one 1-selective GABAA agonists (zolpidem, and another full agonist (alprazolam were examined. Pharmacological selectivity was assessed by determination of regression lines for the change from baseline of saccadic-peak-velocity- (ΔSPV- relative effect, relative to changes in different pharmacodynamic endpoints (ΔPD. SPV was chosen for its sensitivity to the anxiolysis of benzodiazepines. Slopes of the ΔSPV-ΔPD relations were consistently lower with the 2,3 selective GABA-A agonists than with lorazepam, indicating that their PD effects are less than their SPV-effects. The ΔSPV-ΔPD relations of lorazepam were comparable to alprazolam. Zolpidem showed relatively higher impairments in ΔPD relative to ΔSPV, but did not significantly differ from lorazepam. These PD results support the pharmacological selectivity of the 2,3-selective GABA-A agonists, implying an improved therapeutic window.

  10. Beta blockers, norepinephrine, and cancer: an epidemiological viewpoint

    Directory of Open Access Journals (Sweden)

    Fitzgerald PJ

    2012-06-01

    Full Text Available Paul J FitzgeraldThe Zanvyl Krieger Mind/Brain Institute, Solomon H Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, MD, USAAbstract: There is growing evidence that the neurotransmitter norepinephrine (NE and its sister molecule epinephrine (EPI (adrenaline affect some types of cancer. Several recent epidemiological studies have shown that chronic use of beta blocking drugs (which antagonize NE/EPI receptors results in lower recurrence, progression, or mortality of breast cancer and malignant melanoma. Preclinical studies have shown that manipulation of the levels or receptors of NE and EPI with drugs affects experimentally induced cancers. Psychological stress may play an etiological role in some cases of cancer (which has been shown epidemiologically, and this could be partly mediated by NE and EPI released by the sympathetic nervous system as part of the body’s “fight or flight” response. A less well-appreciated phenomenon is that the genetic tone of NE/EPI may play a role in cancer. NE and EPI may affect cancer by interacting with molecular pathways already implicated in abnormal cellular replication, such as the P38/MAPK pathway, or via oxidative stress. NE/EPI-based drugs other than beta blockers also may prevent or treat various types of cancer, as may cholinesterase inhibitors that inhibit the sympathetic nervous system, which could be tested epidemiologically.Keywords: clonidine, guanfacine, aspirin, acetylcholine, epinephrine, adrenaline, sympathetic nervous system, parasympathetic nervous system, inflammation

  11. Intermedin inhibits norepinephrine-inducedcontraction of ratseminal vesicle

    Institute of Scientific and Technical Information of China (English)

    P F Wong; M P L Cheung; WS O; F Tang

    2014-01-01

    Objective:To study the effect of inter medin(IMD) on smooth muscle of rat seminal vesicles including the specific receptors and the signal pathways involved.Methods:The contraction of the seminal vesicle in response to norepinephrine(NE) andADM2/IMD was studied by the organ bath method.The effects of antagonists for calcitonin gene related peptide(CGRP), adrenomedullin(ADM) andIMD receptors, and inhibitors of nitric oxide synthase, [L-NG-NitroarginineMethylEster,L-NAME) and cAMP-dependent protein kinase(PKA),KT5720] were also investigated.The first overshoot, amplitude, frequency and basal tone were measured. Results:There is no significant effect ofIMD on the initial overshoot, frequency and the basal tone in the seminal vesicle contraction.Only the amplitude of the contraction induced byNE was inhibited byIMD.TheIMD inhibitory actions on amplitude were completely blocked by hADM22-52 andL-NAME, but not by hCGRP8-37 orKT5720.Furthermore, the action was diminished byIMD17-47.Conclusion:The results demonstrated that the inhibitory action ofIMD onNE-induced seminal vesicle contraction was mediated via theADM receptor(s) and the nitric oxide production pathway, partially by theIMD receptor, but not by theCGRP receptor and the cAMP-PKA pathway.

  12. Orienting of attention, pupil size, and the norepinephrine system.

    Science.gov (United States)

    Gabay, Shai; Pertzov, Yoni; Henik, Avishai

    2011-01-01

    This research examined a novel suggestion regarding the involvement of the locus coeruleus-norepinephrine (LC-NE) system in orienting reflexive (exogenous) attention. A common procedure for studying exogenous orienting of attention is Posner's cuing task. Importantly, one can manipulate the required level of target processing by changing task requirements, which, in turn, can elicit a different time course of inhibition of return (IOR). An easy task (responding to target location) produces earlier onset IOR, whereas a demanding task (responding to target identity) produces later onset IOR. Aston-Jones and Cohen (Annual Review of Neuroscience, 28, 403-450, 2005) presented a theory suggesting two different modes of LC activity: tonic and phasic. Accordingly, we suggest that in the more demanding task, the LC-NE system is activated in phasic mode, and in the easier task, it is activated in tonic mode. This, in turn, influences the appearance of IOR. We examined this suggestion by measuring participants' pupil size, which has been demonstrated to correlate with the LC-NE system, while they performed cuing tasks. We found a response-locked phasic dilation of the pupil in the discrimination task, as compared with the localization task, which may reflect different firing modes of the LC-NE system during the two tasks. We also demonstrated a correlation between pupil size at the time of cue presentation and magnitude of IOR.

  13. Epinephrine in the heart: uptake and release, but no facilitation of norepinephrine release

    NARCIS (Netherlands)

    Th.W. Lameris (Thomas); P.A. de Zeeuw (Sandra); D.J.G.M. Duncker (Dirk); W. Tietge; G. Alberts; F. Boomsma (Frans); P.D. Verdouw (Pieter); A.H. van den Meiracker (Anton)

    2002-01-01

    textabstractBACKGROUND: Several studies have suggested that epinephrine augments the release of norepinephrine from sympathetic nerve terminals through stimulation of presynaptic receptors, but evidence pertaining to this mechanism in the heart is scarce and conflicting. Using the

  14. Exogenous angiotensin II does not facilitate norepinephrine release in the heart

    NARCIS (Netherlands)

    Th.W. Lameris (Thomas); P.A. de Zeeuw (Sandra); D.J.G.M. Duncker (Dirk); G. Alberts; F. Boomsma (Frans); P.D. Verdouw (Pieter); A.H. van den Meiracker (Anton)

    2002-01-01

    textabstractStudies on the effect of angiotensin II on norepinephrine release from sympathetic nerve terminals through stimulation of presynaptic angiotensin II type 1 receptors are equivocal. Furthermore, evidence that angiotensin II activates the cardiac sympathetic nervous syste

  15. Impact of shock requiring norepinephrine on the accuracy and reliability of subcutaneous continuous glucose monitoring.

    Science.gov (United States)

    Holzinger, Ulrike; Warszawska, Joanna; Kitzberger, Reinhard; Herkner, Harald; Metnitz, Philipp G H; Madl, Christian

    2009-08-01

    To evaluate the impact of circulatory shock requiring norepinephrine therapy on the accuracy and reliability of a subcutaneous continuous glucose monitoring system (CGMS) in critically ill patients. A prospective, validation study of a medical intensive care unit at a university hospital was carried out. Continuous glucose monitoring was performed subcutaneously in 50 consecutive patients on intensive insulin therapy (IIT), who were assessed according to the a priori strata of circulatory shock requiring norepinephrine therapy or not. A total of 736 pairs of sensor glucose (SG)/blood glucose (BG) values were analysed (502 without and 234 with norepinephrine therapy). For all values, repeated measures Bland-Altman analysis showed a mean difference of 0.08 mmol/l (limits of agreement: -1.26 and 1.43 mmol/l). Circulatory shock requiring norepinephrine therapy did not influence the relation of arterial BG with SG in a multivariable random effects linear regression analysis. The covariates norepinephrine dose, body mass index (BMI), glucose level and severity of illness also had no influence. Insulin titration grid analysis showed that 98.6% of the data points were in the acceptable treatment zone. No data were in the life-threatening zone. Circulatory shock requiring norepinephrine therapy, as well as other covariates, had no influence on the accuracy and reliability of the CGMS in critically ill patients.

  16. Selective Serotonin Reuptake Inhibitors and Violent Crime: A Cohort Study.

    Directory of Open Access Journals (Sweden)

    Yasmina Molero

    2015-09-01

    Full Text Available Although selective serotonin reuptake inhibitors (SSRIs are widely prescribed, associations with violence are uncertain.From Swedish national registers we extracted information on 856,493 individuals who were prescribed SSRIs, and subsequent violent crimes during 2006 through 2009. We used stratified Cox regression analyses to compare the rate of violent crime while individuals were prescribed these medications with the rate in the same individuals while not receiving medication. Adjustments were made for other psychotropic medications. Information on all medications was extracted from the Swedish Prescribed Drug Register, with complete national data on all dispensed medications. Information on violent crime convictions was extracted from the Swedish national crime register. Using within-individual models, there was an overall association between SSRIs and violent crime convictions (hazard ratio [HR] = 1.19, 95% CI 1.08-1.32, p < 0.001, absolute risk = 1.0%. With age stratification, there was a significant association between SSRIs and violent crime convictions for individuals aged 15 to 24 y (HR = 1.43, 95% CI 1.19-1.73, p < 0.001, absolute risk = 3.0%. However, there were no significant associations in those aged 25-34 y (HR = 1.20, 95% CI 0.95-1.52, p = 0.125, absolute risk = 1.6%, in those aged 35-44 y (HR = 1.06, 95% CI 0.83-1.35, p = 0.666, absolute risk = 1.2%, or in those aged 45 y or older (HR = 1.07, 95% CI 0.84-1.35, p = 0.594, absolute risk = 0.3%. Associations in those aged 15 to 24 y were also found for violent crime arrests with preliminary investigations (HR = 1.28, 95% CI 1.16-1.41, p < 0.001, non-violent crime convictions (HR = 1.22, 95% CI 1.10-1.34, p < 0.001, non-violent crime arrests (HR = 1.13, 95% CI 1.07-1.20, p < 0.001, non-fatal injuries from accidents (HR = 1.29, 95% CI 1.22-1.36, p < 0.001, and emergency inpatient or outpatient treatment for alcohol intoxication or misuse (HR = 1.98, 95% CI 1.76-2.21, p < 0.001. With

  17. Cyclo-oxygenase-2 inhibitors or nonselective NSAIDs plus gastroprotective agents: What to prescribe in daily clinical practice?

    NARCIS (Netherlands)

    G.M.C. Masclee (Gwen); V.E. Valkhoff (Vera); E.M. van Soest; R. Schade (René); G. Mazzaglia (Giampiero); M. Molokhia (Mariam); G. Trifiro (Gianluca); J.L. Goldstein; S. Hernández-Díaz (Sonia); E.J. Kuipers (Ernst); M.C.J.M. Sturkenboom (Miriam)

    2013-01-01

    textabstractBackground Two strategies for prevention of upper gastrointestinal (UGI) events for nonselective nonsteroidal anti-inflammatory drug (nsNSAID) users are replacement of the nsNSAID by a cyclo-oxygenase-2-selective inhibitor (coxib) or co-prescription of a gastroprotective agent (GPA). Aim

  18. Cyclo-oxygenase-2 inhibitors or nonselective NSAIDs plus gastroprotective agents: What to prescribe in daily clinical practice?

    NARCIS (Netherlands)

    G.M.C. Masclee (Gwen); V.E. Valkhoff (Vera); E.M. van Soest; R. Schade (René); G. Mazzaglia (Giampiero); M. Molokhia (Mariam); G. Trifiro (Gianluca); J.L. Goldstein; S. Hernández-Díaz (Sonia); E.J. Kuipers (Ernst); M.C.J.M. Sturkenboom (Miriam)

    2013-01-01

    textabstractBackground Two strategies for prevention of upper gastrointestinal (UGI) events for nonselective nonsteroidal anti-inflammatory drug (nsNSAID) users are replacement of the nsNSAID by a cyclo-oxygenase-2-selective inhibitor (coxib) or co-prescription of a gastroprotective agent (GPA). Aim

  19. Norepinephrine stimulates mobilization of endothelial progenitor cells after limb ischemia.

    Directory of Open Access Journals (Sweden)

    Qijun Jiang

    Full Text Available OBJECTIVE: During several pathological processes such as cancer progression, thermal injury, wound healing and hindlimb ischemia, the mobilization of endothelial progenitor cells (EPCs mobilization was enhanced with an increase of sympathetic nerve activity and norepinephrine (NE secretion, yet the cellular and molecular mechanisms involved in the effects of NE on EPCs has less been investigated. METHODS AND RESULTS: EPCs from BMs, peripheral circulation and spleens, the VEGF concentration in BM, skeletal muscle, peripheral circulation and spleen and angiogenesis in ischemic gastrocnemius were quantified in mice with hindlimbs ischemia. Systemic treatment of NE significantly increased EPCs number in BM, peripheral circulation and spleen, VEGF concentration in BM and skeletal muscle and angiogenesis in ischemic gastrocnemius in mice with hind limb ischemia, but did not affair VEGF concentration in peripheral circulation and spleen. EPCs isolated from healthy adults were cultured with NE in vitro to evaluate proliferation potential, migration capacity and phosphorylations of Akt and eNOS signal moleculars. Treatment of NE induced a significant increase in number of EPCs in the S-phase in a dose-dependent manner, as well as migrative activity of EPCs in vitro (p<0.05. The co-treatment of Phentolamine, I127, LY294002 and L-NAME with NE blocked the effects of NE on EPCs proliferation and migration. Treatment with NE significantly increased phosphorylation of Akt and eNOS of EPCs. Addition of phentolamine and I127 attenuated the activation of Akt/eNOS pathway, but metoprolol could not. Pretreatment of mice with either Phentolamine or I127 significantly attenuated the effects of NE on EPCs in vivo, VEGF concentration in BM, skeletal muscle and angiogenesis in ischemic gastrocnemius, but Metoprolol did not. CONCLUSION: These results unravel that sympathetic nervous system regulate EPCs mobilization and their pro-angiogenic capacity via α adrenoceptor

  20. Genomic saturation mutagenesis and polygenic analysis identify novel yeast genes affecting ethyl acetate production, a non-selectable polygenic trait

    Directory of Open Access Journals (Sweden)

    Tom Den Abt

    2016-03-01

    Full Text Available Isolation of mutants in populations of microorganisms has been a valuable tool in experimental genetics for decades. The main disadvantage, however, is the inability of isolating mutants in non-selectable polygenic traits. Most traits of organisms, however, are non-selectable and polygenic, including industrially important properties of microorganisms. The advent of powerful technologies for polygenic analysis of complex traits has allowed simultaneous identification of multiple causative mutations among many thousands of irrelevant mutations. We now show that this also applies to haploid strains of which the genome has been loaded with induced mutations so as to affect as many non-selectable, polygenic traits as possible. We have introduced about 900 mutations into single haploid yeast strains using multiple rounds of EMS mutagenesis, while maintaining the mating capacity required for genetic mapping. We screened the strains for defects in flavor production, an important non-selectable, polygenic trait in yeast alcoholic beverage production. A haploid strain with multiple induced mutations showing reduced ethyl acetate production in semi-anaerobic fermentation, was selected and the underlying quantitative trait loci (QTLs were mapped using pooled-segregant whole-genome sequence analysis after crossing with an unrelated haploid strain. Reciprocal hemizygosity analysis and allele exchange identified PMA1 and CEM1 as causative mutant alleles and TPS1 as a causative genetic background allele. The case of CEM1 revealed that relevant mutations without observable effect in the haploid strain with multiple induced mutations (in this case due to defective mitochondria can be identified by polygenic analysis as long as the mutations have an effect in part of the segregants (in this case those that regained fully functional mitochondria. Our results show that genomic saturation mutagenesis combined with complex trait polygenic analysis could be used

  1. Characteristics of the Nonselective Cation Current (NSCCs) in Rabbit Left Ventricular Epicardial, Midmyocardial and Endocardial Myocytes

    Institute of Scientific and Technical Information of China (English)

    Min Zong; Xinchun Yang; Xiulan Liu; Liang Shi; Taifeng Liu

    2007-01-01

    Recent studies have described regional differences in the electrophysiology and pharmacology of ventricular myocardium in canine,feline,rat,guinea pig,and human hearts.This has been shown to be due to a smaller IKs and a lager sodium-calcium exchange current (INa-Ca ) and late INa in M region (deep subepicardial to midmyocardial).Studies from our laboratory have found a new repolarization current-nonselective cation current (NSCCs) existing in rabbit right ventricular myocytes.Methods We examined the characteristics of NSCCs in epicardial,M region,and endocardial cells isolated from the rabbit left ventricle with standard microelectrode and whole-cell patch-clamp techniques.The permeability to Na+,K + ,Li + ,Cs + but not to Cl-indicating that it was a nonselective cation current.Gd3+ (0.1 mmol/1) and La3+ (0.1 mmol/1) can block the current markedly.Results Further characterization of NSCCs was significantly smaller in M cells than in epicardial and endocardial cells.NSCCs current density was significantly smaller in M cells than in epicardial and endocardial cells.With repolarization to-80 mV,INs current density was (-0.44 ±0.05) PA/PF in endocardial cells,(-0.12 ±0.05) PA/PF in M cells and (-0.28 ±0.07) PA/PF in epicardial cells;and with repolarization to + 30 mV,INs current density was ( 1.09 ± 0.29) PA/PF in endocardial cells,(0.38 ± 0.09) PA/PF in M cells and (0.91 ± 0.32) PA/PF in epicardial cells.Conclusions Transmural dispersion of repolarization was due to the heterogeneity of NSCCs in rabbit left ventricle epicardial,endocardial myocytes and M cells.These findings may advance our understanding of the ionic basis for our understanding of factors contributing to the development of cardiac arrhythmias.

  2. Dependence and withdrawal reactions to benzodiazepines and selective serotonin reuptake inhibitors. How did the health authorities react?

    DEFF Research Database (Denmark)

    Nielsen, Margrethe; Hansen, Ebba Holme; Gøtzsche, Peter C

    2013-01-01

    Our objective was to explore communications from drug agencies about benzodiazepine dependence and selective serotonin reuptake inhibitors (SSRIs) withdrawal reactions over time.......Our objective was to explore communications from drug agencies about benzodiazepine dependence and selective serotonin reuptake inhibitors (SSRIs) withdrawal reactions over time....

  3. Drug: D02360 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available (Selective Serotonin Reuptake Inhibitors/Serotonin and Norepinephrine Reuptake Inhibitors) Sertraline D02360 Sertraline (INN) Anxiol...ytics SSRIs/SNRIs (Selective Serotonin Reuptake Inhibito

  4. Nonselective beta-blockers in cirrhotic patients with no or small varices: A meta-analysis.

    Science.gov (United States)

    Qi, Xing-Shun; Bao, Yong-Xin; Bai, Ming; Xu, Wen-Da; Dai, Jun-Na; Guo, Xiao-Zhong

    2015-03-14

    To explore effects of nonselective beta-blockers (NSBBs) in cirrhotic patients with no or small varices. The PubMed, EMBASE, Science Direct, and Cochrane library databases were searched for relevant papers. A meta-analysis was performed using ORs with 95%CI as the effect sizes. Subgroup analysis was conducted according to the studies including patients without varices and those with small varices. Overall, 784 papers were initially retrieved from the database searches, of which six randomized controlled trials were included in the meta-analysis. The incidences of large varices development (OR = 1.05, 95%CI: 0.25-4.36; P = 0.95), first upper gastrointestinal bleeding (OR = 0.59, 95%CI: 0.24-1.47; P = 0.26), and death (OR = 0.70, 95%CI: 0.45-1.10; P = 0.12) were similar between NSBB and placebo groups. However, the incidence of adverse events was significantly higher in the NSBB group compared with the placebo group (OR = 3.47, 95%CI: 1.45-8.33; P = 0.005). The results of subgroup analyses were similar to those of overall analyses. The results of this meta-analysis indicate that NSBBs should not be recommended for cirrhotic patients with no or small varices.

  5. The characteristics of action potential and nonselective cation current of cardiomyocytes in rabbit superior vena cava

    Institute of Scientific and Technical Information of China (English)

    WANG Pan; YANG XinChun; LIU XiuLan; BAO RongFeng; LIU TaiFeng

    2008-01-01

    As s special focus in initiating and maintaining atrial fibrillation (AF), cardiomyocytes in superior vena cavs (SVC) have distinctive electrophysiological characters. In this study, we found that comparing with the right atrial (RA) cardiomyoctyes, the SVC cardiomyoctyes had longer APD90 at the different basic cycle lengths; the conduction block could be observed on both RA and SVC cardiomyoctyes. A few of SVC cardiomyoctyes showed slow response action potentials with automatic activity and some others showed early afterdepolarization (EAD) spontaneously. Further more, we found that there are nonselective cation current (INs) in both SVC and RA cardiomyocytes. The peak density of INs in SVC cardiomyocytes was smaller than that in RA cardiomyocytes. Removal of extracellular divalent cation and glucose could increase INs in SVC cardiomyocytes. The agonist or the antagonist of INs may increase or decrease APD. To sum up, some SVC cardiomyocytes possess the ability of spontaneous activity; the difference of transmembrane action potentials between SVC and RA cardiomyocytes is partly because of the different density of INs between them; the agonist or the antagonist of INs can increase or decrease APD leading to the enhancement or reduction of EAD genesis in SVC cardiomyocytes. INs in rabbit myocytes is fairly similar to TRPC3 current in electrophysiological property, which might play an important role in the mechanisms of AF.

  6. Non-selective cation channels mediate chloroquine-induced relaxation in precontracted mouse airway smooth muscle.

    Directory of Open Access Journals (Sweden)

    Ting Zhang

    Full Text Available Bitter tastants can induce relaxation in precontracted airway smooth muscle by activating big-conductance potassium channels (BKs or by inactivating voltage-dependent L-type Ca2+ channels (VDLCCs. In this study, a new pathway for bitter tastant-induced relaxation was defined and investigated. We found nifedipine-insensitive and bitter tastant chloroquine-sensitive relaxation in epithelium-denuded mouse tracheal rings (TRs precontracted with acetylcholine (ACH. In the presence of nifedipine (10 µM, ACH induced cytosolic Ca2+ elevation and cell shortening in single airway smooth muscle cells (ASMCs, and these changes were inhibited by chloroquine. In TRs, ACH triggered a transient contraction under Ca2+-free conditions, and, following a restoration of Ca2+, a strong contraction occurred, which was inhibited by chloroquine. Moreover, the ACH-activated whole-cell and single channel currents of non-selective cation channels (NSCCs were blocked by chloroquine. Pyrazole 3 (Pyr3, an inhibitor of transient receptor potential C3 (TRPC3 channels, partially inhibited ACH-induced contraction, intracellular Ca2+ elevation, and NSCC currents. These results demonstrate that NSCCs play a role in bitter tastant-induced relaxation in precontracted airway smooth muscle.

  7. The effects of maternal depression and maternal selective serotonin reuptake inhibitor exposure on offspring

    NARCIS (Netherlands)

    Olivier, J D A; Akerud, H; Kaihola, H; Pawluski, J L; Skalkidou, A; Högberg, U; Sundström-Poromaa, I

    2013-01-01

    It has been estimated that 20% of pregnant women suffer from depression and it is well-documented that maternal depression can have long-lasting effects on the child. Currently, common treatment for maternal depression has been the selective serotonin reuptake inhibitor medications (SSRIs) which are

  8. Selective serotonin reuptake inhibitor antidepressant use in first trimester pregnancy and risk of specific congenital anomalies

    DEFF Research Database (Denmark)

    Wemakor, Anthony; Casson, Karen; Garne, Ester

    2015-01-01

    Evidence of an association between early pregnancy exposure to selective serotonin reuptake inhibitors (SSRI) and congenital heart defects (CHD) has contributed to recommendations to weigh benefits and risks carefully. The objective of this study was to determine the specificity of association be...

  9. The age-dependent effects of selective serotonin reuptake inhibitors in humans and rodents : A review

    NARCIS (Netherlands)

    Olivier, J D A; Blom, T; Arentsen, T; Homberg, J R

    2011-01-01

    The selective serotonin reuptake inhibitor (SSRI) Prozac® (fluoxetine) is widely prescribed for the treatment of depression and anxiety-related disorders. While extensive research has established that fluoxetine is safe for adults, safety is not guaranteed for (unborn) children and adolescents. Some

  10. Extrapyramidal syndromes associated with selective serotonin reuptake inhibitors : a case-control study using spontaneous reports

    NARCIS (Netherlands)

    Schillevoort, I; van Puijenbroek, E P; de Boer, Anthonius; Roos, R A C; Jansen, Paul A F; Leufkens, H G M

    2002-01-01

    The aim of this study was to assess whether use of selective serotonin reuptake inhibitors (SSRIs) is associated with extrapyramidal syndromes (EPS). We analysed the spontaneous reports of adverse drug reactions (ADRs) collected by The Netherlands Pharmacovigilance Foundation Lareb in the period 198

  11. QT interval prolongation in users of selective serotonin reuptake inhibitors in an elderly surgical population

    DEFF Research Database (Denmark)

    van Haelst, Ingrid M M; van Klei, Wilton A; Doodeman, Hieronymus J;

    2014-01-01

    OBJECTIVE: To investigate the association between the use of a selective serotonin reuptake inhibitor (SSRI) and the occurrence of QT interval prolongation in an elderly surgical population. METHOD: A cross-sectional study was conducted among patients (> 60 years) scheduled for outpatient preanes...

  12. Do selective serotonin reuptake inhibitors acutely increase frontal cortex levels of serotonin?

    NARCIS (Netherlands)

    Beyer, Chad E.; Cremers, Thomas I. F. H.

    2008-01-01

    Selective serotonin uptake inhibitors (SSRIs) exert their effects by inhibiting serotonin (5-HT) re-uptake. Although blockade occurs almost immediately, the neurochemical effects on 5-HT, as measured by in vivo microdialysis, have been a matter of considerable debate. In particular, literature repor

  13. Increased Bleeding Risk With Concurrent Use of Selective Serotonin Reuptake inhibitors and Coumarins

    NARCIS (Netherlands)

    Schalekamp, Tom; Klungel, Olaf H; Souverein, Patrick C; de Boer, Anthonius

    2008-01-01

    BACKGROUND: Treatment with vitamin K antagonists (coumarins) is associated with an increased risk of bleeding. Because use of selective serotonin reuptake inhibitors (SSRIs) is also associated with an increased risk of bleeding, we assessed the odds ratio (OR) of abnormal bleeding associated with SS

  14. Extrapyramidal syndromes associated with selective serotonin reuptake inhibitors : a case-control study using spontaneous reports

    NARCIS (Netherlands)

    Schillevoort, I; van Puijenbroek, E P; de Boer, Anthonius; Roos, R A C; Jansen, Paul A F; Leufkens, H G M

    2002-01-01

    The aim of this study was to assess whether use of selective serotonin reuptake inhibitors (SSRIs) is associated with extrapyramidal syndromes (EPS). We analysed the spontaneous reports of adverse drug reactions (ADRs) collected by The Netherlands Pharmacovigilance Foundation Lareb in the period 198

  15. Helicobacter pylori and risk of upper gastrointestinal bleeding among users of selective serotonin reuptake inhibitors

    DEFF Research Database (Denmark)

    Dall, Michael; Schaffalitzky de Muckadell, Ove B; Møller Hansen, Jane

    2011-01-01

    A number of studies have reported a possible association between use of selective serotonin reuptake inhibitors (SSRIs) and serious upper gastrointestinal bleeding (UGB). We conducted this case-control study to assess if Helicobacter pylori (H. pylori) potentiates the risk of serious UGB in SSRI ...

  16. Anhedonia Predicts Poorer Recovery among Youth with Selective Serotonin Reuptake Inhibitor Treatment-Resistant Depression

    Science.gov (United States)

    McMakin, Dana L.; Olino, Thomas M.; Porta, Giovanna; Dietz, Laura J.; Emslie, Graham; Clarke, Gregory; Wagner, Karen Dineen; Asarnow, Joan R.; Ryan, Neal D.; Birmaher, Boris; Shamseddeen, Wael; Mayes, Taryn; Kennard, Betsy; Spirito, Anthony; Keller, Martin; Lynch, Frances L.; Dickerson, John F.; Brent, David A.

    2012-01-01

    Objective: To identify symptom dimensions of depression that predict recovery among selective serotonin reuptake inhibitor (SSRI) treatment-resistant adolescents undergoing second-step treatment. Method: The Treatment of Resistant Depression in Adolescents (TORDIA) trial included 334 SSRI treatment-resistant youth randomized to a medication…

  17. Are Selective Serotonin Reuptake Inhibitors Safe for Drivers? What is the Evidence?

    NARCIS (Netherlands)

    Ravera, Silvia; Ramaekers, Johannes G.; de Jong-van den Berg, Lolkje T. W.; de Gier, Johan J.; de Jong-van den Berg, [No Value

    2012-01-01

    Background: Selective serotonin reuptake inhibitors (SSRIs) are widely used medications to treat several psychiatric diseases and, above all, depression. They seem to be as effective as older antidepressants but have a different adverse effect profile. Despite their favorable safety profile, little

  18. In Utero Exposure to Selective Serotonin Reuptake Inhibitors and Risk for Autism Spectrum Disorder

    Science.gov (United States)

    Gidaya, Nicole B.; Lee, Brian K.; Burstyn, Igor; Yudell, Michael; Mortensen, Erik L.; Newschaffer, Craig J.

    2014-01-01

    We investigated whether there is an association between increased risk for autism spectrum disorders (ASD) and selective serotonin reuptake inhibitors (SSRIs) used during pregnancy. This study used Denmark's health and population registers to obtain information regarding prescription drugs, ASD diagnosis, and health and socioeconomic status. There…

  19. Increased Bleeding Risk With Concurrent Use of Selective Serotonin Reuptake inhibitors and Coumarins

    NARCIS (Netherlands)

    Schalekamp, Tom; Klungel, Olaf H; Souverein, Patrick C; de Boer, Anthonius

    2008-01-01

    BACKGROUND: Treatment with vitamin K antagonists (coumarins) is associated with an increased risk of bleeding. Because use of selective serotonin reuptake inhibitors (SSRIs) is also associated with an increased risk of bleeding, we assessed the odds ratio (OR) of abnormal bleeding associated with

  20. Sertraline causes strong coronary vasodilation : Possible relevance for cardioprotection by selective serotonin reuptake inhibitors

    NARCIS (Netherlands)

    van Melle, JP; Buikema, H; van den Berg, MP; van Buiten, A; van Veldhuisen, DJ; Boonstra, PW; van Gilst, WH

    2004-01-01

    Objective: Although Selective Serotonin Reuptake Inhibitors (SSRIs) are important antidepressant drugs, knowledge of their vaso active effects is limited. Vaso active effects of the SSRI sertraline were studied in rings of rat aorta, human Internal Mammary Arteries (IMAs) and in Langendorff perfused

  1. Anhedonia Predicts Poorer Recovery among Youth with Selective Serotonin Reuptake Inhibitor Treatment-Resistant Depression

    Science.gov (United States)

    McMakin, Dana L.; Olino, Thomas M.; Porta, Giovanna; Dietz, Laura J.; Emslie, Graham; Clarke, Gregory; Wagner, Karen Dineen; Asarnow, Joan R.; Ryan, Neal D.; Birmaher, Boris; Shamseddeen, Wael; Mayes, Taryn; Kennard, Betsy; Spirito, Anthony; Keller, Martin; Lynch, Frances L.; Dickerson, John F.; Brent, David A.

    2012-01-01

    Objective: To identify symptom dimensions of depression that predict recovery among selective serotonin reuptake inhibitor (SSRI) treatment-resistant adolescents undergoing second-step treatment. Method: The Treatment of Resistant Depression in Adolescents (TORDIA) trial included 334 SSRI treatment-resistant youth randomized to a medication…

  2. Norepinephrine and Epinephrine Enhanced the Infectivity of Enterovirus 71.

    Directory of Open Access Journals (Sweden)

    Yu-Ting Liao

    Full Text Available Enterovirus 71 (EV71 infections may be associated with neurological complications, including brainstem encephalitis (BE. Severe EV71 BE may be complicated with autonomic nervous system (ANS dysregulation and/or pulmonary edema (PE. ANS dysregulation is related to the overactivation of the sympathetic nervous system, which results from catecholamine release.The aims of this study were to explore the effects of catecholamines on severe EV71 infection and to investigate the changes in the percentages of EV71-infected cells, virus titer, and cytokine production on the involvement of catecholamines.Plasma levels of norepinephrine (NE and epinephrine (EP in EV71-infected patients were measured using an enzyme-linked immunoassay. The expression of adrenergic receptors (ADRs on RD, A549, SK-N-SH, THP-1, Jurkat and human peripheral blood mononuclear cells (hPBMCs were detected using flow cytometry. The percentages of EV71-infected cells, virus titer, and cytokine production were investigated after treatment with NE and EP.The plasma levels of NE and EP were significantly higher in EV71-infected patients with ANS dysregulation and PE than in controls. Both α1A- and β2-ADRs were expressed on A549, RD, SK-N-SH, HL-60, THP-1, Jurkat cells and hPBMCs. NE treatment elevated the percentages of EV71-infected cells to 62.9% and 22.7% in THP-1 and Jurkat cells, respectively. Via treatment with EP, the percentages of EV71-infected cells were increased to 64.6% and 26.9% in THP-1 and Jurkat cells. The percentage of EV71-infected cells increased upon NE or EP treatment while the α- and β-blockers reduced the percentages of EV71-infected cells with NE or EP treatment. At least two-fold increase in virus titer was observed in EV71-infected A549, SK-N-SH and hPBMCs after treatment with NE or EP. IL-6 production was enhanced in EV71-infected hPBMCs at a concentration of 102 pg/mL NE.The plasma levels of NE and EP elevated in EV71-infected patients with ANS

  3. Interaction Between Brain Histamine and Serotonin, Norepinephrine, and Dopamine Systems: In Vivo Microdialysis and Electrophysiology Study.

    Science.gov (United States)

    Flik, Gunnar; Folgering, Joost H A; Cremers, Thomas I H F; Westerink, Ben H C; Dremencov, Eliyahu

    2015-06-01

    Brain monoamines (serotonin, norepinephrine, dopamine, and histamine) play an important role in emotions, cognition, and pathophysiology and treatment of mental disorders. The interactions between serotonin, norepinephrine, and dopamine were studied in numerous works; however, histamine system received less attention. The aim of this study was to investigate the interactions between histamine and other monoamines, using in vivo microdialysis and electrophysiology. It was found that the inverse agonist of histamine-3 receptors, thioperamide, increased the firing activity of dopamine neurons in the ventral tegmental area. Selective agonist of histamine-3 receptors, immepip, reversed thiperamide-induced stimulation of firing activity of dopamine neurons. The firing rates of serotonin and norpeinephrine neurons were not attenuated by immepip or thioperamide. Thioperamide robustly and significantly increased extracellular concentrations of serotonin, norepinephrine, and dopamine in the rat prefrontal cortex and slightly increased norepinephrine and dopamine levels in the tuberomammillary nucleus of the hypothalamus. It can be concluded that histamine stimulates serotonin, norepinephrine, and dopamine transmission in the brain. Modulation of firing of dopamine neurons is a key element in functional interactions between histamine and other monoamines. Antagonists of histamine-3 receptors, because of their potential ability to stimulate monoamine neurotransmission, might be beneficial in the treatment of mental disorders.

  4. Norepinephrine transporter function and desipramine: residual drug effects versus short-term regulation.

    Science.gov (United States)

    Ordway, Gregory A; Jia, Weihong; Li, Jing; Zhu, Meng-Yang; Mandela, Prashant; Pan, Jun

    2005-04-30

    Previous research has shown that exposure of norepinephrine transporter (NET)-expressing cells to desipramine (DMI) downregulates the norepinephrine transporter, although changes in the several transporter parameters do not demonstrate the same time course. Exposures to desipramine for effects of residual desipramine on norepinephrine transporter binding and uptake were re-evaluated following exposures of PC12 cells to desipramine using different methods to remove residual drug. Using a method that minimizes residual drug, exposure of intact PC12 cells to desipramine for 4h had no effect on uptake capacity or [(3)H]nisoxetine binding to the norepinephrine transporter, while exposures for > or =16 h reduced uptake capacity. Desipramine-induced reductions in binding to the transporter required >24 h or greater periods of desipramine exposure. This study confirms that uptake capacity of the norepinephrine transporter is reduced earlier than changes in radioligand binding, but with a different time course than originally shown. Special pre-incubation procedures are required to abolish effects of residual transporter inhibitor when studying inhibitor-induced transporter regulation.

  5. Ivermectin is a nonselective inhibitor of mammalian P-type ATPases.

    Science.gov (United States)

    Pimenta, Paulo Henrique Cotrim; Silva, Claudia Lucia Martins; Noël, François

    2010-02-01

    Ivermectin is a large spectrum antiparasitic drug that is very safe at the doses actually used. However, as it is being studied for new applications that would require higher doses, we should pay attention to its effects at high concentrations. As micromolar concentrations of ivermectin have been reported to inhibit the sarco-endoplasmic reticulum Ca(2+)-ATPase (SERCA), we decided to investigate its putative inhibitory effect on other two important P-type ATPases, namely the Na(+) , K(+)-ATPase and H(+)/K(+)-ATPase. We first extended the data on SERCA, using preparations from rat enriched in SERCA1a (extensor digitorum longus) and 1b (heart) isoforms. Secondly, we tested the effect of ivermectin in two preparations of rat Na(+), K(+)-ATPase in order to appreciate its putative selectivity towards the alpha(1) isoform (kidney) and the alpha(2)/alpha(3) isoforms (brain), and in an H(+)/K(+)-ATPase preparation from rat stomach. Ivermectin inhibited all these ATPases with similar IC(50) values (6-17 microM). With respect to the inhibition of the Na(+), K(+)-ATPase, ivermectin acts by a mechanism different from the classical cardiac glycosides, based on selectivity towards the isoforms, sensibility to the antagonistic effect of K(+) and to ionic conditions favoring different conformations of the enzyme. We conclude that ivermectin is a nonselective inhibitor of three important mammalian P-type ATPases, which is indicative of putative important adverse effects if this drug were used at high doses. As a consequence, we propose that novel analogs of ivermectin should be developed and tested both for their parasitic activity and in vitro effects on P-type ATPases.

  6. A double-blind, placebo-controlled study of edivoxetine as an adjunctive treatment for patients with major depressive disorder who are partial responders to selective serotonin reuptake inhibitor treatment.

    Science.gov (United States)

    Ball, Susan; Dellva, Mary Anne; D'Souza, Deborah N; Marangell, Lauren B; Russell, James M; Goldberger, Celine

    2014-01-01

    This phase 2 study examined the efficacy and tolerability of edivoxetine, a highly selective norepinephrine reuptake inhibitor, as an adjunctive treatment for patients with major depressive disorder (MDD) who have a partial response to selective serotonin reuptake inhibitor (SSRI) treatment. Study design consisted of double-blind, 10-week therapy of adjunctive edivoxetine (6-18 mg once daily) or adjunctive placebo with SSRI. Inclusion/entry criteria included partial response to current SSRI by investigator opinion and a GRID 17-item Hamilton Rating Scale for Depression (HAMD17) total score ≥16. The primary efficacy measure was the Montgomery-Asberg Depression Rating Scale (MADRS). Safety measures included treatment-emergent adverse events (TEAE) and vital signs. For the primary evaluable population (n=63 for adjunctive edivoxetine and n=68 for adjunctive placebo), the treatment groups did not differ significantly on the primary outcome of change from baseline to week 8 in the MADRS total score; the effect size of edivoxetine treatment was 0.26. Significant treatment differences, favoring adjunctive edivoxetine (p≤.05), were shown for improvements in role functioning and the functional impact of fatigue. For the adjunctive edivoxetine randomized group (N=111), the most frequent TEAEs were hyperhidrosis (7.2%), nausea (7.2%), erectile dysfunction (6.3%) and testicular pain (6.3%). Hemodynamic changes were observed in blood pressure and pulse rate between treatment groups. Study was underpowered for an alpha 2-sided 0.05 significance level for the primary outcome. For patients with MDD who had a partial response to SSRIs, adjunctive edivoxetine treatment was not statistically superior to adjunctive placebo on the primary outcome measure. However, pending further study, improved functioning and remission rate suggest a potential role for edivoxetine for patients with depression. Copyright © 2014 Elsevier B.V. All rights reserved.

  7. Evaluation of radioiodinated (2S,{alpha}S)-2-({alpha}-(2-iodophenoxy)benzyl)morpholine as a radioligand for imaging of norepinephrine transporter in the heart

    Energy Technology Data Exchange (ETDEWEB)

    Kiyono, Yasushi [Biomedical Imaging Research Center, University of Fukui, Fukui 910-1193 (Japan); Radioisotopes Research Laboratory, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto 606-8507 (Japan)], E-mail: ykiyono@u-fukui.ac.jp; Sugita, Taku [Department of Pathofunctional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501 (Japan); Ueda, Masashi [Radioisotopes Research Laboratory, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto 606-8507 (Japan); Kawashima, Hidekazu [Department of Nuclear Medicine and Diagnostic Imaging, Graduate School of Medicine, Kyoto University, Kyoto 606-8507 (Japan); Kanegawa, Naoki; Kuge, Yuji [Department of Pathofunctional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501 (Japan); Fujibayashi, Yasuhisa [Biomedical Imaging Research Center, University of Fukui, Fukui 910-1193 (Japan); Saji, Hideo [Department of Pathofunctional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501 (Japan)

    2008-02-15

    Introduction: The norepinephrine transporter (NET) is located presynaptically on noradrenergic nerve terminals and plays a critical role in the regulation of the synaptic norepinephrine (NE) concentration via the reuptake of NE. Changes in NET have been recently reported in several cardiac failures. Therefore, a NET-specific radioligand is useful for in vivo assessment of changes in NET density in various cardiac disorders. Recently, we developed a radioiodinated reboxetine analogue, (2S,{alpha}S)-2-({alpha}-(2-iodophenoxy)benzyl)morpholine ((S,S)-IPBM), for NET imaging. In the current study, we assessed the applicability of radioiodinated (S,S)-IPBM to NET imaging in the heart. Methods: The NET affinity and selectivity were measured from the ability to displace specific [{sup 3}H]nisoxetine and (S,S)-[{sup 125}I]IPBM binding to rat heart membrane, respectively. To evaluate the distribution of (S,S)-[{sup 125}I]IPBM in vivo, biodistribution experiment was performed in rats. With the use of several monoamine transporter binding agents, pharmacological blocking experiments were performed in rats. Results: In vitro binding assays showed that the affinity of (S,S)-IPBM to NET was similar to those of the well-known NET-specific binding agents, nisoxetine and desipramine. Furthermore, (S,S)-[{sup 125}I]IPBM binding was inhibited by nisoxetine and desipramine, but not by dopamine or serotonin transporter binding agents. These data indicated that (S,S)-IPBM had high affinity and selectivity for NET in vitro. Biodistribution studies in rats showed rapid and high uptake of (S,S)-[{sup 125}I]IPBM by the heart and rapid clearance from the blood. The heart-to-blood ratio was 31.9 at 180 min after the injection. The administration of nisoxetine and desipramine decreased (S,S)-[{sup 125}I]IPBM accumulation in the heart, but injection of fluoxetine and GBR12909 had little influence. Conclusions: Radioiodinated (S,S)-IPBM is a potential radioligand for NET imaging in the heart.

  8. Computational modeling suggests distinct, location-specific function of norepinephrine in olfactory bulb and piriform cortex

    Directory of Open Access Journals (Sweden)

    Licurgo ede Almeida

    2015-06-01

    Full Text Available Noradrenergic modulation from the locus coerulus is often associated with the regulation of sensory signal-to-noise ratio. In the olfactory system, noradrenergic modulation affects both bulbar and cortical processing, and has been show to modulate the detection of low concentration stimuli. We here implemented a computational model of the olfactory bulb and piriform cortex, based on known experimental results, to explore how noradrenergic modulation in the olfactory bulb and piriform cortex interact to regulate odor processing. We show that as predicted by behavioral experiments in our lab, norepinephrine can play a critical role in modulating the detection and associative learning of very low odor concentrations. Our simulations show that bulbar norepinephrine serves to pre-process odor representations to facilitate cortical learning, but not recall. We observe the typical non-uniform dose – response functions described for norepinephrine modulation and show that these are imposed mainly by bulbar, but not cortical processing.

  9. Computational modeling suggests distinct, location-specific function of norepinephrine in olfactory bulb and piriform cortex.

    Science.gov (United States)

    de Almeida, Licurgo; Reiner, Seungdo J; Ennis, Matthew; Linster, Christiane

    2015-01-01

    Noradrenergic modulation from the locus coerulus is often associated with the regulation of sensory signal-to-noise ratio. In the olfactory system, noradrenergic modulation affects both bulbar and cortical processing, and has been shown to modulate the detection of low concentration stimuli. We here implemented a computational model of the olfactory bulb and piriform cortex, based on known experimental results, to explore how noradrenergic modulation in the olfactory bulb and piriform cortex interact to regulate odor processing. We show that as predicted by behavioral experiments in our lab, norepinephrine can play a critical role in modulating the detection and associative learning of very low odor concentrations. Our simulations show that bulbar norepinephrine serves to pre-process odor representations to facilitate cortical learning, but not recall. We observe the typical non-uniform dose-response functions described for norepinephrine modulation and show that these are imposed mainly by bulbar, but not cortical processing.

  10. Is cerebral oxygenation negatively affected by infusion of norepinephrine in healthy subjects?

    DEFF Research Database (Denmark)

    Brassard, P.; Seifert, T.; Secher, Niels H.

    2009-01-01

    )) and internal jugular venous oxygen saturation (Sjv(O2)), middle cerebral artery mean flow velocity (MCA Vmean), cardiac output (CO), and arterial partial pressure for carbon dioxide (Pa(CO2)) were evaluated. RESULTS: MAP increased from 88 (79-101) [median (range)] to 115 (98-128) mm Hg with increasing doses......BACKGROUND: Vasopressor agents are commonly used to increase mean arterial pressure (MAP) in order to secure a pressure gradient to perfuse vital organs. The influence of norepinephrine on cerebral oxygenation is not clear. The aim of this study was to evaluate the impact of the infusion...... of norepinephrine on cerebral oxygenation in healthy subjects. METHODS: Three doses of norepinephrine (0.05, 0.1, and 0.15 microg kg(-1) min(-1) for 20 min each) were infused in nine healthy subjects [six males; 26 (6) yr, mean (SD)]. MAP, cerebral oxygenation characterized by frontal lobe oxygenation (Sc(O2...

  11. Cilantro microbiome before and after nonselective pre-enrichment for Salmonella using 16S rRNA and metagenomic sequencing

    OpenAIRE

    Jarvis, Karen G.; White, James R; Grim, Christopher J.; Ewing, Laura; Ottesen, Andrea R; Beaubrun, Junia Jean-Gilles; Pettengill, James B.; Brown, Eric; Hanes, Darcy E.

    2015-01-01

    Background Salmonella enterica is a common cause of foodborne gastroenteritis in the United States and is associated with outbreaks in fresh produce such as cilantro. Salmonella culture-based detection methods are complex and time consuming, and improvments to increase detection sensitivity will benefit consumers. In this study, we used 16S rRNA sequencing to determine the microbiome of cilantro. We also investigated changes to the microbial community prior to and after a 24-hour nonselective...

  12. Potassium current inhibition by nonselective cation channel-mediated sodium entry in rat pheochromocytoma (PC-12) cells.

    OpenAIRE

    Strübing, C; J Hescheler

    1996-01-01

    Under physiological conditions, nonselective cation (NSC) channels mediate the entry of cations into cells, the most important being Na+ and Ca2+. In contrast to the Ca(2+)-dependent signaling mechanisms, little is known about the consequences and the spatial distribution of intracellular [Na+] elevation. In this study we demonstrate that Na+ entry, during the opening of ATP-activated NSC channels, leads to an inhibition of voltage-dependent K+ currents (IK) in cromaffin-like undifferentiated...

  13. β3-ADRENOCEPTORS INHIBIT STIMULATED NOREPINEPHRINE RELEASE IN SPONTANEOUSLY HYPERTENSIVE RATS

    Directory of Open Access Journals (Sweden)

    Torill eBerg

    2014-12-01

    Full Text Available Here, the influence of β3-adrenoceptors on catecholamine release in normotensive and spontaneously hypertensive rats was analysed. Blood pressure was recorded through a femoral artery catheter, and cardiac output by ascending aorta flow. Time from onset of flow to maximum rise in flow indicated inotropy. Total peripheral vascular resistance (TPR was calculated. Norepinephrine release was stimulated with tyramine, which allowed presynaptic release-control to be reflected as changes in the plasma norepinephrine concentration. β3-adrenoceptor agonist (BRL37344 reduced baseline vascular resistance, the tyramine-stimulated norepinephrine overflow and the positive inotropic response to tyramine in hypertensive but not normotensive rats. β3-adrenoceptor antagonist (SR59230A reduced tyramine-stimulated norepinephrine release in both strains and the secretion of epinephrine in hypertensive rats. SR59230A reduced tyramine-induced tachycardia in normotensive rats, and prevented down-regulation of the tyramine-induced rise in resistance in hypertensive rats. It was concluded that the contradicting results obtained by agonist versus antagonist, could be explained by their interaction with two different β-adrenoceptors: The BRL37344-dependent inhibition of stimulated norepinephrine release and positive inotropic response to tyramine was compatible with stimulation of β3-adrenoceptor coupling to inhibitory G-protein. This was observed only in hypertensive rats during stimulated, high levels of circulating catecholamines. The effect of BRL37344 on baseline vascular resistance was compatible with activation of β3-adrenoceptor coupling to endothelial nitric oxide synthase. The inhibitory effect of SR59230A on tyramine-stimulated norepinephrine release in both strains, the increased TPR-response to tyramine in hypertensive rats and tachycardia in normotensive rats may result from inhibition of the low-affinity-state β1-adrenoceptor, also known as the

  14. Characteristics of the norepinephrine-stimulated phosphatidylinositol turnover in rat pineal cell dispersions

    Energy Technology Data Exchange (ETDEWEB)

    Hauser, G.; Smith, T.L.

    1981-10-01

    Dispersed rat pineal cells can be used for the study of the phosphatidylinositol effect. The response to ( - )-norepinephrine of the incorporation of 32Pi into phospholipids is linear with time and cell concentration, stereospecific, and mediated through alpha-1-adrenergic receptors. Na+ in the incubation medium is obligatory for labeling of phosphatidylinositol and phosphatidylcholine by 32P. In the absence of K+, incorporation of 32P is drastically lowered and no stimulation by norepinephrine occurs. Rb+ can replace K+. Omission of Ca2+ or substitution with Sr2+ preferentially lowers incorporation of radioactivity into phosphatidylcholine. Mg2+ is not required for basal or stimulated labeling.

  15. Comparison of Nonshivering Thermogenesis Induced by Norepinephrine Stress in Tree Shrews

    OpenAIRE

    Wan-long Zhu; Di Zhang; Jia Zheng; Lin ZHang; Jin-hu Liu; Jin Cheng; Zheng-kun Wang

    2013-01-01

    Nonshivering thermogenesis (NST)is an important thermogenic mechanism for small mammals. Quantitative measurement of NST is usually stimulated by injection of norepinephrine. The injection dosage of norepinephrine (NE) is critical for eliciting the maximum NST. Three empirical equations of NE dosages were often referenced in previous studies: (1) NE (mg / kg)= 2.53W-0.4; (2) NE(mg/kg) = 3.3W-0.458 and (3) NE(mg/kg)= 6.6W-0.458. In the present study , we used tree shrews (Tupaia bel...

  16. Antidepressant-like drug effects in juvenile and adolescent mice in the tail suspension test: Relationship with hippocampal serotonin and norepinephrine transporter expression and function.

    Directory of Open Access Journals (Sweden)

    Nathan C Mitchell

    2013-10-01

    Full Text Available Depression is a major health problem for which most patients are not effectively treated. This problem is further compounded in children and adolescents where only two antidepressants [both selective serotonin reuptake inhibitors (SSRIs] are currently approved for clinical use. Mouse models provide tools to identify mechanisms that might account for poor treatment response to antidepressants. However, there are few studies in adolescent mice and none in juvenile mice. The tail suspension test (TST is commonly used to assay for antidepressant-like effects of drugs in adult mice. Here we show that the TST can also be used to assay antidepressant-like effects of drugs in C57Bl/6 mice aged 21 (juvenile and 28 (adolescent days post-partum (P. We found that the magnitude of antidepressant-like response to the SSRI escitalopram was less in P21 mice than in P28 or adult mice. The smaller antidepressant response of juveniles was not related to either maximal binding (Bmax or affinity (Kd for [3H]citalopram binding to the serotonin transporter (SERT in hippocampus, which did not vary significantly among ages. Magnitude of antidepressant-like response to the tricyclic desipramine was similar among ages, as were Bmax and Kd values for [3H]nisoxetine binding to the norepinephrine transporter (NET in hippocampus. Together, these findings suggest that juvenile mice are less responsive to the antidepressant-like effects of escitalopram than adults, but that this effect is not due to delayed maturation of SERT in hippocampus. Showing that the TST is a relevant behavioral assay of antidepressant-like activity in juvenile and adolescent mice sets the stage for future studies of the mechanisms underlying the antidepressant response in these young populations.

  17. Inhibitors of serotonin reuptake and specific imipramine binding in human blood plasma

    Energy Technology Data Exchange (ETDEWEB)

    Brusov, O.S.; Fomenko, A.M.; Katasonov, A.B.; Lidemann, R.R.

    1985-12-01

    This paper describes a method of extraction of endogenous inhibitors of specific IMI binding and of 5-HT reuptake, from human blood plasma and the heterogeneity of these compounds is demonstrated. Specific binding was determined as the difference between binding of /sup 3/H-IMI in the absence and in the presence of 50 microM IMI. Under these conditions, specific binding amounted to 70-80% of total binding of /sup 3/H-IMI. It is shown that extract obtained from human blood contains a material which inhibits dose-dependently both 5-HT reuptake and specific binding of /sup 3/H-IMI. Gel-chromatography of extracts of human blood plasma on Biogel P-2 is also shown.

  18. Distinct effects of the serotonin-noradrenaline reuptake inhibitors milnacipran and venlafaxine on rat pineal monoamines.

    Science.gov (United States)

    Muneoka, Katsumasa; Kuwagata, Makiko; Ogawa, Tetsuo; Shioda, Seiji

    2015-06-17

    Monoamine systems are involved in the pathology and therapeutic mechanism of depression. The pineal gland contains large amounts of serotonin as a precursor for melatonin, and its activity is controlled by noradrenergic sympathetic nerves. Pineal diurnal activity and its release of melatonin are relevant to aberrant states observed in depression. We investigated the effects on pineal monoamines of serotonin-noradrenaline reuptake inhibitors, which are widely used antidepressants. Four days of milnacipran treatment led to an increase in noradrenaline and serotonin levels, whereas 4 days of venlafaxine treatment reduced 5-hydroxyindoleacetic acid levels; both agents induced an increase in dopamine levels. Our data suggest that milnacipran increases levels of the precursor for melatonin synthesis by facilitating the noradrenergic regulation of pineal activity and that venlafaxine inhibits serotonin reuptake into noradrenergic terminals on the pineal gland.

  19. Acute selective serotonin reuptake inhibitors regulate the dorsal raphe nucleus causing amplification of terminal serotonin release

    OpenAIRE

    Dankoski, Elyse C.; Carroll, Susan; Wightman, Robert Mark

    2016-01-01

    Abstract Selective serotonin reuptake inhibitors (SSRIs) were designed to treat depression by increasing serotonin levels throughout the brain via inhibition of clearance from the extracellular space. Although increases in serotonin levels are observed after acute SSRI exposure, 3–6 weeks of continuous use is required for relief from the symptoms of depression. Thus, it is now believed that plasticity in multiple brain systems that are downstream of serotonergic inputs contributes to the ther...

  20. Prevalence of Selective Serotonin Reuptake Inhibitors in Pilot Fatalities of Civil Aviation Accidents, 1990-2001

    Science.gov (United States)

    2003-05-01

    Some of the drugs—such as atropine, lidocaine , etomidate, and analgesics—found in the pilot fatalities could have been administered by emergency...system of the pilots prior to the accidents. Thus, pharmacodynamic and pharmacokinetic- level interactions of SSRIs and their active metabolites...2002. 17 6. Baumann P. Pharmacokinetic- pharmacodynamic relationship of the selective serotonin reuptake inhibitors. Clin Pharmacokinet 1996; 31:444

  1. Relationship between brain serotonin transporter binding, plasma concentration and behavioural effect of selective serotonin reuptake inhibitors

    OpenAIRE

    2005-01-01

    The present study was undertaken to characterise the relationship between in vivo brain serotonin transporter (SERT) binding, plasma concentration and pharmacological effect of selective serotonin reuptake inhibitors (SSRIs) in mice. Oral administration of fluvoxamine, fluoxetine, paroxetine and sertraline at pharmacologically relevant doses exerted dose- and time-dependent binding activity of brain SERT as revealed by significant increases in KD for specific [3H]paroxetine binding, and the i...

  2. Norepinephrine Triggers Metaplasticity of LTP by Increasing Translation of Specific mRNAs

    Science.gov (United States)

    Maity, Sabyasachi; Rah, Sean; Sonenberg, Nahum; Gkogkas, Christos G.; Nguyen, Peter V.

    2015-01-01

    Norepinephrine (NE) is a key modulator of synaptic plasticity in the hippocampus, a brain structure crucially involved in memory formation. NE boosts synaptic plasticity mostly through initiation of signaling cascades downstream from beta (ß)-adrenergic receptors (ß-ARs). Previous studies demonstrated that a ß-adrenergic receptor agonist,…

  3. Norepinephrine uptake by hypothalamic tissue from the rat related to feeding

    NARCIS (Netherlands)

    Gugten, J. van der; Slangen, J.L.

    1957-01-01

    Norepinephrine (NE) uptake by rat hypothalamus in vitro was studied in relation to food intake. Significant daily variations in NE uptake were observed in caudal hypothalamus from freely feeding rats. A maximal elevation occurred at the beginning of the night when food intake is also increasing to a

  4. Dietary supplement increases plasma norepinephrine, lipolysis, and metabolic rate in resistance trained men

    OpenAIRE

    Schilling Brian K; Hammond Kelley G; Fisher-Wellman Kelsey H; Bloomer Richard J; Weber Adrianna A; Cole Bradford J

    2009-01-01

    Abstract Correction to Richard J Bloomer, Kelsey H Fisher-Wellman, Kelley G Hammond, Brian K Schilling, Adrianna A Weber and Bradford J Cole: Dietary supplement increases plasma norepinephrine, lipolysis, and metabolic rate in resistance trained men. Journal of the International Society of Sports Nutrition 2009, 6: 4

  5. Dietary supplement increases plasma norepinephrine, lipolysis, and metabolic rate in resistance trained men

    Directory of Open Access Journals (Sweden)

    Schilling Brian K

    2009-04-01

    Full Text Available Abstract Correction to Richard J Bloomer, Kelsey H Fisher-Wellman, Kelley G Hammond, Brian K Schilling, Adrianna A Weber and Bradford J Cole: Dietary supplement increases plasma norepinephrine, lipolysis, and metabolic rate in resistance trained men. Journal of the International Society of Sports Nutrition 2009, 6: 4

  6. Role of norepinephrine in the regulation of rapid eye movement sleep

    Indian Academy of Sciences (India)

    Birendra N Mallick; Sudipta Majumdar; Mohd Faisal; Vikas Yadav; Vibha Madan; Dinesh Pal

    2002-09-01

    Sleep and wakefulness are instinctive behaviours that are present across the animal species. Rapid eye movement (REM) sleep is a unique biological phenomenon expressed during sleep. It evolved about 300 million years ago and is noticed in the more evolved animal species. Although it has been objectively identified in its present characteristic form about half a century ago, the mechanics of how REM is generated, and what happens upon its loss are not known. Nevertheless, extensive research has shown that norepinephrine plays a crucial role in its regulation. The present knowledge that has been reviewed in this manuscript suggests that neurons in the brain stem are responsible for controlling this state and presence of excess norepinephrine in the brain does not allow its generation. Furthermore, REM sleep loss increases levels of norepinephrine in the brain that affects several factors including an increase in Na-K ATPase activity. It has been argued that such increased norepinephrine is ultimately responsible for REM sleep deprivation, associated disturbances in at least some of the physiological conditions leading to alteration in behavioural expression and settling into pathological conditions.

  7. Increasing arterial blood pressure with norepinephrine does not improve microcirculatory blood flow: a prospective study

    NARCIS (Netherlands)

    A. Dubin; M.O. Pozo; C.A. Casabella; F.,Jr Pálizas; G. Murias; M.C. Moseinco; V.S. Kanoore Edul; F. Pálizas; E. Estenssoro; C. Ince

    2009-01-01

    Introduction Our goal was to assess the effects of titration of a norepinephrine infusion to increasing levels of mean arterial pressure (MAP) on sublingual microcirculation. Methods Twenty septic shock patients were prospectively studied in two teaching intensive care units. The patients were mecha

  8. Lack of effect of norepinephrine on cranial haemodynamics and headache in healthy volunteers

    DEFF Research Database (Denmark)

    Lindholt, M; Petersen, K A; Tvedskov, J F

    2009-01-01

    Stress is a provoking factor for both tension-type headache and migraine attacks. In the present single-blind study, we investigated if stress induced by norepinephrine (NE) could elicit delayed headache in 10 healthy subjects and recorded the cranial arterial responses. NE at a dose of 0.025 mic...

  9. The norepinephrine transporter gene is a candidate gene for panic disorder

    DEFF Research Database (Denmark)

    Buttenschøn, H N; Kristensen, A S; Buch, H N

    2011-01-01

    Panic disorder (PD) is an anxiety disorder characterized by recurrent panic attacks with a lifetime prevalence of 4.7%. Genetic factors are known to contribute to the development of the disorder. Several lines of evidence point towards a major role of the norepinephrine system in the pathogenesis...

  10. Intrahippocampal Infusions of Anisomycin Produce Amnesia: Contribution of Increased Release of Norepinephrine, Dopamine, and Acetylcholine

    Science.gov (United States)

    Qi, Zhenghan; Gold, Paul E.

    2009-01-01

    Intra-amygdala injections of anisomycin produce large increases in the release of norepinephrine (NE), dopamine (DA), and serotonin in the amygdala. Pretreatment with intra-amygdala injections of the beta-adrenergic receptor antagonist propranolol attenuates anisomycin-induced amnesia without reversing the inhibition of protein synthesis, and…

  11. Plasma norepinephrine, blood pressure and heart rate response to graded change in body position.

    Science.gov (United States)

    Fiorica, V; Kem, D C

    1985-12-01

    In this study, 44 human subjects underwent either an orthostatic postural change (supine to stand, n = 17) or a graded change in body position (head-up) on a tilt-table (n = 27). No significant changes in systolic blood pressure or mean blood pressure were observed during either maneuver; significant increases, under both conditions, were observed in diastolic blood pressure and heart rate. Plasma norepinephrine concentrations after orthostatic position change increased significantly (supine 181 +/- 14 (S.E.M.) pg X ml-1; stand, 472 +/- 35 pg X ml-1, p less than 0.01). Plasma norepinephrine concentrations during graded postural change increased proportionately with increasing degrees of tilt (r = 0.76, p less than 0.01). A significant correlation between plasma norepinephrine and heart rate was observed during both positional change maneuvers (graded tilt-table, r = 0.80, p less than 0.01; orthostatic, r = 0.50, p less than 0.01). These results suggest that the degree of sympathetic nervous system activity for blood pressure regulation during graded postural change is appropriately reflected by plasma norepinephrine concentrations.

  12. Intrahippocampal Infusions of Anisomycin Produce Amnesia: Contribution of Increased Release of Norepinephrine, Dopamine, and Acetylcholine

    Science.gov (United States)

    Qi, Zhenghan; Gold, Paul E.

    2009-01-01

    Intra-amygdala injections of anisomycin produce large increases in the release of norepinephrine (NE), dopamine (DA), and serotonin in the amygdala. Pretreatment with intra-amygdala injections of the beta-adrenergic receptor antagonist propranolol attenuates anisomycin-induced amnesia without reversing the inhibition of protein synthesis, and…

  13. Fluctuating Estrogen and Progesterone Receptor Expression in Brainstem Norepinephrine Neurons through the Rat Estrous Cycle

    NARCIS (Netherlands)

    Haywood, S.A.; Simonian, S.X.; Beek, van der E.M.; Bicknell, R.J.; Herbison, A.E.

    1999-01-01

    Norepinephrine (NE) neurons within the nucleus tractus solitarii (NTS; A2 neurons) and ventrolateral medulla (A1 neurons) represent gonadal steroid-dependent components of several neural networks regulating reproduction. Previous studies have shown that both A1 and A2 neurons express estrogen recept

  14. Anxiety-induced plasma norepinephrine augmentation increases reactive oxygen species formation by monocytes in essential hypertension.

    Science.gov (United States)

    Yasunari, Kenichi; Matsui, Tokuzo; Maeda, Kensaku; Nakamura, Munehiro; Watanabe, Takanori; Kiriike, Nobuo

    2006-06-01

    An association between anxiety and depression and increased blood pressure (BP) and cardiovascular disease risk has not been firmly established. We examined the hypothesis that anxiety and depression lead to increased plasma catecholamines and to production of reactive oxygen species (ROS) by mononuclear cells (MNC) in hypertensive individuals. We also studied the role of BP in this effect. In Protocol 1, a cross-sectional study was performed in 146 hypertensive patients to evaluate whether anxiety and depression affect BP and ROS formation by MNC through increasing plasma catecholamines. In Protocol 2, a 6-month randomized controlled trial using a subtherapeutic dose of the alpha(1)-adrenergic receptor antagonist doxazosin (1 mg/day) versus placebo in 86 patients with essential hypertension was performed to determine whether the increase in ROS formation by MNC was independent of BP. In Protocol 1, a significant relationship was observed between the following: trait anxiety and plasma norepinephrine (r = 0.32, P < .01); plasma norepinephrine and ROS formation by MNC (r = 0.36, P < .01); and plasma norepinephrine and systolic, diastolic, and mean BP (r = 0.17, P = .04; r = 0.26, P = .02; r = 0.23, P < .01, respectively). In Protocol 2, subtherapeutic doxazosin treatment (1 mg/day) had no significant effect on BP. However doxazosin significantly decreased ROS formation by MNC compared with placebo (P < .01). Trait anxiety may increase plasma norepinephrine and increase ROS formation by MNC independent of BP in hypertensive patients.

  15. Norepinephrine drives persistent activity in prefrontal cortex via synergistic α1 and α2 adrenoceptors.

    Directory of Open Access Journals (Sweden)

    Zizhen Zhang

    Full Text Available Optimal norepinephrine levels in the prefrontal cortex (PFC increase delay-related firing and enhance working memory, whereas stress-related or pathologically high levels of norepinephrine are believed to inhibit working memory via α1 adrenoceptors. However, it has been shown that activation of Gq-coupled and phospholipase C-linked receptors can induce persistent firing, a cellular correlate of working memory, in cortical pyramidal neurons. Therefore, despite its importance in stress and cognition, the exact role of norepinephrine in modulating PFC activity remains elusive. Using electrophysiology and optogenetics, we report here that norepinephrine induces persistent firing in pyramidal neurons of the PFC independent of recurrent fast synaptic excitation. This persistent excitatory effect involves presynaptic α1 adrenoceptors facilitating glutamate release and subsequent activation of postsynaptic mGluR5 receptors, and is enhanced by postsynaptic α2 adrenoceptors inhibiting HCN channel activity. Activation of α2 adrenoceptors or inhibition of HCN channels also enhances cholinergic persistent responses in pyramidal neurons, providing a mechanism of crosstalk between noradrenergic and cholinergic inputs. The present study describes a novel cellular basis for the noradrenergic control of cortical information processing and supports a synergistic combination of intrinsic and network mechanisms for the expression of mnemonic properties in pyramidal neurons.

  16. Fluctuating Estrogen and Progesterone Receptor Expression in Brainstem Norepinephrine Neurons through the Rat Estrous Cycle

    NARCIS (Netherlands)

    Haywood, S.A.; Simonian, S.X.; Beek, van der E.M.; Bicknell, R.J.; Herbison, A.E.

    1999-01-01

    Norepinephrine (NE) neurons within the nucleus tractus solitarii (NTS; A2 neurons) and ventrolateral medulla (A1 neurons) represent gonadal steroid-dependent components of several neural networks regulating reproduction. Previous studies have shown that both A1 and A2 neurons express estrogen

  17. Comparison of norepinephrine and dopamine in the management of septic shock using impedance cardiography

    Directory of Open Access Journals (Sweden)

    Mathur Sharad

    2007-01-01

    Full Text Available Objective: Vasoconstrictors are one of the therapeutic modalities in the treatment of septic shock. In the present study, we have compared the effects of dopamine and norepinephrine in the treatment of septic shock with pre-defined end-points and continuous non-invasive cardiac output monitoring using impedance cardiography. Design: Randomized controlled trial. Settings: Sixteen-bedded mixed intensive care unit of a tertiary care teaching institution. Materials and Methods: The study included 50 consecutive patients presenting with septic shock and divided randomly into two groups with 25 patients in each group. Group I patients were treated with dopamine and those in Group II were treated with norepinephrine. They were optimized with fluid resuscitation upto CVP>10 cm of H 2 O, packed red cells transfusion upto hematocrit> 30, oxygenation and ventilation upto PaO 2 >60 mmHg before the inotropes were started. The goal of therapy was to achieve and maintain for six hours, all of the following: (1 SBP> 90 mm Hg, (2 SVRI> 1100 dynes.s/cm 5 m 2 , (3 Cardiac Index> 4.0L/min/m 2 , (4 IDO 2 > 550 ml/min/m 2 and (5 IVO 2 > 150 ml/min/m 2 . Measurements: The demographic data, baseline parameters and post-treatment parameters were statistically analyzed by using t-test. Results: The post-treatment parameters were statistically significant showing the superiority of norepinephrine over dopamine in optimization of hemodynamics and patient survival. Significant improvement in systolic blood pressure, heart rate, cardiac index, SVRI, IVO 2 and urine output were found in norepinephrine group than the dopamine group. Dopamine showed a response in 10 out of 25 patients up to a maximum dose of 25 mcg/kg/min while with norepinephrine, 19 patients responded up to a maximum dose of 2.5 mcg/kg/min The hemodynamic parameters were preserved in norepinephrine group with better preservation of organ perfusion and oxygen utilization with maintenance of splanchnic and

  18. Protein acylation in the inhibition of insulin secretion by norepinephrine, somatostatin, galanin, and PGE2.

    Science.gov (United States)

    Cheng, Haiying; Straub, Susanne G; Sharp, Geoffrey W G

    2003-08-01

    The major physiological inhibitors of insulin secretion, norepinephrine, somatostatin, galanin, and prostaglandin E2, act via specific receptors that activate pertussis toxin (PTX)-sensitive G proteins. Four inhibitory mechanisms are known: 1) activation of ATP-sensitive K channels and repolarization of the beta-cell; 2) inhibition of L-type Ca2+ channels; 3) decreased activity of adenylyl cyclase; and 4) inhibition of exocytosis at a "distal" site in stimulus-secretion coupling. We have examined the underlying mechanisms of inhibition at this distal site. In rat pancreatic islets, 2-bromopalmitate, cerulenin, and polyunsaturated fatty acids, all of which suppress protein acyltransferase activity, blocked the distal inhibitory effects of norepinephrine in a concentration-dependent manner. In contrast, control compounds such as palmitate, 16-hydroxypalmitate, and etomoxir, which do not block protein acylation, had no effect. Furthermore, 2-bromopalmitate also blocked the distal inhibitory actions of somatostatin, galanin, and prostaglandin E2. Importantly, neither 2-bromopalmitate nor cerulenin affected the action of norepinephrine to decrease cAMP production. We also examined the effects of norepinephrine, 2-bromopalmitate, and cerulenin on palmitate metabolism. Palmitate oxidation and its incorporation into lipids seemed not to contribute to the effects of 2-bromopalmitate and cerulenin on norepinephrine action. These data suggest that protein acylation mediates the distal inhibitory effect on insulin secretion. We propose that the inhibitors of insulin secretion, acting via PTX-sensitive G proteins, activate a specific protein acyltransferase, causing the acylation of a protein or proteins critical to exocytosis. This particular acylation and subsequent disruption of the essential and precise interactions involved in core complex formation would block exocytosis.

  19. Randomized trial of switching from prescribed non-selective non-steroidal anti-inflammatory drugs to prescribed celecoxib

    DEFF Research Database (Denmark)

    Macdonald, Thomas M; Hawkey, Chris J; Ford, Ian;

    2016-01-01

    BACKGROUND: Selective cyclooxygenase-2 inhibitors and conventional non-selective non-steroidal anti-inflammatory drugs (nsNSAIDs) have been associated with adverse cardiovascular (CV) effects. We compared the CV safety of switching to celecoxib vs. continuing nsNSAID therapy in a European setting...... primary events per 1000 patient-years exposure. There were only 15 adjudicated secondary upper gastrointestinal complication endpoints (0.078/100 patient-years on celecoxib vs. 0.053 on nsNSAIDs OT, 0.078 vs. 0.053 ITT). More gastrointestinal serious adverse reactions and haematological adverse reactions...

  20. Sympathetic re-innervation after heart transplantation: dual-isotope neurotransmitter scintigraphy, norepinephrine content and historical examination

    Energy Technology Data Exchange (ETDEWEB)

    Guertner, C. [Univ. Hospital Frankfurt am Main (Germany). Dept. of Nuclear Medicine; Krause, B.J. [Univ. Hospital Frankfurt am Main (Germany). Dept. of Nuclear Medicine; Klepzig, H. Jr. [Univ. Hospital Frankfurt am Main (Germany). Dept. of Cardiology; Herrmann, G. [Univ. Hospital Frankfurt am Main (Germany). Dept. of Pathology; Lelbach, S. [Univ. Hospital Frankfurt am Main (Germany). Dept. of Nuclear Medicine; Vockert, E.K. [Biocenter Niederursel, Frankfurt am Main (Germany). Dept. of Pharmacology; Hartmann, A. [Univ. Hospital Frankfurt am Main (Germany). Dept. of Cardiology; Maul, F.D. [Univ. Hospital Frankfurt am Main (Germany). Dept. of Nuclear Medicine; Kranert, T.W. [Univ. Hospital Frankfurt am Main (Germany). Dept. of Nuclear Medicine; Mutschler, E. [Biocenter Niederursel, Frankfurt am Main (Germany). Dept. of Pharmacology; Huebner, K. [Univ. Hospital Frankfurt am Main (Germany). Dept. of Pathology; Hoer, G. [Univ. Hospital Frankfurt am Main (Germany). Dept. of Nuclear Medicine

    1995-05-01

    Cardiac transplantation entails surgical disruption of the sympathetic nerve fibres from their somata, resulting in sympathetic denervation. In order to investigate the occurrence of sympathetic re-innervation, neurotransmitter scintigraphy using the norepinephrine analogue iodine-123 metaiodobenzylguanidine (MIBG) was performed in 15 patients 2-69 months after transplantation. In addition, norepinephrine content and immunohistochemical reactions of antibodies to Schwann cell-associated S100 protein, to neuron-specific enolase (NSE) and to norepinephrine were examined in 34 endomyocardial biopsies of 29 patients 1-88 months after transplantation. Anterobasal {sup 123}I-MIBG uptake indicating partial sympathetic re-innervation could be shown in 40% of the scintigraphically investigated patients 37-69 months after transplantation. In immunohistochemical studies 83% of the patients investigated 1-72 Months after transplantation showed nerve fibres in their biopsies but not positive reaction to norepinephrine. Significant norepinephrine content indicating re-innervation could not be detected in any biopsy. It was concluded that in spite of the lack of norepinephrine content there seemed to be immunohistological and scintigraphic evidence of sympathetic re-innervation. An explanation for this contradictory finding may be the reduced or missing norepinephrine storage ability compared to the restored uptake ability of regenerated sympathetic nerve fibres. (orig.)

  1. In vivo comparison of norepinephrine and dopamine release in rat brain by simultaneous measurements with fast-scan cyclic voltammetry.

    Science.gov (United States)

    Park, Jinwoo; Takmakov, Pavel; Wightman, R Mark

    2011-12-01

    Brain norepinephrine and dopamine regulate a variety of critical behaviors such as stress, learning, memory, and drug addiction. In this study, we demonstrate differences in the regulation of in vivo neurotransmission for dopamine in the anterior nucleus accumbens (NAc) and norepinephrine in the ventral bed nucleus of the stria terminalis (vBNST) of the anesthetized rat. Release of the two catecholamines was measured simultaneously using fast-scan cyclic voltammetry at two different carbon-fiber microelectrodes, each implanted in the brain region of interest. Simultaneous dopamine and norepinephrine release was evoked by electrical stimulation of a region where the ventral noradrenergic bundle, the pathway of noradrenergic neurons, courses through the ventral tegmental area/substantia nigra, the origin of dopaminergic cell bodies. The release and uptake of norepinephrine in the vBNST were both significantly slower than for dopamine in the NAc. Pharmacological manipulations in the same animal demonstrated that the two catecholamines are differently regulated. The combination of a dopamine autoreceptor antagonist and amphetamine significantly increased basal extracellular dopamine whereas a norepinephrine autoreceptor antagonist and amphetamine did not change basal norepinephrine concentration. α-Methyl-p-tyrosine, a tyrosine hydroxylase inhibitor, decreased electrically evoked dopamine release faster than norepinephrine. The dual-microelectrode fast-scan cyclic voltammetry technique along with anatomical and pharmacological evidence confirms that dopamine in the NAc and norepinephrine in the vBNST can be monitored selectively and simultaneously in the same animal. The high temporal and spatial resolution of the technique enabled us to examine differences in the dynamics of extracellular norepinephrine and dopamine concurrently in two different limbic structures.

  2. The mouse defense test battery: evaluation of the effects of non-selective and BZ-1 (omega1) selective, benzodiazepine receptor ligands.

    Science.gov (United States)

    Griebel, G.; Sanger, D.J.; Perrault, G.

    1996-11-01

    The behavioral effects of several benzodiazepine (BZ) (omega) receptor ligands were compared using the Mouse Defense Test Battery which has been designed to assess defensive reactions of Swiss mice confronted with a natural threat (a rat) and situations associated with this threat. Primary measures taken before, during and after rat confrontation were escape attempts, flight, risk assessment and defensive threat and attack. The drugs used included non-selective BZ (omega) full (clonazepam, clorazepate, chlordiazepoxide and diazepam) and partial (bretazenil and imidazenil) agonists, and BZ-1 (omega1) selective (abecarnil, CL 218,872 and zolpidem) receptor ligands. With the exception of clonazepam, non-selective BZ (omega) receptor compounds only partially affected flight behaviors. The drugs reduced some but not all flight measures in response to the approaching rat, whereas clonazepam attenuated all flight reactions. In contrast to their mild and inconsistent actions on flight, the non-selective BZ (omega) receptor agonists displayed clear effects on risk assessment when subjects were chased by the rat. When contact was forced between the subject and the rat, the non-selective BZ (omega) receptor full agonists reduced defensive threat and attack reactions, while the partial agonists imidazenil and bretazenil only weakly attenuated defensive attack behavior. Similarly, after the rat had been removed from the test area, the non-selective BZ (omega) receptor full agonists displayed greater efficacy than the partial agonists in reducing escape attempts. Overall, results obtained with the selective BZ-1 (omega1) receptor ligands demonstrated either no clear effects or no specific action on defensive reactions. Taken together, these data demonstrate that: (1) non-selective BZ (omega) agonists displaying high intrinsic activity affect a wider range of defensive behaviors than non-selective BZ (omega) receptor partial agonists; (2) the defense system does not involve

  3. Early Recovery of Salmonella from Food Using a 6-Hour Non-selective Pre-enrichment and Reformulation of Tetrathionate Broth

    Science.gov (United States)

    Daquigan, Ninalynn; Grim, Christopher J.; White, James R.; Hanes, Darcy E.; Jarvis, Karen G.

    2016-01-01

    Culture based methods are commonly employed to detect pathogens in food and environmental samples. These methods are time consuming and complex, requiring multiple non-selective and selective enrichment broths, and usually take at least 1 week to recover and identify pathogens. Improving pathogen detection in foods is a primary goal for regulatory agencies and industry. Salmonella detection in food relies on a series of culture steps in broth formulations optimized to resuscitate Salmonella and reduce the abundance of competitive bacteria. Examples of non-selective pre-enrichment broths used to isolate Salmonella from food include Lactose, Universal Pre-enrichment, BPW, and Trypticase Soy broths. Tetrathionate (TT) and Rappaport–Vassiliadis (RV) broths are employed after a 24-h non-selective enrichment to select for Salmonella and hamper the growth of competitive bacteria. In this study, we tested a new formulation of TT broth that lacks brilliant green dye and has lower levels of TT . We employed this TT broth formulation in conjunction with a 6-h non-selective pre-enrichment period and determined that Salmonella recovery was possible one day earlier than standard food culture methods. We tested the shortened culture method in different non-selective enrichment broths, enumerated Salmonella in the non-selective enrichments, and used 16S rRNA gene sequencing to determine the proportional abundances of Salmonella in the TT and RV selective enrichments. Together these data revealed that a 6-h non-selective pre-enrichment reduces the levels of competitive bacteria inoculated into the selective TT and RV broths, enabling the recovery of Salmonella 1 day earlier than standard culture enrichment methods. PMID:28082968

  4. Capillary electrophoresis for the characterization of quantum dots after non-selective or selective bioconjugation with antibodies for immunoassay

    Directory of Open Access Journals (Sweden)

    Lai Edward PC

    2008-10-01

    Full Text Available Abstract Capillary electrophoresis coupled with laser-induced fluorescence was used for the characterization of quantum dots and their conjugates to biological molecules. The CE-LIF was laboratory-built and capable of injection (hydrodynamic and electrokinetic from sample volumes as low as 4 μL via the use of a modified micro-fluidic chip platform. Commercially available quantum dots were bioconjugated to proteins and immunoglobulins through the use of established techniques (non-selective and selective. Non-selective techniques involved the use of EDCHCl/sulfo-NHS for the conjugation of BSA and myoglobin to carboxylic acid-functionalized quantum dots. Selective techniques involved 1 the use of heterobifunctional crosslinker, sulfo-SMCC, for the conjugation of partially reduced IgG to amine-functionalized quantum dots, and 2 the conjugation of periodate-oxidized IgGs to hydrazide-functionalized quantum dots. The migration times of these conjugates were determined in comparison to their non-conjugated QD relatives based upon their charge-to-size ratio values. The performance of capillary electrophoresis in characterizing immunoconjugates of quantum dot-labeled IgGs was also evaluated. Together, both QDs and CE-LIF can be applied as a sensitive technique for the detection of biological molecules. This work will contribute to the advancements in applying nanotechnology for molecular diagnosis in medical field.

  5. The selective serotonin reuptake inhibitor sertraline: its profile and use in psychiatric disorders.

    Science.gov (United States)

    MacQueen, G; Born, L; Steiner, M

    2001-01-01

    The naphthylamine derivative sertraline is a potent and selective inhibitor of serotonin reuptake into presynaptic terminals. Sertraline has a linear pharmacokinetic profile and a half-life of about 26 h. Its major metabolite, desmethylsertraline does not appear to inhibit serotonin reuptake. Sertraline mildly inhibits the CYP2D6 isoform of the cytochrome P450 system but has little effect on CYP1A2, CYP3A3/4, CYP2C9, or CYP2C19. It is, however, highly protein bound and may alter blood levels of other highly protein bound agents. Sertraline is a widely used serotonin reuptake inhibitor that has been shown to have both antidepressant and antianxiety effects. Many clinical trials have demonstrated its efficacy in depression compared with both placebo and other antidepressant drugs. Its efficacy has also been demonstrated in randomized, controlled trials of patients with obsessive-compulsive disorder, panic disorder, social phobia, and premenstrual dysphoric disorder. In short-term, open-label studies it has appeared efficacious and tolerable in children and adolescents and in the elderly, and data are positive for its use in pregnant or lactating women. Typical side effects include gastrointestinal and central nervous system effects as well as treatment-emergent sexual dysfunction; withdrawal reactions may be associated with abrupt discontinuation of the agent. The safety profile of sertraline in overdose is very favorable. Sertraline's efficacy for both mood and anxiety disorders, relatively weak effect on the cytochrome P450 system, and tolerability profile and safety in overdose are factors that contribute to make it a first-line agent for treatment in both primary and tertiary care settings.

  6. 2'-Substitution of cocaine selectively enhances dopamine and norepinephrine transporter binding.

    Science.gov (United States)

    Seale, T W; Avor, K; Singh, S; Hall, N; Chan, H M; Basmadjian, G P

    1997-11-10

    Few studies have characterized the effect of substituents at the 2'-position of cocaine on transporter binding potency and selectivity. We synthesized 2'-OH-, 2'-F- and 2'-acetoxy-cocaines and compared their binding potencies for rat dopamine, norepinephrine and 5-hydroxytryptamine transporters to cocaine, 3'-OH-, 4'-OH-, 2'-OH,4'-I-cocaine derivatives, and to the transporter selective ligands WIN 35,428, nisoxetine and paroxetine. Unlike most substitutions, 2'-OH- and 2'-acetoxy-groups increased cocaine's binding potency for the dopamine transporter (10- and 4-fold, respectively). These substituents also enhanced binding to the norepinephrine transporter (52- and 35-fold, respectively) but had less effect on 5-hydroxytryptamine transporter binding. 2'-Hydroxylation also enhanced binding of 4'-I cocaine, an analog with low DA binding potency. The ability of 2'-substituents to substantially increase cocaine binding potency and to alter selectivity for brain transporters indicates the potential importance of the 2'-position in transporter binding.

  7. Prostacyclin effects on the blood pressure responses to norepinephrine in rats treated with aspirin or indomethacin.

    Science.gov (United States)

    Carmignani, M; Marchetti, P; Caprino, L

    1980-01-01

    The atherosclerotic condition is associated with a reduction of PGI2 synthesis; moreover, in the presence of elevated serum cholesterol levels, pressor responses to norepinephrine are potentiated. In order to verify if a complete inhibition of PGI2 production affects the vascular reactivity, it was assayed two cycloxygenase inhibitors (lysine acetylsalicylate and indomethacin) in rats. The two drugs significantly potentiated the blood pressure responses to norepinephrine, and completely inhibited PGI2-like substances production by arterial rings. The prostacyclin infusion (15 ng/kg/min, i.v.) completely reversed such potentiation, without any major modification in the basal blood pressure values. These results show that PGI2 production is responsible for vascular tone modulation and may partially explain the altered vascular reactivity in the atherosclerotic condition.

  8. Testing whether drugs that weaken norepinephrine signaling prevent or treat various types of cancer

    Directory of Open Access Journals (Sweden)

    Paul J Fitzgerald

    2009-12-01

    Full Text Available Paul J FitzgeraldThe Zanvyl Krieger Mind/Brain Institute, Solomon H. Snyder, Department of Neuroscience, Johns Hopkins University, Baltimore, MD, USAAbstract: Recently, I put forth the hypothesis that the signaling molecule, norepinephrine (NE, is an etiological factor in a number of types of cancer. In this brief commentary, I summarize evidence that NE plays a role in cancer and describe details involved in testing the hypothesis in humans through epidemiological investigation of existing medical records of persons who have taken pharmaceutical drugs that affect NE. If NE plays an etiological role in cancers of a number of organs, then taking a single pharmaceutical drug (such as clonidine, prazosin, or propranolol that weakens NE signaling systemically, may simultaneously prevent or treat many different types of cancer, and this may represent a breakthrough in pharmaceutical prevention and possibly treatment of cancer.Keywords: norepinephrine, acetylcholine, cancer, clonidine, prazosin, propranolol

  9. Impaired glucose-induced thermogenesis and arterial norepinephrine response persist after weight reduction in obese humans

    DEFF Research Database (Denmark)

    Astrup, A; Andersen, T; Christensen, N J;

    1990-01-01

    A reduced thermic response and an impaired activation of the sympathetic nervous system (SNS) has been reported after oral glucose in human obesity. It is, however, not known whether the reduced SNS activity returns to normal along with weight reduction. The thermic effect of glucose was lower...... in eight obese patients than in matched control subjects (1.7% vs 9.2%, p less than 0.002). The increase in arterial norepinephrine after glucose was also blunted in the obese patients. After a 30-kg weight loss their glucose and lipid profiles were markedly improved but the thermic effect of glucose...... was still lower than that of the control subjects (4.2%, p less than 0.001). The glucose-induced arterial norepinephrine response remained diminished in the reduced obese patients whereas the changes in plasma epinephrine were similar in all three groups. The results suggest that a defective SNS may...

  10. Paediatric outcomes following intrauterine exposure to serotonin reuptake inhibitors: a systematic review

    DEFF Research Database (Denmark)

    Fenger-Grøn, Jesper; Thomsen, Morten; Andersen, Kristian Skytte

    2011-01-01

    The use of serotonine reuptake inhibitors (SRIs) is increasing among Danish pregnant women. This systematic review addresses the potential adverse effects on the foetus and child of maternal SRI medication. The literature indicates a slightly increased risk of cardiovascular malformations...... and persistent pulmonary hypertension of the new-born, while evidence regarding the risk of preterm labour, low birth weight, low Apgar score, prolonged QT interval and miscarriage is less clear. An estimated 20-30% of infants will have neonatal symptoms following intrauterine SRI exposure. The symptoms may...

  11. Mixture and single-substance toxicity of selective serotonin reuptake inhibitors toward algae and crustaceans

    DEFF Research Database (Denmark)

    Christensen, Anne Munch; Faaborg-Andersen, S.; Ingerslev, Flemming

    2007-01-01

    with an identical mechanism of action in mammals (inhibit reuptake of serotonin), and they have been found in different aqeous as well as biological samples collected in the environment. In the present study, we tested the toxicities of five SSRIs (citalopram, fluoxetine, fluoxamine, paroxetine, and sertraline......) as single substances and of citalopram, fluoxetine. and sertraline in binary mixtures in two standardized bioassays. Test organisms were the freshwater algae Pseudo-kirchneriella subcapitata and the freshwater crustacean Daphnia magna. In algae, test median effect concentrations (EC50s) ranged from 0...

  12. Selective serotonin re-uptake inhibitors (SSRIs) in the aquatic environment: an ecopharmacovigilance approach.

    Science.gov (United States)

    Silva, Liliana J G; Lino, Celeste M; Meisel, Leonor M; Pena, Angelina

    2012-10-15

    Selective serotonin re-uptake inhibitors (SSRIs) antidepressants are among the most prescribed pharmaceutical active substances throughout the world. The occurrence of these widely used compounds in different environmental compartments (wastewaters, surface, ground and drinking waters, and sediments), justify the growing concern about these emerging environmental pollutants. Viewing an ecopharmacovigilance approach, a comprehensive discussion of the state of the art regarding different contamination sources, fate, degradation and occurrence is presented. Information on the current distribution levels and fate in different environmental matrices continues to be sparse and measures are imperative to improve awareness and encourage precautionary actions to minimize SSRIs' environmental impact.

  13. [HYPERPROLACTINEMIA AND SELECTIVE SEROTONIN REUPTAKE INHIBITORS. A NARRATIVE REVIEW OF THE LITERATURE].

    Science.gov (United States)

    Rosón-González, Mirian; Tajima-Pozo, Kazuhiro; Montañés-Rada, Francisco

    2015-01-01

    A large number of scientific papers have reported the relationship between the development of hyperprolactinemia and the use of psychotropic drugs, especially the role of antipsychotics which are antidopaminergic drugs. However, less information is known about the role of antidepressants in the development of hyperprolactinemia, specially the selective reuptake inhibitors (SSRIs). The prevalence of hyperprolactinemia as a pharmacological side effect of SSRIs is still unknown, despite the widespread use over the last decade. The aim of this review is to explore the relationship between hyperprolactinemia and SSRIs.

  14. Maternal use of selective serotonin reuptake inhibitors and risk of miscarriage

    DEFF Research Database (Denmark)

    Johansen, Rie Laurine Rosenthal; Mortensen, Laust Hvas; Andersen, Anne-Marie Nybo

    2015-01-01

    BACKGROUND: The use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy has been associated with miscarriage, but the association may be biased by maternal mental illness, lifestyle and exposure misclassification. METHODS: A register study on all pregnancies in Denmark between 1996......-exposed pregnancies were characterised by an unhealthier maternal lifestyle and mental health profile than unexposed pregnancies, whereas no convincing differences were observed between pregnancies exposed to SSRIs during versus before pregnancy. Substantial disagreement was found between prescriptions and self......-reported use of SSRIs, but it did not affect the estimated hazard ratios. CONCLUSION: Confounding by indication and lifestyle in pregnancy may explain the association between SSRI use and miscarriage....

  15. Retrospective review of selective serotonin reuptake inhibitors and falling in older nursing home residents.

    Science.gov (United States)

    Arfken, C L; Wilson, J G; Aronson, S M

    2001-03-01

    We compared the rate of falling in older nursing home residents who had been prescribed selective serotonin reuptake inhibitors (SSRIs), other classes of antidepressants, and no antidepressants. Data were obtained from pharmacy records, medical records, fall logs, and incidence reports for one nursing home (1995 data). Older adults on SSRIs were more likely to fall than older adults not on antidepressants (p = .003) and were more likely to have an injurious fall (p = .03). The association with falling remained significant even when including potential confounders (p = .007). Older nursing home residents should be treated for depression. However, SSRIs may also carry an increased risk for falling.

  16. Social Isolation is associated with Elevated Tumor Norepinephrine in Ovarian Carcinoma Patients

    OpenAIRE

    Lutgendorf, Susan K.; DeGeest, Koen; Dahmoush, Laila; Farley, Donna; Penedo, Frank; Bender, David; Goodheart, Michael; Buekers, Thomas E.; Mendez, Luis; Krueger, Gina; Clevenger, Lauren; Lubaroff, David M.; Anil K Sood; Cole, Steve W.

    2010-01-01

    Noradrenergic pathways have been implicated in growth and progression of ovarian cancer. Intratumoral norepinephrine (NE) has been shown to increase with stress in an animal cancer model, but little is known regarding how tumor NE varies with disease stage and with biobehavioral factors in ovarian cancer patients. This study examined relationships between pre-surgical measures of social support, depressed mood, perceived stress, anxiety, tumor histology and tumor catecholamine (NE and epineph...

  17. Cortical serotonin and norepinephrine denervation in parkinsonism: Preferential loss of the beaded serotonin innervation

    OpenAIRE

    2009-01-01

    Parkinson’s Disease (PD) is marked by prominent motor symptoms that reflect striatal dopamine insufficiency. However, non-motor symptoms, including depression, are common in PD. These changes have been suggested to reflect pathological involvement of non-dopaminergic systems. We examined regional changes in serotonin and norepinephrine systems in mice treated with two different 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment paradigms and that survived for 3 or 16 weeks after th...

  18. Manipulation of norepinephrine metabolism with yohimbine in the treatment of autonomic failure

    Science.gov (United States)

    Biaggioni, I.; Robertson, R. M.; Robertson, D.

    1994-01-01

    It has been postulated that alpha 2-adrenergic receptors play a modulatory role in the regulation of blood pressure. Activation of alpha 2-receptors located in the central nervous system results in inhibition of sympathetic tone and decrease of blood pressure. This indeed may be the mechanism of action of central sympatholytic antihypertensives such as alpha-methyldopa. Presynaptic alpha 2-receptors also are found in adrenergic nerve terminals. These receptors act as a negative feedback mechanism by inhibiting the release of norepinephrine. The relevance of alpha 2-adrenergic receptors for blood pressure regulation can be explored with yohimbine, a selective antagonist of these receptors. Yohimbine increases blood pressure in resting normal volunteers. This effect is associated with an increase in both sympathetic nerve activity, reflecting an increase in central sympathetic outflow, and in norepinephrine spillover, reflecting potentiation of the release of norepinephrine from adrenergic nerve terminals. These actions, therefore, underscore the importance of alpha 2-adrenergic receptors for blood pressure regulation even under resting conditions. Patients with autonomic failure, even those with severe sympathetic deprivation, are hypersensitive to the pressor effects of yohimbine. This increased responsiveness can be explained by sensitization of adrenergic receptors, analogous to denervation supersensitivity, and by the lack of autonomic reflexes that would normally buffer any increase in blood pressure. Preliminary studies suggest that the effectiveness of yohimbine in autonomic failure can be enhanced with monoamine oxidase inhibitors. Used in combination, yohimbine increases norepinephrine release, whereas monoamine oxidase inhibitors inhibit its degradation. Therefore, yohimbine is not only a useful tool in the study of blood pressure regulation, but may offer a therapeutic option in autonomic dysfunction.

  19. Stereoselective Actions of Methylenedioxypyrovalerone (MDPV) To Inhibit Dopamine and Norepinephrine Transporters and Facilitate Intracranial Self-Stimulation in Rats

    National Research Council Canada - National Science Library

    Kolanos, R; Partilla, J S; Baumann, M H; Hutsell, B A; Banks, M L; Negus, S S; Glennon, R A

    2015-01-01

    ...) and norepinephrine (NET) that produces a constellation of abuse-related behavioral effects. MDPV possesses a chiral center, and the abused formulation of the drug is a racemic mixture, but no data are available on the pharmacology of its isomers...

  20. Reference intervals and variation for urinary epinephrine, norepinephrine and cortisol in healthy men and women in Denmark

    DEFF Research Database (Denmark)

    Hansen, Åse Marie; Garde, A H; Christensen, J M

    2001-01-01

    Reference intervals for urinary epinephrine, norepinephrine and cortisol in 120 healthy individuals performing their routine work were established according to the International Union of Pure and Applied Chemistry (IUPAC) and the International Federation of Clinical Chemistry and Laboratory...

  1. Changes in evolution of free epinephrine, norepinephrine, and vanillylmandelic acid in the urine of rabbits during late pregnancy and parturition.

    Science.gov (United States)

    Parvez, S; Parvez, H

    1976-02-01

    The present study describes evolutionary changes in urinary excretion of epinephrine, norepinephrine, and vanillylmandelic acid during pregnancy and parturition. Both the catecholamines and their metabolite were determined in 24 hour urine samples of rabbits from day 13 of pregnancy. During 13 and 28 days of gestation, urinary excretion of epinephrine was at its lowest value. As compared to normal rabbits, an increase of 135 per cent in epinephrine excretion during day 30 of pregnancy was observed. Norepinephrine excretion reached its maximum level during day 13 but constant declines occurred afterward. Contrary to epinephine, urinary excretion of norepinephrine was at the highest value days 23 and 30 of pregnancy. After day 19 vanillylmandelic acid declined continuously up to day 30. During parturition vanillymandelic acid and norepinephrine excretion returned to the control values but epinephrine remained slightly higher. These alterations in catecholamine urinary excretion have been suggested as a consequence of modified endocrine and sympathetic activity.

  2. Orexin A promotes histamine, but not norepinephrine or serotonin, release in frontal cortex of mice

    Institute of Scientific and Technical Information of China (English)

    Zong-yuan HONG; Zhi-li HUANG; Wei-min QU; Naomi EGUCHI

    2005-01-01

    Aim: To investigate the effects of orexin A on release of histamine, norepinephrine, and serotonin in the frontal cortex of mice. Methods: Samples for measuring histamine, norepinephrine, and serotonin contents were collected by in vivo microdialysis of the frontal cortex of anesthetized mice. The histamine,noradrenaline, and serotonin content in dialysates were measured by HPLC techniques. Results: Intracrebroventricular injection of orexin A at doses of 12.5, 50, and 200 pmol per mouse promoted histamine release from the frontal cortex in a dose-dependent manner. At the highest dose given, 200 pmol, orexin A significantly induced histamine release, with the maximal magnitude being 230% over the mean basal release. The enhanced histamine release was sustained for 140 min, and then gradually returned to the basal level. However, no change in nore pinephrine or serotonin release was observed under application of the same dose of orexin A. Conclusion: These results suggest that the arousal effect of orexin A is mainly mediated by histamine, not by norepinephrine or serotonin.

  3. Cardiovascular alterations after injection of 2% lidocaine with norepinephrine 1:50,000 (xylestesin) in rats.

    Science.gov (United States)

    Faraco, Fatima Neves; Armonia, Paschoal Laercio; Malamed, Stanley F

    2007-01-01

    The purpose of the present study is to determine the cardiovascular effects produced by intravascular injection of 2% lidocaine with 20 microg/mL of norepinephrine on systolic, diastolic, and mean arterial pressures and heart rate of rats at the following times: control period, during the injection (first 15 seconds), during the first minute, and at the end of 1, 2, 3, 4, 5, 10, 15, 20, 25, and 30 minutes after drug administration. The study was performed on 13 male Wistar rats with weights between 200 grams and 220 grams that were awake during the recording of these parameters. The dose administered was proportional to 1 cartridge of local anesthetic (1.8 mL) in an average-size human, which is equivalent to 0.51 mg/kg of lidocaine hydrochloride and 0.51 microg/kg of norepinephrine hydrochloride. The average time of injection was 15.7 seconds. The results of this study showed significant increases in systolic, diastolic, and mean arterial pressure and a noticeable decrease in heart rate. The greatest variation occurred in the systolic blood pressure. The greatest alterations occurred during injection and within the first minute following administration of the anesthetic solution. We would anticipate these changes in the parameters analyzed to be clinically significant. Thus, dentists using 2% lidocaine with norepinephrine 20 mug/mL should be very careful to avoid intravascular injection.

  4. The influence of age on dorsal hand vein responsiveness to norepinephrine.

    Science.gov (United States)

    Martin, S A; Alexieva, S; Carruthers, S G

    1986-09-01

    The influence of age on the responsiveness of dorsal hand vein alpha-receptors to local infusions of norepinephrine was investigated by the use of a novel technique, the linear variable differential transformer. Studies were conducted in two groups of healthy subjects, 26 elderly individuals (14 men and 12 women) 60 to 78 years old and 32 young individuals (24 men and eight women) 16 to 29 years old. There was wide interindividual variation in responsiveness to norepinephrine within both groups of subjects. The dose of norepinephrine required to produce 50% venoconstriction in the elderly ranged from 1.5 to 300 ng/min (geometric mean 24.0 ng/min). The dose required to produce 50% venoconstriction in younger individuals ranged from 1.6 to 360 ng/min (geometric mean 23.8 ng/min). These results suggest that there is no systematic influence of age on dorsal hand vein alpha-receptor responsiveness. A power calculation demonstrates a very small likelihood of a type II error.

  5. Dopamine and norepinephrine depletion in ring doves fed DDE, dieldrin, and Aroclor 1254

    Science.gov (United States)

    Heinz, G.H.; Hill, E.F.; Contrera, J.F.

    1980-01-01

    The levels of dopamine and norepinephrine were measured in one-half of the brain of ring doves fed a control diet or a diet containing 2, 20, or 200 ppm DDE; 1, 4, or 16 ppm dieldrin; or 1, 10, or 100 ppm Aroclor 1254. Levels of DDE, dieldrin, or Aroclor 1254 were determined in the other half of each brain. The intermediate and high levels of each chemical caused depletions in both neurotransmitters, and brain residues of each chemical were negatively correlated with levels of neurotransmitters. The highest concentrations of DDE, dieldrin, and Aroclor 1254 depressed averages of dopamine to 42.4, 41.4, and 45.2% of the control level and norepinephrine to 61.6, 62.0, and 56.9% of controls, respectively. Depletions of dopamine and norepinephrine could result in abnormal behavior of contaminated birds in the wild, and the detection of such depletions could become an important tool in assessing contaminant-induced behavioral aberrations in birds.

  6. Norepinephrine remains increased in the six-minute walking test after heart transplantation

    Directory of Open Access Journals (Sweden)

    Guilherme Veiga Guimarães

    2010-01-01

    Full Text Available OBJECTIVE: We sought to evaluate the neurohormonal activity in heart transplant recipients and compare it with that in heart failure patients and healthy subjects during rest and just after a 6-minute walking test. INTRODUCTION: Despite the improvements in quality of life and survival provided by heart transplantation, the neurohormonal profile is poorly described. METHODS: Twenty heart transplantation (18 men, 49±11 years and 8.5±3.3 years after transplantation, 11 heart failure (8 men, 43±10 years, and 7 healthy subjects (5 men 39±8 years were included in this study. Blood samples were collected immediately before and during the last minute of the exercise. RESULTS: During rest, patients' norepinephrine plasma level (659±225 pg/mL was higher in heart transplant recipients (463±167 pg/mL and heathy subjects (512±132, p<0.05. Heart transplant recipient's norepinephrine plasma level was not different than that of healthy subjects. Just after the 6-minute walking test, the heart transplant recipient's norepinephrine plasma level (1248±692 pg/mL was not different from that of heart failure patients (1174±653 pg/mL. Both these groups had a higher level than healthy subjects had (545±95 pg/mL, p<0.05. CONCLUSION: Neurohormonal activity remains increased after the 6-minute walking test after heart transplantation.

  7. Heart rate variability, overnight urinary norepinephrine, and plasma cholesterol in apparently healthy human adults.

    Science.gov (United States)

    Thayer, Julian F; Fischer, Joachim E

    2013-01-20

    The aim of this study was to assess the relationship between autonomic nervous system activity as indexed by measures of heart rate variability and overnight urinary norepinephrine, and plasma cholesterol levels in a large sample of working adults. The study population comprised 611 apparently healthy employees of an airplane manufacturing plant in Southern Germany. Heart rate variability was calculated as beat-to-beat intervals over the course of one 24-hour weekday measured with an ambulatory ECG recorder. Overnight urine collection and blood samples were also obtained. We found an inverse association between indices of vagally-mediated heart rate variability and plasma levels of total cholesterol, low density lipoprotein (LDL), and the ratio of LDL to high density lipoprotein (HDL) that remained significant in multivariate models after controlling for relevant covariates including norepinephrine. Urinary norepinephrine was not significantly related to any measure of cholesterol in multivariate models. We report here for the first time, in a large sample of healthy human adults, evidence supporting the hypothesis of a clinically relevant inverse relationship between measures of plasma cholesterol and vagally-mediated heart rate variability after controlling for sympathetic nervous system activity. This suggests an important role for the vagal control of plasma cholesterol levels in cardiovascular disease. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  8. Stimulatory effects of neuronally released norepinephrine on renin release in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Matsumura, Yasuo; Kawazoe, Shinka; Ichihara, Toshio; Shinyama, Hiroshi; Kageyama, Masaaki; Morimoto, Shiro (Osaka Univ. of Pharmaceutical Sciences (Japan))

    1988-10-01

    Extracellular high potassium inhibits renin release in vitro by increasing calcium concentrations in the juxtaglomerular cells. The authors found that the decreased response of renin release from rat kidney cortical slices in high potassium solution changed to a strikingly increased one in the presence of nifedipine at doses over 10{sup {minus}6} M. They then examined the stimulatory effect of extracellular high potassium in the presence of nifedipine on renin release. The enhancement of release was significantly suppressed either by propranolol or by metoprolol but not by prazosin. High potassium plus nifedipine-induced increase in renin release was markedly attenuated by renal denervation. The enhancing effect was not observed when the slices were incubated in calcium-free medium. Divalent cations such as Cd{sup 2+}, Co{sup 2+}, and Mn{sup 2+} blocked this enhancement in a concentration-dependent manner. High potassium elicited an increase in {sup 3}H efflux from the slices preloaded with ({sup 3}H)-norepinephrine. The increasing effect was not influenced by nifedipine but was abolished by the removal of extracellular calcium or by the addition of divalent cations. These observations suggest to us that the high potassium plus nifedipine-induced increase in renin release from the slices is mediated by norepinephrine derived from renal sympathetic nerves and that this neuronally released norepinephrine stimulates renin release via activation of {beta}-adrenoceptors.

  9. Cardiovascular Alterations After Injection of 2% Lidocaine With Norepinephrine 1:50,000 (Xylestesin) in Rats

    Science.gov (United States)

    Faraco, Fatima Neves; Armonia, Paschoal Laercio; Malamed, Stanley F

    2007-01-01

    The purpose of the present study is to determine the cardiovascular effects produced by intravascular injection of 2% lidocaine with 20 μg/mL of norepinephrine on systolic, diastolic, and mean arterial pressures and heart rate of rats at the following times: control period, during the injection (first 15 seconds), during the first minute, and at the end of 1, 2, 3, 4, 5, 10, 15, 20, 25, and 30 minutes after drug administration. The study was performed on 13 male Wistar rats with weights between 200 grams and 220 grams that were awake during the recording of these parameters. The dose administered was proportional to 1 cartridge of local anesthetic (1.8 mL) in an average-size human, which is equivalent to 0.51 mg/kg of lidocaine hydrochloride and 0.51 μg/kg of norepinephrine hydrochloride. The average time of injection was 15.7 seconds. The results of this study showed significant increases in systolic, diastolic, and mean arterial pressure and a noticeable decrease in heart rate. The greatest variation occurred in the systolic blood pressure. The greatest alterations occurred during injection and within the first minute following administration of the anesthetic solution. We would anticipate these changes in the parameters analyzed to be clinically significant. Thus, dentists using 2% lidocaine with norepinephrine 20 μg/mL should be very careful to avoid intravascular injection. PMID:17579502

  10. Norepinephrine causes epigenetic repression of PKCε gene in rodent hearts by activating Nox1-dependent reactive oxygen species production.

    Science.gov (United States)

    Xiong, Fuxia; Xiao, Daliao; Zhang, Lubo

    2012-07-01

    Heart disease is the leading cause of death in the United States. Recent studies demonstrate that fetal programming of PKCε gene repression results in ischemia-sensitive phenotype in the heart. The present study tests the hypothesis that increased norepinephrine causes epigenetic repression of PKCε gene in the heart via Nox1-dependent reactive oxygen species (ROS) production. Prolonged norepinephrine treatment increased ROS production in fetal rat hearts and embryonic ventricular myocyte H9c2 cells via a selective increase in Nox1 expression. Norepinephrine-induced ROS resulted in an increase in PKCε promoter methylation at Egr-1 and Sp-1 binding sites, leading to PKCε gene repression. N-acetylcysteine, diphenyleneiodonium, and apocynin blocked norepinephrine-induced ROS production and the promoter methylation, and also restored PKCε mRNA and protein to control levels in vivo in fetal hearts and in vitro in embryonic myocyte cells. Accordingly, norepinephrine-induced ROS production, promoter methylation, and PKCε gene repression were completely abrogated by knockdown of Nox1 in cardiomyocytes. These findings provide evidence of a novel interaction between elevated norepinephrine and epigenetic repression of PKCε gene in the heart mediated by Nox1-dependent oxidative stress and suggest new insights of molecular mechanisms linking the heightened sympathetic activity to aberrant cardioprotection and increased ischemic vulnerability in the heart.

  11. Fluid loading and norepinephrine infusion mask the left ventricular preload decrease induced by pleural effusion.

    Science.gov (United States)

    Wemmelund, Kristian Borup; Ringgård, Viktor Kromann; Vistisen, Simon Tilma; Hyldebrandt, Janus Adler; Sloth, Erik; Juhl-Olsen, Peter

    2017-09-11

    Pleural effusion (PLE) may lead to low blood pressure and reduced cardiac output. Low blood pressure and reduced cardiac output are often treated with fluid loading and vasopressors. This study aimed to determine the impact of fluid loading and norepinephrine infusion on physiologic determinants of cardiac function obtained by ultrasonography during PLE. In this randomised, blinded, controlled laboratory study, 30 piglets (21.9 ± 1.3 kg) had bilateral PLE (75 mL/kg) induced. Subsequently, the piglets were randomised to intervention as follows: fluid loading (80 mL/kg/h for 1.5 h, n = 12), norepinephrine infusion (0.01, 0.03, 0.05, 0.1, 0.2 and 0.3 μg/kg/min (15 min each, n = 12)) or control (n = 6). Main outcome was left ventricular preload measured as left ventricular end-diastolic area. Secondary endpoints included contractility and afterload as well as global measures of circulation. All endpoints were assessed with echocardiography and invasive pressure-flow measurements. PLE decreased left ventricular end-diastolic area, mean arterial pressure and cardiac output (p values  0.05) to baseline. Left ventricular contractility increased with norepinephrine infusion (p = 0.002), but was not affected by fluid loading (p = 0.903). Afterload increased in both active groups (p values > 0.001). Overall, inferior vena cava distensibility remained unchanged during intervention (p values ≥ 0.085). Evacuation of PLE caused numerical increases in left ventricular end-diastolic area, but only significantly so in controls (p = 0.006). PLE significantly reduced left ventricular preload. Both fluid and norepinephrine treatment reverted this effect and normalised global haemodynamic parameters. Inferior vena cava distensibility remained unchanged. The haemodynamic significance of PLE may be underestimated during fluid or norepinephrine administration, potentially masking the presence of PLE.

  12. Hospital patients' perceptions during treatment and early discontinuation of serotonin selective reuptake inhibitor antidepressants.

    Science.gov (United States)

    Woolley, Stephen B; Fredman, Lisa; Goethe, John W; Lincoln, Alisa K; Heeren, Timothy

    2010-12-01

    Studies have suggested that discontinuation of treatment in depressed patients is associated with their perceptions about their treatment. We surveyed 403 adults treated for major depressive disorder with a selective serotonin reuptake inhibitor (SSRI) 3 months after onset of treatment to assess their interactions with clinicians, reasons they stopped SSRI treatment, and SSRI side effects (SEs). Bothersome SEs, poorer instruction by physicians about SSRI SEs, and self-reported change in depression, sex, marital status, and employment were significantly (P < 0.05) associated with discontinuation. Logistic regression examined the associations between patients' perceptions during treatment planning and SSRI discontinuation. Seventeen percent of patients felt uninvolved in treatment decisions, 9% disagreed with the diagnosis, and 24% subsequently stopped treatment. Elevated risk of discontinuation was found among patients who felt uninvolved in treatment decisions (unadjusted risk ratio [RR], 2.3; 95% confidence interval [CI], 1.2-4.3) and those who disagreed with the diagnosis (RR, 2.0; CI, 0.9-4.4). Patients who both felt uninvolved and disagreed with the diagnosis were 7-fold as likely to discontinue their SSRI (RR, 7.3; CI, 1.5-36.3) compared with those who felt neither uninvolved nor disagreed. Selective serotonin reuptake inhibitor SEs, specific interactions with clinicians, self-assessed outcomes, and sociodemographics did not explain these associations. To improve adherence to medications, clinicians should consider patients' perceptions about their involvement in treatment decisions and agreement with their diagnosis.

  13. Selective Serotonin Reuptake Inhibitors: A Review of its Effects on Intraocular Pressure

    Science.gov (United States)

    Costagliola, Ciro; Parmeggiani, Francesco; Semeraro, Francesco; Sebastiani, Adolfo

    2008-01-01

    The increase in serotonin (5-HT) neurotransmission is considered to be one of the most efficacious medical approach to depression and its related disorders. The selective serotonin reuptake inhibitors (SSRIs) represent the most widely antidepressive drugs utilized in the medical treatment of depressed patients. Currently available SSRIs include fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram and escitalopram. The primary SSRIs pharmacological action’s mechanism consists in the presynaptic inhibition on the serotonin reuptake, with an increased availability of this amine into the synaptic cleft. Serotonin produces its effects as a consequence of interactions with appropriate receptors. Seven distinct families of 5-HT receptors have been identified (5-HT1 to 5-HT7), and subpopulations have been described for several of these. The interaction between serotonin and post-synaptic receptors mediates a wide range of functions. The SSRIs have a very favorable safety profile, although clinical signs of several unexpected pathologic events are often misdiagnosed, in particular, those regarding the eye. In all cases reported in the literature the angle-closure glaucoma represents the most important SSRIs-related ocular adverse event. Thus, it is not quite hazardous to hypothesize that also the other reported and unspecified visual disturbances could be attributed - at least in some cases - to IOP modifications. The knowledge of SSRIs individual tolerability, angle-closure predisposition and critical IOP could be important goals able to avoid further and more dangerous ocular side effects. PMID:19587851

  14. Reduced serotonin reuptake transporter (SERT) function causes insulin resistance and hepatic steatosis independent of food intake.

    Science.gov (United States)

    Chen, Xiaoning; Margolis, Kara J; Gershon, Michael D; Schwartz, Gary J; Sze, Ji Y

    2012-01-01

    Serotonin reuptake transporter (SERT) is a key regulator of serotonin neurotransmission and a major target of antidepressants. Antidepressants, such as selectively serotonin reuptake inhibitors (SSRIs), that block SERT function are known to affect food intake and body weight. Here, we provide genetic evidence that food intake and metabolism are regulated by separable mechanisms of SERT function. SERT-deficient mice ate less during both normal diet and high fat diet feeding. The reduced food intake was accompanied with markedly elevated plasma leptin levels. Despite reduced food intake, SERT-deficient mice exhibited glucose intolerance and insulin resistance, and progressively developed obesity and hepatic steatosis. Several lines of evidence indicate that the metabolic deficits of SERT-deficient mice are attributable to reduced insulin-sensitivity in peripheral tissues. First, SERT-deficient mice exhibited beta-cell hyperplasia and islet-mass expansion. Second, biochemical analyses revealed constitutively elevated JNK activity and diminished insulin-induced AKT activation in the liver of SERT-deficient mice. SERT-deficient mice exhibited hyper-JNK activity and hyperinsulinemia prior to the development of obesity. Third, enhancing AKT signaling by PTEN deficiency corrected glucose tolerance in SERT-deficient mice. These findings have potential implications for designing selective SERT drugs for weight control and the treatment of metabolic syndromes.

  15. Reduced serotonin reuptake transporter (SERT function causes insulin resistance and hepatic steatosis independent of food intake.

    Directory of Open Access Journals (Sweden)

    Xiaoning Chen

    Full Text Available Serotonin reuptake transporter (SERT is a key regulator of serotonin neurotransmission and a major target of antidepressants. Antidepressants, such as selectively serotonin reuptake inhibitors (SSRIs, that block SERT function are known to affect food intake and body weight. Here, we provide genetic evidence that food intake and metabolism are regulated by separable mechanisms of SERT function. SERT-deficient mice ate less during both normal diet and high fat diet feeding. The reduced food intake was accompanied with markedly elevated plasma leptin levels. Despite reduced food intake, SERT-deficient mice exhibited glucose intolerance and insulin resistance, and progressively developed obesity and hepatic steatosis. Several lines of evidence indicate that the metabolic deficits of SERT-deficient mice are attributable to reduced insulin-sensitivity in peripheral tissues. First, SERT-deficient mice exhibited beta-cell hyperplasia and islet-mass expansion. Second, biochemical analyses revealed constitutively elevated JNK activity and diminished insulin-induced AKT activation in the liver of SERT-deficient mice. SERT-deficient mice exhibited hyper-JNK activity and hyperinsulinemia prior to the development of obesity. Third, enhancing AKT signaling by PTEN deficiency corrected glucose tolerance in SERT-deficient mice. These findings have potential implications for designing selective SERT drugs for weight control and the treatment of metabolic syndromes.

  16. Exploration of structure-activity relationships for dual serotonin transporter reuptake inhibitors-histamine H3 receptor antagonists.

    Science.gov (United States)

    Stocking, Emily M; Letavic, Michael A; Bonaventure, Pascal; Carruthers, Nicholas I

    2010-01-01

    Depression is a major health issue, which is routinely treated with selective serotonin reuptake inhibitors. However, although these agents display a favorable effect on mood, they often fail to improve conditions that accompany depression including cognitive impairment and fatigue. In pre-clinical studies histamine H(3) receptor antagonists have demonstrated both pro-cognitive and wake-promoting effects suggesting that the combination of a histamine H(3) receptor antagonist and a serotonin reuptake inhibitor may have utility as an antidepressant therapy. To this end we sought to introduce histamine H(3) receptor antagonist activity into both known selective serotonin reuptake inhibitors and novel templates. These efforts have afforded several series of compounds with the desired activities. Selected examples demonstrated in vivo efficacy both in pre-clinical models of depression and wakefulness.

  17. Dopamine reuptake transporter (DAT) "inverse agonism"--a novel hypothesis to explain the enigmatic pharmacology of cocaine.

    Science.gov (United States)

    Heal, David J; Gosden, Jane; Smith, Sharon L

    2014-12-01

    The long held view is cocaine's pharmacological effects are mediated by monoamine reuptake inhibition. However, drugs with rapid brain penetration like sibutramine, bupropion, mazindol and tesofensine, which are equal to or more potent than cocaine as dopamine reuptake inhibitors, produce no discernable subjective effects such as drug "highs" or euphoria in drug-experienced human volunteers. Moreover they are dysphoric and aversive when given at high doses. In vivo experiments in animals demonstrate that cocaine's monoaminergic pharmacology is profoundly different from that of other prescribed monoamine reuptake inhibitors, with the exception of methylphenidate. These findings led us to conclude that the highly unusual stimulant profile of cocaine and related compounds, eg methylphenidate, is not mediated by monoamine reuptake inhibition alone. We describe the experimental findings which suggest cocaine serves as a negative allosteric modulator to alter the function of the dopamine reuptake transporter (DAT) and reverse its direction of transport. This results in a firing-dependent, retro-transport of dopamine into the synaptic cleft. The proposed mechanism of cocaine is, therefore, different from other small molecule negative allostereric modulators of the monoamine reuptake transporters, eg SoRI-6238, which merely reduce the rate of inward transport. Because the physiological role of DAT is to remove dopamine from the synapse and the action of cocaine is the opposite of this, we have postulated that cocaine's effect is analogous to an inverse agonist. If this hypothesis is validated then cocaine is the prototypical compound that exemplifies a new class of monoaminergic drugs; DAT "inverse agonists". This article is part of the Special Issue entitled 'CNS Stimulants'.

  18. Pyrrolo- and pyridomorphinans: non-selective opioid antagonists and delta opioid agonists/mu opioid partial agonists.

    Science.gov (United States)

    Kumar, V; Clark, M J; Traynor, J R; Lewis, J W; Husbands, S M

    2014-08-01

    Opioid ligands have found use in a number of therapeutic areas, including for the treatment of pain and opiate addiction (using agonists) and alcohol addiction (using antagonists such as naltrexone and nalmefene). The reaction of imines, derived from the opioid ligands oxymorphone and naltrexone, with Michael acceptors leads to pyridomorphinans with structures similar to known pyrrolo- and indolomorphinans. One of the synthesized compounds, 5e, derived from oxymorphone had substantial agonist activity at delta opioid receptors but not at mu and/or kappa opioid receptors and in that sense profiled as a selective delta opioid receptor agonist. The pyridomorphinans derived from naltrexone and naloxone were all found to be non-selective potent antagonists and as such could have utility as treatments for alcohol abuse.

  19. Effects of the non-selective phosphodiesterase inhibitor pentoxifylline on regional cerebral blood flow and large arteries in healthy subjects

    DEFF Research Database (Denmark)

    Kruuse, Christina; Jacobsen, T B; Thomsen, Lars Lykke

    2000-01-01

    -inhalation SPECT. High-frequency ultrasound was used for measurements of temporal and radial artery diameter. Cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) concentrations were assessed in plasma. Except for increased heart rate (P blood pressure (P ... or to other mechanisms is not clear. In the present double-blind crossover study, 10 healthy subjects received pentoxifylline 300 mg or placebo intravenously on separate days. Blood flow velocity in the middle cerebral artery (V(mca)) was recorded by transcranial Doppler and rCBF was measured using (133)Xenon......The vasodilating properties of the non-selective phosphodiesterase (PDE) inhibitor pentoxifylline were evaluated. Pentoxifylline has been reported to increase cerebral blood flow (CBF) and improve recovery rate of stroke patients. Whether these results are due to a dilating effect on arteries...

  20. Non-selective beta-adrenergic blockade prevents reduction of the cerebral metabolic ratio during exhaustive exercise in humans

    DEFF Research Database (Denmark)

    Larsen, T.S.; Rasmussen, P.; Overgaard, M.

    2008-01-01

    of a non-selective beta-adrenergic (beta(1) + beta(2)) receptor antagonist (propranolol) reduced heart rate (69 +/- 8 to 58 +/- 6 beats min(-1)) and exercise capacity (239 +/- 42 to 209 +/- 31 W; P exercise with propranolol, the increase in a......Intense exercise decreases the cerebral metabolic ratio of oxygen to carbohydrates [O(2)/(glucose + (1/2)lactate)], but whether this ratio is influenced by adrenergic stimulation is not known. In eight males, incremental cycle ergometry increased arterial lactate to 15.3 +/- 4.2 mm (mean +/- s.......d.) and the arterial-jugular venous (a-v) difference from -0.02 +/- 0.03 mm at rest to 1.0 +/- 0.5 mm (P increased from 0.7 +/- 0.3 to 0.9 +/- 0.1 mm (P

  1. Comparison of cardiovascular thrombotic events in patients with osteoarthritis treated with rofecoxib versus nonselective nonsteroidal anti-inflammatory drugs (ibuprofen, diclofenac, and nabumetone).

    Science.gov (United States)

    Reicin, Alise S; Shapiro, Deborah; Sperling, Rhoda S; Barr, Eliav; Yu, Qinfen

    2002-01-15

    Aspirin, nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), and specific cyclooxygenase-2 (COX-2) inhibitors each have distinctive effects on COX-1-mediated thromboxane biosynthesis, the major determinant of platelet aggregation. It is unclear whether these effects are associated with differences in thrombogenic risks. To compare the risk for thrombotic cardiovascular events among patients receiving rofecoxib, nonselective NSAIDs, and placebo, cardiovascular safety was assessed in 5,435 participants in 8 phase IIB/III osteoarthritis trials. The median treatment exposure was 31/2 months. The primary end point assessed was the risk of any arterial or venous thrombotic cardiovascular adverse event (AE). A second analysis assessed differences in the Anti-Platelet Trialists' Collaboration (APTC) events, a cluster end point that consists of the combined incidence of (1) cardiovascular, hemorrhagic, and unknown death; (2) myocardial infarction; and (3) cerebrovascular accident. Similar rates of thrombotic cardiovascular AEs were reported with rofecoxib, placebo, and comparator nonselective NSAIDs (ibuprofen, diclofenac, or nabumetone). In trials that compared rofecoxib with NSAIDs, the incidence of thrombotic cardiovascular AEs was 1.93/100 patient-years in the rofecoxib treatment group compared with 2.27/100 patient-years in the combined nonselective NSAID group. In trials that compared rofecoxib with placebo, the incidence of thrombotic cardiovascular AEs was 2.71/100 patient-years in the rofecoxib group compared with 2.57/100 patient-years in the placebo group. Consistent with the risks of cardiovascular AEs, similar rates of APTC events were reported with rofecoxib, placebo, and comparator nonselective NSAIDs. Thus, in the rofecoxib osteoarthritis development program, there was no difference between rofecoxib, comparator nonselective NSAIDs, and placebo in the risks of cardiovascular thrombotic events.

  2. Cilantro microbiome before and after nonselective pre-enrichment for Salmonella using 16S rRNA and metagenomic sequencing.

    Science.gov (United States)

    Jarvis, Karen G; White, James R; Grim, Christopher J; Ewing, Laura; Ottesen, Andrea R; Beaubrun, Junia Jean-Gilles; Pettengill, James B; Brown, Eric; Hanes, Darcy E

    2015-08-12

    Salmonella enterica is a common cause of foodborne gastroenteritis in the United States and is associated with outbreaks in fresh produce such as cilantro. Salmonella culture-based detection methods are complex and time consuming, and improvments to increase detection sensitivity will benefit consumers. In this study, we used 16S rRNA sequencing to determine the microbiome of cilantro. We also investigated changes to the microbial community prior to and after a 24-hour nonselective pre-enrichment culture step commonly used by laboratory analysts to resuscitate microorganisms in foods suspected of contamination with pathogens. Cilantro samples were processed for Salmonella detection according to the method in the United States Food and Drug Administration Bacteriological Analytical Manual. Genomic DNA was extracted from culture supernatants prior to and after a 24-hour nonselective pre-enrichment step and 454 pyrosequencing was performed on 16S rRNA amplicon libraries. A database of Enterobacteriaceae 16S rRNA sequences was created, and used to screen the libraries for Salmonella, as some samples were known to be culture positive. Additionally, culture positive cilantro samples were examined for the presence of Salmonella using shotgun metagenomics on the Illumina MiSeq. Time zero uncultured samples had an abundance of Proteobacteria while the 24-hour enriched samples were composed mostly of Gram-positive Firmicutes. Shotgun metagenomic sequencing of Salmonella culture positive cilantro samples revealed variable degrees of Salmonella contamination among the sequenced samples. Our cilantro study demonstrates the use of high-throughput sequencing to reveal the microbiome of cilantro, and how the microbiome changes during the culture-based protocols employed by food safety laboratories to detect foodborne pathogens. Finding that culturing the cilantro shifts the microbiome to a predominance of Firmicutes suggests that changing our culture-based methods will improve

  3. Stretch-activated nonselective cation, Cl- and K+ channels in apical membrane of epithelial cells of Reissner's membrane.

    Science.gov (United States)

    Yeh, T H; Tsai, M C; Lee, S Y; Hsu, M M; Tran Ba Huy, P

    1997-07-01

    Ion channels on the apical membrane of epithelial cells (the surface facing the endolymph) of acutely isolated Reissner's membrane from guinea-pig cochlea were investigated by using patch-clamp technique in cell-attached and inside-out configurations. Three types of ion channel were identified: namely, a stretch-activated nonselective cation, a chloride and a potassium channel. When the pipette was filled with high-K+ endolymph-like solution, the most significant channel activity was nonselective cation channels (85/110, 77% patches). The current versus voltage relationship was linear with a unitary conductance of 22.1 +/- 0.4 pS and reversal potential (Vr) of 2.3 +/- 0.8 mV (n = 18). The channel exhibited a lower conductance (14.0 +/- 0.6 pS, n = 8) to Ca2+. The open probability was low (NPo approximately 0.1) in cell-attached configuration under +60 mV pipette potential and increased when the membrane was stretched with negative pressure. The channel was blocked by 10 microM extracellular Gd3+. The two other types of channels were a small voltage-sensitive Cl- channel (6.0 +/- 0.3 pS; 91/99, 92% patches) and a K+ channel (approximately 30 pS; 29/191, 15% patches). These channels might play roles in the regulation of cell volume, in balancing the hydrostatic pressure across Reissner's membrane and in maintaining the electrochemical composition of endolymph.

  4. Similar reductions in the risk of human colon cancer by selective and nonselective cyclooxygenase-2 (COX-2 inhibitors

    Directory of Open Access Journals (Sweden)

    Alshafie Galal A

    2008-08-01

    Full Text Available Abstract Background Epidemiologic and laboratory investigations suggest that aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs have chemopreventive effects against colon cancer perhaps due at least in part to their activity against cyclooxygenase-2 (COX-2, the rate-limiting enzyme of the prostaglandin cascade. Methods We conducted a case control study of colon cancer designed to compare effects of selective and non-selective COX-2 inhibitors. A total of 326 incident colon cancer patients were ascertained from the James Cancer Hospital, Columbus, Ohio, during 2003–2004 and compared with 652 controls with no history of cancer and matched to the cases at a 2:1 ratio on age, race, and county of residence. Data on the past and current use of prescription and over the counter medications and colon cancer risk factors were ascertained using a standardized risk factor questionnaire. Effects of COX-2 inhibiting agents were quantified by calculating odds ratios (OR and 95% confidence intervals. Results Results showed significant risk reductions for selective COX-2 inhibitors (OR = 0.31, 95% CI = 0.16–0.57, regular aspirin (OR = 0.33, 95% CI = 0.20–0.56, and ibuprofen or naproxen (0.28, 95% CI = 0.15–0.54. Acetaminophen, a compound with negligible COX-2 activity and low dose aspirin (81 mg produced no significant change in the risk of colon cancer. Conclusion These results suggest that both non-selective and selective COX-2 inhibitors produce significant reductions in the risk of colon cancer, underscoring their strong potential for colon cancer chemoprevention.

  5. Effects of selective serotonin reuptake inhibition on neural activity related to risky decisions and monetary rewards in healthy males

    DEFF Research Database (Denmark)

    Macoveanu, Julian; Fisher, Patrick M; Haahr, Mette E

    2014-01-01

    Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine are commonly prescribed antidepressant drugs targeting the dysfunctional serotonin (5-HT) system, yet little is known about the functional effects of prolonged serotonin reuptake inhibition in healthy individuals. Here we used...... functional MRI (fMRI) to investigate how a three-week fluoxetine intervention influences neural activity related to risk taking and reward processing. Employing a double-blinded parallel-group design, 29 healthy young males were randomly assigned to receive 3 weeks of a daily dose of 40 mg fluoxetine...

  6. β1-blockers lower norepinephrine release by inhibiting presynaptic, facilitating β1-adrenoceptors in normotensive and hypertensive rats

    Directory of Open Access Journals (Sweden)

    Torill eBerg

    2014-04-01

    Full Text Available Peripheral norepinephrine release is facilitated by presynaptic β-adrenoceptors (AR, believed to involve the β2-subtype exclusively. However, β1-selective blockers are the most commonly used β-blockers in hypertension. Here I tested the hypothesis that β1AR may function as presynaptic, release-facilitating auto-receptors. Since β1AR-blockers are injected during myocardial infarction, their influence on the cardiovascular response to acute norepinephrine release was also studied. By a newly established method, using tyramine-stimulated release through the norepinephrine transporter (NET, presynaptic control of catecholamine release was studied in normotensive and spontaneously hypertensive rats. β1AR-selective antagonists (CGP20712A, atenolol, metoprolol reduced norepinephrine overflow to plasma equally efficient as β2AR-selective (ICI-118551 and β1+2AR (nadolol antagonists in both strains. Neither antagonist lowered epinephrine secretion. Atenolol, which does not cross the blood-brain barrier, reduced norepinephrine overflow after adrenalectomy, adrenalectomy+ganglion blockade, losartan or nephrectomy. Atenolol and metoprolol reduced resting cardiac work load. During tyramine-stimulated norepinephrine release, they had little effect on work load, and increased the transient rise in total peripheral vascular resistance, particularly atenolol when combined with losartan. In conclusion, β1AR, like β2AR, stimulated norepinephrine but not epinephrine release, independent of adrenal catecholamines, ganglion transmission, or renal renin release/angiotensin AT1-receptor activation. β1AR therefore functioned as a peripheral, presynaptic, facilitating auto-receptor. Like tyramine, hypoxia may induce NET-mediated release. Augmented tyramine-induced vasoconstriction, as observed after injection of β1AR-blocker, particularly atenolol combined with losartan, may hamper organ perfusion, and may have clinical relevance in hypoxic conditions such as

  7. The role of norepinephrine and insulin resistance in an early stage of hypertension.

    Science.gov (United States)

    Penesova, Adela; Radikova, Zofia; Cizmarova, Eva; Kvetnanský, Richard; Blazicek, Pavel; Vlcek, Miroslav; Koska, Juraj; Vigas, Milan

    2008-12-01

    The interrelationship between activity of sympathetic nervous system and metabolic risk factors in youth with hypertension (HT) has been poorly studied. The aim of our present study was to assess the interrelationship between metabolic risk factors, such as insulin resistance, concentration of plasminogen activator inhibitor (PAI)-1, and catecholamines in an early stage of HT onset. An oral glucose tolerance test was performed in 17 young males with early-diagnosed nontreated HT grade 1 and 16 gender-, age-, and BMI-matched normotensive controls. Concentrations of glucose, insulin, epinephrine, norepinephrine, PAI-1, and plasma renin activity (PRA) were determined in venous plasma. Insulin sensitivity indices (ISIs) proposed by Cederholm, Matsuda, and Gutt were calculated. HT had higher baseline levels of norepinephrine, insulin (P= 0.02), and PAI-1 (P= 0.04). ISIs were lower in HT subjects (P < 0.001). Baseline concentrations of epinephrine were negatively associated with HDL cholesterol (r=-0.415, P= 0.02), ISI Matsuda (r=-0.361, P= 0.04), ISI Cederholm (r=-0.354, P= 0.04), and ISI Gutt (r=-0.429, P= 0.01), and positively with PRA (r= 0.609, P < 0.0001). Positive association was found between baseline concentrations of norepinephrine and PAI-1 (r= 0.418, P= 0.02). The sympathetic overactivity, which occurs in the early stage of HT may contribute to reduced insulin sensitivity even in young patients and intensify the undesirable development of metabolic cardiovascular risk factors and progress of the disease.

  8. Comparative study of dopamine and norepinephrine in the management of septic shock

    Directory of Open Access Journals (Sweden)

    Avinash Agrawal

    2011-01-01

    Full Text Available Objective: The objective was to compare the ability of norepinephrine and dopamine in reversing the hemodynamic and metabolic abnormalities of septic shock using Edwards Vigileo Monitor with Flotrac Sensor. Design: Prospective randomized control study. Methods: Fifty consecutive patients presenting with hyperdynamic septic shock who fulfilled the inclusion criteria were randomly allocated to either group I or group II. The goal of therapy was to achieve and maintain for 6 hours, all of the following - systolic blood pressure (SBP >90 mmHg, systemic vascular resistance index (SVRI >1800 dynes.s/cm 5 m 2 ,cardiac index (CI >4.0 lt/min/m 2 , index of oxygen delivery >550 ml/min/m 2 , index of oxygen uptake >150 ml/min/m 2 . The patients in group I were started on dopamine infusion at 10 μg/kg/min which was increased by 2.5 μg/kg/min, every 15 minutes till the goals were achieved. The patients in group II received norepinephrine infusion started at a dose of 0.5 μg/kg/min with a dose increment of 0.25 μg/kg/min, every 15 minutes till the goals were achieved. Results: Post-treatment heart rate showed an increase in the mean value in group I patients and a decrease in group II patients. The post-treatment mean SBP and SVRI in group II was significantly higher than that in group I. Patients in group I showed a significantly higher increase in post-treatment CI and index of oxygen delivery compared to patients in group II. Nineteen out of 25 patients responded to the treatment in group II while only 10 out of 25 responded in group I. Conclusion: Norepinephrine was more useful in reversing the hemodynamic and metabolic abnormalities of hyperdynamic septic shock compared to dopamine.

  9. Effect of severe acidosis on vasoactive effects of epinephrine and norepinephrine in human distal mammary artery.

    Science.gov (United States)

    Vidal, Charles; Grassin-Delyle, Stanislas; Devillier, Philippe; Naline, Emmanuel; Lansac, Emmanuel; Ménasché, Philippe; Faisy, Christophe

    2014-05-01

    Acidosis is a very common pathologic process in perioperative management. However, how to correct severe acidosis to improve the efficacy of vasoconstrictors in hemodynamically unstable patients is still debated. The present study investigated whether severe extracellular acidosis influences the vasoactive properties of vasoconstrictors on human isolated arteries. Segments of intact distal internal mammary arteries were removed from 41 patients undergoing artery bypass grafting. The arterial rings were washed in Krebs-Henseleit solution and suspended in an organ bath. The rings were set at a pretension equivalent of 100 mm Hg, and the relaxation response to 10 μM acetylcholine was verified. Concentration-response curves for epinephrine, norepinephrine, methoxamine (α1A/D-adrenoceptor agonist), phenylephrine (equipotent agonist of α1A/B-adrenoceptors), and clonidine (α2-adrenoceptor agonist) were achieved under control conditions (pH 7.40) and under acidic conditions by substitution of the Krebs-Henseleit solution with a modified solution. Decreasing the pH from 7.40 to 7.20, 7.0, or 6.80 did not significantly alter the potency and efficacy of epinephrine and norepinephrine, although the standardized effect size was sometimes large. Severe acidosis (pH 6.80) did not significantly change the potency and efficacy of phenylephrine and clonidine, although it increased the efficacy and potency of methoxamine (P acidosis did not impair the vasoactive properties of epinephrine and norepinephrine in human medium-size arteries until pH 6.80. The results of the present study also suggest that acidosis might potentiate arterial responsiveness to vasoconstrictors, mostly by way of the α1D-adrenoceptor. Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

  10. Negative feedback regulation of Homer 1a on norepinephrine-dependent cardiac hypertrophy

    Energy Technology Data Exchange (ETDEWEB)

    Chiarello, Carmelina; Bortoloso, Elena; Carpi, Andrea; Furlan, Sandra; Volpe, Pompeo, E-mail: pompeo.volpe@unipd.it

    2013-07-15

    Homers are scaffolding proteins that modulate diverse cell functions being able to assemble signalling complexes. In this study, the presence, sub-cellular distribution and function of Homer 1 was investigated. Homer 1a and Homer 1b/c are constitutively expressed in cardiac muscle of both mouse and rat and in HL-1 cells, a cardiac cell line. As judged by confocal immunofluorescence microscopy, Homer 1a displays sarcomeric and peri-nuclear localization. In cardiomyocytes and cultured HL-1 cells, the hypertrophic agonist norepinephrine (NE) induces α{sub 1}-adrenergic specific Homer 1a over-expression, with a two-to-three-fold increase within 1 h, and no up-regulation of Homer 1b/c, as judged by Western blot and qPCR. In HL-1 cells, plasmid-driven over-expression of Homer 1a partially antagonizes activation of ERK phosphorylation and ANF up-regulation, two well-established, early markers of hypertrophy. At the morphometric level, NE-induced increase of cell size is likewise and partially counteracted by exogenous Homer 1a. Under the same experimental conditions, Homer 1b/c does not have any effect on ANF up-regulation nor on cell hypertrophy. Thus, Homer 1a up-regulation is associated to early stages of cardiac hypertrophy and appears to play a negative feedback regulation on molecular transducers of hypertrophy. -- Highlights: • Homer 1a is constitutively expressed in cardiac tissue. • In HL-1 cells, norepinephrine activates signaling pathways leading to hypertrophy. • Homer 1a up-regulation is an early event of norepinephrine-induced hypertrophy. • Homer 1a plays a negative feedback regulation modulating pathological hypertrophy. • Over-expression of Homer 1a per se does not induce hypertrophy.

  11. Leptin Modulates Norepinephrine-Mediated Melatonin Synthesis in Cultured Rat Pineal Gland

    OpenAIRE

    Rodrigo Antonio Peliciari-Garcia; Jéssica Andrade-Silva; José Cipolla-Neto; Carla Roberta de Oliveira Carvalho

    2013-01-01

    Pineal melatonin synthesis can be modulated by many peptides, including insulin. Because melatonin appears to alter leptin synthesis, in this work we aimed to investigate whether leptin would have a role on norepinephrine- (NE-)mediated melatonin synthesis in cultured rat pineal glands. According to our data, cultured rat pineal glands express leptin receptor isoform b (Ob-Rb). Pineal expression of Ob-Rb mRNA was also observed in vivo. Administration of leptin (1 nM) associated with NE (1 µM)...

  12. The modulatory effect of substance P on rat pineal norepinephrine release and melatonin secretion

    DEFF Research Database (Denmark)

    Mukda, Sujira; Ebadi, Manuchair; Govitrapong, Piyarat

    2009-01-01

    Secretion of melatonin by the mammalian pineal gland is primarily regulated by the release of norepinephrine (NE) from sympathetic nerve terminals that originate from the superior cervical ganglia. Peptidergic nerves that originate in the perikarya located in the sensory trigeminal ganglia also...... or melatonin secretion in rat pineal organ cultures. However, in the presence of NE, substance P inhibited the NE-induced increase in AANAT activity and melatonin secretion. This is the first time that a function for substance P in the mammalian pineal gland has been demonstrated....

  13. Reviewing the serotonin reuptake inhibitors (SSRIs) footprint in the aquatic biota: uptake, bioaccumulation and ecotoxicology.

    Science.gov (United States)

    Silva, Liliana J G; Pereira, André M P T; Meisel, Leonor M; Lino, Celeste M; Pena, Angelina

    2015-02-01

    Selective serotonin re-uptake inhibitors (SSRIs) antidepressants are amongst the most prescribed pharmaceutical active substances throughout the world. Their presence, already described in different environmental compartments such as wastewaters, surface, ground and drinking waters, and sediments, and their remarkable effects on non-target organisms justify the growing concern about these emerging environmental pollutants. A comprehensive review of the literature data with focus on their footprint in the aquatic biota, namely their uptake, bioaccumulation and both acute and chronic ecotoxicology is presented. Long-term multigenerational exposure studies, at environmental relevant concentrations and in mixtures of related compounds, such as oestrogenic endocrine disruptors, continue to be sparse and are imperative to better know their environmental impact. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. Pharmacogenetics of selective serotonin reuptake inhibitors in pediatric depression and anxiety.

    Science.gov (United States)

    Kronenberg, Sefi; Frisch, Amos; Rotberg, Beni; Carmel, Miri; Apter, Alan; Weizman, Abraham

    2008-11-01

    Selective serotonin reuptake inhibitors (SSRIs) are now an accepted and widely used first-line treatment for pediatric depression and anxiety. However, the data indicate that SSRI treatment achieves a clinical response in only 55-60% of children, and some may develop drug-induced suicidal behavior. Clinicians have no reliable tools to help them identify in advance those youths who are not likely to respond to an SSRI, or who are likely to develop SSRI-induced suicidality. Pharmacogenetic research attempts to identify genetic markers that are associated with response and side-effect profile. This review covers all the pharmacogenetic studies conducted as yet on pediatric samples and compares them with available data on adult samples. An emphasis is put on serotonergic genes such as the serotonin transporter (5-HTT) and additional genes known to be active in the CNS.

  15. A randomized controlled trial of a novel mixed monoamine reuptake inhibitor in adults with ADHD

    Directory of Open Access Journals (Sweden)

    Wesnes Keith

    2008-06-01

    Full Text Available Abstract Background NS2359 is a potent reuptake blocker of noradrenalin, dopamine, and serotonin. The aim of the study was to investigate the efficacy, safety and cognitive function of NS2359 in adults with a DSM IV diagnosis of ADHD. Methods The study was a multi-centre, double-blind, randomized placebo-controlled, parallel group design in outpatient adults (18–55 years testing 0.5 mg NS2359 vs. placebo for 8 weeks. Multiple assessments including computerized neuropsychological evaluation were performed. Results There was no significant difference between NS2359 (n = 63 versus placebo (n = 63 on the primary outcome measure reduction in investigator rated ADHD-RS total score (7.8 versus 6.4; p Conclusion No overall effect of NS2359 was found on overall symptoms of ADHD. There was also a modest signal of improvement in the inattentive adults with ADHD and cognition warranting further exploration using differing doses.

  16. In utero exposure to selective serotonin reuptake inhibitors and risk for autism spectrum disorder

    DEFF Research Database (Denmark)

    Gidaya, Nicole B; Lee, Brian K; Burstyn, Igor

    2014-01-01

    We investigated whether there is an association between increased risk for autism spectrum disorders (ASD) and selective serotonin reuptake inhibitors (SSRIs) used during pregnancy. This study used Denmark's health and population registers to obtain information regarding prescription drugs, ASD...... diagnosis, and health and socioeconomic status. There were 1.5 % of cases and 0.7 % of controls exposed to SSRIs during the pregnancy period, and higher effect estimates observed with longer use. We found evidence that in utero exposure to SSRIs increases a child's risk associated with ASD. These results......, while adding to the limited knowledge on prenatal pharmacological exposures as potential ASD risk factors, need to be balanced against the benefits of indicated medication use by pregnant mothers....

  17. Severe hyponatremia associated with the combined use of thiazide diuretics and selective serotonin reuptake inhibitors.

    Science.gov (United States)

    Rosner, Mitchell H

    2004-02-01

    Thiazide diuretics and selective serotonin reuptake inhibitors (SSRIs) are among the most commonly prescribed medications. Each medication has been associated with the development of severe hyponatremia. The mechanisms involved in the development of hyponatremia differ for each medication. Thiazide diuretics induce hyponatremia by impairment of urinary dilution, renal loss of sodium and potassium, stimulation of antidiuretic hormone (ADH), and perhaps from a dipsogenic effect. SSRIs cause hyponatremia through the syndrome of inappropriate ADH release. Two cases of severe hyponatremia in patients taking both a thiazide diuretic and an SSRI highlight the possibility of a synergistic effect in impairment of renal free water clearance when both medications are given. These two cases serve as a cautionary example and should prompt careful monitoring of patients prescribed both an SSRI and a thiazide diuretic (especially in elderly women, who seem to be at increased risk for this complication).

  18. Selective serotonin reuptake inhibitor antidepressant use in first trimester pregnancy and risk of congenital anomalies

    DEFF Research Database (Denmark)

    Wemakor, A.; Casson, K.; Garne, E.

    2015-01-01

    Objective / Background The Selective Serotonin Reuptake Inhibitor (SSRI) antidepressants are widely prescribed in pregnancy, but there is evidence that they may cause congenital anomalies, particularly congenital heart defects (CHD). Objective: To determine the specificity of association between...... first trimester pregnancy exposure to individual SSRI and specific congenital anomalies (CAs). Methods Population-based case-malformed control study covering 3.3 million births from 12 EUROCAT registries 1995-2009. CAs included non-syndromic live births, fetal deaths and terminations of pregnancy...... % CI 1.67-6.75, n=9), and Ebstein's anomaly (OR 8.23, 95 % CI 2.91-23.28, n=4) were detected. Statistically significant associations between SSRI and four of the 15 non- CHDsignals (anorectal atresia and stenosis, gastroschisis, renal dysplasia, clubfoot) were found. In all the statistically...

  19. Exposure to Selective Serotonin Reuptake Inhibitors in Early Pregnancy and the Risk of Miscarriage

    DEFF Research Database (Denmark)

    Andersen, Jon Thor Trærup; Andersen, Nadia Lyhne; Horwitz, Henrik

    2014-01-01

    OBJECTIVE: To investigate whether exposure to selective serotonin reuptake inhibitors (SSRIs) in early pregnancy is associated with miscarriage. METHODS: This was a nationwide cohort study identifying all registered pregnancies in Denmark from 1997 to 2010. All births were identified using...... the Medical Birth Registry, and all records of induced abortion or miscarriage were gathered from the National Hospital Register. Data on SSRI use were gathered from the National Prescription Register. Cox proportional hazard regression models were used to calculate the hazard of miscarriage in women exposed......,883) ended in miscarriage compared with 11.1% among unexposed. The adjusted hazard ratio of having a miscarriage after exposure to an SSRI was 1.27 (95% confidence interval [CI] 1.22-1.33) compared with unexposed. Women discontinuing SSRI treatment 3-12 months before pregnancy also had an increased hazard...

  20. Selective Serotonin Reuptake Inhibitor (SSRI) Antidepressants in Pregnancy and Congenital Anomalies

    DEFF Research Database (Denmark)

    Jordan, Sue; Morris, Joan K; Davies, Gareth I;

    2016-01-01

    BACKGROUND: Hypothesised associations between in utero exposure to selective serotonin reuptake inhibitors (SSRIs) and congenital anomalies, particularly congenital heart defects (CHD), remain controversial. We investigated the putative teratogenicity of SSRI prescription in the 91 days either side......-analyses. SSRI prescription 91 days either side of LMP was associated with increased prevalence of severe congenital heart defects (CHD) (as defined by EUROCAT guide 1.3, 2005) (34/12,962 [0.26%] vs. 865/506,155 [0.17%] OR 1.50, 1.06-2.11), and the composite adverse outcome of 'anomaly or stillbirth' (473...... of first day of last menstrual period (LMP). METHODS AND FINDINGS: Three population-based EUROCAT congenital anomaly registries- Norway (2004-2010), Wales (2000-2010) and Funen, Denmark (2000-2010)-were linked to the electronic healthcare databases holding prospectively collected prescription information...

  1. Possible role of selective serotonin reuptake inhibitor sertraline on oxidative stress responses.

    Science.gov (United States)

    Battal, D; Yalin, S; Eker, E D; Aktas, A; Sahin, N O; Cebo, M; Berköz, M

    2014-01-01

    The naphthylamine derivative sertraline is a potent and selective inhibitor of serotonin reuptake into presynaptic terminals and the most widely used that has been shown to have both antidepressant and antianxiety effects. In the present study the possible role of sertraline (acute and chronically doses) was evaluated on lipid peroxidation levels and antioxidant enzyme activities in plasma and brain tissues of (10, 40, 80 mg/kg) sertraline treated Wistar albino rats (n=48). Lipid peroxidation levels (MDA) of plasma and brain tissue increased in all acute and chronic sertraline treated rats (p sertraline administration enhances oxidative stress. Therefore, dose adjustment in depression patients seems significant as it may help prevention of further prognosis of the diseases.

  2. Effects of sustained serotonin reuptake inhibition on the firing of dopamine neurons in the rat ventral tegmental area

    NARCIS (Netherlands)

    Dremencov, Eliyahu; El Mansari, Mostafa; Blier, Pierre

    2009-01-01

    Background: Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are efficacious in depression because of their ability to increase 5-HT neurotransmission. However, owing to a purported inhibitory effect of 5- HT on dopamine (DA) neuronal activity in the ventral tegmental area (VTA), this increase

  3. Treatment of Selective Serotonin Reuptake Inhibitor-Resistant Depression in Adolescents: Predictors and Moderators of Treatment Response

    Science.gov (United States)

    Asarnow, Joan Rosenbaum; Emslie, Graham; Clarke, Greg; Wagner, Karen Dineen; Spirito, Anthony; Vitiello, Benedetto; Iyengar, Satish; Shamseddeen, Wael; Ritz, Louise; Birmaher, Boris; Ryan, Neal; Kennard, Betsy; Mayes, Taryn; DeBar, Lynn; McCracken, James; Strober, Michael; Suddath, Robert; Leonard, Henrietta; Porta, Giovanna; Keller, Martin; Brent, David

    2009-01-01

    Adolescents who did not improve with Selective Serotonin Reuptake Inhibitor (SSRI) were provided an alternative SSRI plus cognitive-behavioral therapy (CBT). The superiority of the CBT/combined treatment as compared to medication alone is more evident in youths who had more comorbid disorders, no abuse history, and lower hopelessness.

  4. The selective serotonin re-uptake inhibitors fluvoxamine and paroxetine differ in sexual inhibitory effects after chronic treatment.

    NARCIS (Netherlands)

    Waldinger, M.D.; Plas, A.; Pattij, T.; Oorschot, R. van; Coolen, L.M.; Veening, J.G.; Olivier, B.

    2002-01-01

    RATIONALE: The selective serotonin re-uptake inhibitors (SSRIs) delay orgasm and ejaculation in men. In men with rapid ejaculation it was shown that, of the SSRIs, paroxetine exerted the strongest delay in ejaculation and fluvoxamine the weakest. OBJECTIVES: In the present study, we compared the acu

  5. Selective serotonin reuptake inhibitor prescribing before, during and after pregnancy : a population-based study in six European regions

    NARCIS (Netherlands)

    Charlton, R. A.; Jordan, S.; Pierini, A.; Garne, E.; Neville, A. J.; Hansen, A. V.; Gini, R.; Thayer, D.; Tingay, K.; Puccini, A.; Bos, H. J.; Andersen, A. M. Nybo; Sinclair, M.; Dolk, H.; de Jong-van den Berg, L. T. W.

    2015-01-01

    ObjectiveTo explore the prescribing patterns of selective serotonin reuptake inhibitors (SSRIs) before, during and after pregnancy in six European population-based databases. DesignDescriptive drug utilisation study. SettingSix electronic healthcare databases in Denmark, the Netherlands, Italy (Emil

  6. The effect of antenatal depression and selective serotonin reuptake inhibitor treatment on nerve growth factor signaling in human placenta

    NARCIS (Netherlands)

    Kaihola, Helena; Olivier, Jocelien; Poromaa, Inger Sundström; Åkerud, Helena

    2015-01-01

    Depressive symptoms during pregnancy are common and may have impact on the developing child. Selective serotonin reuptake inhibitors (SSRIs) are the most prescribed antidepressant treatment, but unfortunately, these treatments can also negatively affect the behavioral development and health of a chi

  7. Treatment of Selective Serotonin Reuptake Inhibitor-Resistant Depression in Adolescents: Predictors and Moderators of Treatment Response

    Science.gov (United States)

    Asarnow, Joan Rosenbaum; Emslie, Graham; Clarke, Greg; Wagner, Karen Dineen; Spirito, Anthony; Vitiello, Benedetto; Iyengar, Satish; Shamseddeen, Wael; Ritz, Louise; Birmaher, Boris; Ryan, Neal; Kennard, Betsy; Mayes, Taryn; DeBar, Lynn; McCracken, James; Strober, Michael; Suddath, Robert; Leonard, Henrietta; Porta, Giovanna; Keller, Martin; Brent, David

    2009-01-01

    Adolescents who did not improve with Selective Serotonin Reuptake Inhibitor (SSRI) were provided an alternative SSRI plus cognitive-behavioral therapy (CBT). The superiority of the CBT/combined treatment as compared to medication alone is more evident in youths who had more comorbid disorders, no abuse history, and lower hopelessness.

  8. Cell swelling activates K+ and Cl- channels as well as nonselective, stretch-activated cation channels in ehrlich ascites tumor cells

    DEFF Research Database (Denmark)

    Christensen, Ove; Hoffmann, Else Kay

    1992-01-01

    Cell-attached patch-clamp recordings from Ehrlich ascites tumor cells reveal nonselective cation channels which are activated by mechanical deformation of the membrane. These channels are seen when suction is applied to the patch pipette or after osmotic cell swelling. The channel activation does...

  9. Treatment with non-selective beta blockers is associated with reduced severity of systemic inflammation and improved survival of patients with acute-on-chronic liver failure

    DEFF Research Database (Denmark)

    Mookerjee, Rajeshwar P; Pavesi, Marco; Thomsen, Karen Louise

    2016-01-01

    BACKGROUND AND AIMS: Non-selective beta-blockers (NSBBs) have been shown to have deleterious outcomes in patients with refractory ascites, alcoholic hepatitis and spontaneous bacterial peritonitis leading many physicians to stop the drug in these cases. Acute on chronic liver failure (ACLF...

  10. Growth characteristics and ion contents of non-selected and salt-selected callus lines of highbush blueberry (Vacdnium corymbosum) cultivars Blue Crop and Denise Blue.

    Science.gov (United States)

    Muralitharan, M S; Van Steveninck, R F; Chandler, S E

    1990-07-01

    Non-selected and sodium chloride selected callus lines of Vacdnium corymbosum L.cv Blue Crop and cv. Denise Blue were grown on media supplemented with 0-100 mM NaCl. For both cultivars, fresh weight and dry weight yields were greater in selected lines on all levels of NaCl. Selected lines of Blue Crop displayed better growth than selected lines of Denise Blue at most concentrations of NaCl. Internal Na(+) and Cl(-) concentrations in selected and non-selected lines of both cultivars increased as external concentration was raised. However, selected lines of Blue Crop and Denise Blue accumulated more Na(+) and Cl(-) than non-selected lines. Selected lines of both cultivars maintained higher levels of K(+) than non-selected lines on all external NaCl levels. Selected lines of Blue Crop had higher levels of Na(+) and Cl(-) than that of Denise Blue. The results suggest Na(+) and Cl(-) accumulation could be a mechanism allowing better growth in selected lines at moderate salinity levels (50-75 mM NaCl).

  11. Use of selective cyclooxygenase-2 inhibitors and nonselective nonsteroidal antiinflammatory drugs in high doses increases mortality and risk of reinfarction in patients with prior myocardial infarction

    DEFF Research Database (Denmark)

    Sørensen, Rikke; Abildstrøm, Steen Zabell; Torp-Pedersen, C.

    2008-01-01

    The selective cyclooxygenase-2 (COX-2) inhibitors and other nonselective nonsteroidal antiinflammatory drugs (NSAIDs) have been associated with increased cardiovascular risk, but the risk in patients with established cardiovascular disease is unknown. In the present study, we analyzed the risk of...

  12. Comparison of subtypes of Listeria monocytogenes isolates from naturally contaminated watershed samples using a combination of non-selective and selective enrichment methods

    Science.gov (United States)

    Two enrichment methods for Listeria monocytogenes using Immuno Magnetic Separation were tested to determine if they selected the same subtypes of isolates. Both methods included a non-selective enrichment and one included subculture in Fraser Broth. Naturally contaminated watershed samples from the ...

  13. Effects of Selective Serotonin Reuptake Inhibitors on Interregional Relation of Serotonin Transporter Availability in Major Depression

    Science.gov (United States)

    James, Gregory M.; Baldinger-Melich, Pia; Philippe, Cecile; Kranz, Georg S.; Vanicek, Thomas; Hahn, Andreas; Gryglewski, Gregor; Hienert, Marius; Spies, Marie; Traub-Weidinger, Tatjana; Mitterhauser, Markus; Wadsak, Wolfgang; Hacker, Marcus; Kasper, Siegfried; Lanzenberger, Rupert

    2017-01-01

    Selective serotonin reuptake inhibitors (SSRIs) modulate serotonergic neurotransmission by blocking reuptake of serotonin from the extracellular space. Up to now, it remains unclear how SSRIs achieve their antidepressant effect. However, task-based and resting state functional magnetic resonance imaging studies, have demonstrated connectivity changes between brain regions. Here, we use positron emission tomography (PET) to quantify SSRI’s main target, the serotonin transporter (SERT), and assess treatment-induced molecular changes in the interregional relation of SERT binding potential (BPND). Nineteen out-patients with major depressive disorder (MDD) and 19 healthy controls (HC) were included in this study. Patients underwent three PET measurements with the radioligand [11C]DASB: (1) at baseline, (2) after a first SSRI dose; and (3) following at least 3 weeks of daily intake. Controls were measured once with PET. Correlation analyses were restricted to brain regions repeatedly implicated in MDD pathophysiology. After 3 weeks of daily SSRI administration a significant increase in SERT BPND correlations of anterior cingulate cortex and insula with the amygdala, midbrain, hippocampus, pallidum and putamen (p < 0.05; false discovery rate, FDR corrected) was revealed. No significant differences were found when comparing MDD patients and HC at baseline. These findings are in line with the clinical observation that treatment response to SSRIs is often achieved only after a latency of several weeks. The elevated associations in interregional SERT associations may be more closely connected to clinical outcomes than regional SERT occupancy measures and could reflect a change in the regional interaction of serotonergic neurotransmission during antidepressant treatment. PMID:28220069

  14. Effects of acute administration of selective serotonin reuptake inhibitors on sympathetic nerve activity

    Energy Technology Data Exchange (ETDEWEB)

    Tiradentes, R.V. [Departamento de Ciências Fisiológicas, Centro de Ciências da Saúde, Universidade Federal do Espírito Santo, Vitória, ES (Brazil); Centro Universitário do Espírito Santo, Colatina, ES (Brazil); Pires, J.G.P. [Centro Universitário do Espírito Santo, Colatina, ES (Brazil); Escola de Medicina da Empresa Brasileira de Ensino, Vitória, ES (Brazil); Silva, N.F. [Departamento de Morfologia, Centro de Ciências da Saúde, Universidade Federal do Espírito Santo, Vitória, ES (Brazil); Ramage, A.G. [Department of Neuroscience, Physiology and Pharmacology, University College London, London (United Kingdom); Santuzzi, C.H. [Departamento de Ciências Fisiológicas, Centro de Ciências da Saúde, Universidade Federal do Espírito Santo, Vitória, ES (Brazil); Centro Universitário do Espírito Santo, Colatina, ES (Brazil); Futuro, H.A. Neto [Escola de Medicina da Empresa Brasileira de Ensino, Vitória, ES (Brazil); Departamento de Morfologia, Centro de Ciências da Saúde, Universidade Federal do Espírito Santo, Vitória, ES (Brazil); Escola Superior de Ciências da Saúde, Santa Casa de Misericórdia de Vitória, Vitória, ES (Brazil)

    2014-05-30

    Serotonergic mechanisms have an important function in the central control of circulation. Here, the acute effects of three selective serotonin (5-HT) reuptake inhibitors (SSRIs) on autonomic and cardiorespiratory variables were measured in rats. Although SSRIs require 2-3 weeks to achieve their full antidepressant effects, it has been shown that they cause an immediate inhibition of 5-HT reuptake. Seventy male Wistar rats were anesthetized with urethane and instrumented to record blood pressure, heart rate, renal sympathetic nerve activity (RSNA), and respiratory frequency. At lower doses, the acute cardiovascular effects of fluoxetine, paroxetine and sertraline administered intravenously were insignificant and variable. At middle and higher doses, a general pattern was observed, with significant reductions in sympathetic nerve activity. At 10 min, fluoxetine (3 and 10 mg/kg) reduced RSNA by -33±4.7 and -31±5.4%, respectively, without changes in blood pressure; 3 and 10 mg/kg paroxetine reduced RSNA by -35±5.4 and -31±5.5%, respectively, with an increase in blood pressure +26.3±2.5; 3 mg/kg sertraline reduced RSNA by -59.4±8.6%, without changes in blood pressure. Sympathoinhibition began 5 min after injection and lasted approximately 30 min. For fluoxetine and sertraline, but not paroxetine, there was a reduction in heart rate that was nearly parallel to the sympathoinhibition. The effect of these drugs on the other variables was insignificant. In conclusion, acute peripheral administration of SSRIs caused early autonomic cardiovascular effects, particularly sympathoinhibition, as measured by RSNA. Although a peripheral action cannot be ruled out, such effects are presumably mostly central.

  15. Characteristic interactivity of landiolol, an ultra-short-acting highly selective β1-blocker, with biomimetic membranes: Comparisons with β1-selective esmolol and nonselective propranolol and alprenolol

    Directory of Open Access Journals (Sweden)

    Hironori eTsuchiya

    2013-12-01

    Full Text Available Although β1-blockers have been perioperatively used to reduce the cardiac disorders associated with general anesthesia, little is known about the mechanistic characteristics of ultra-short-acting highly selective β1-blocker landiolol. We studied its membrane-interacting property in comparison with other selective and nonselective β1-blockers. Biomimetic membranes prepared with phospholipids and cholesterol of varying compositions were treated with β1-selective landiolol and esmolol and nonselective propranolol and alprenolol at 0.5–200 µM. The membrane interactivity and the antioxidant activity were determined by measuring fluorescence polarization and by peroxidizing membrane lipids with peroxynitrite, respectively. Nonselective β1-blockers, but not selective ones, intensively acted on 1,2-dipalmitoylphosphatidylcholine liposomal membranes and cardiomyocyte-mimetic membranes to increase the membrane fluidity. Landiolol and its inactive metabolite distinctively decreased the fluidity of 1,2-dipalmitoylphosphatidylcholine liposomal membranes, suggesting that a membrane-rigidifying effect is attributed to the morpholine moiety in landiolol structure but unlikely to clinically contribute to the β1-blocking effect of landiolol. Propranolol and alprenolol interacted with lipid raft model membranes, whereas neither landiolol nor esmolol. All drugs fluidized mitochondria-mimetic membranes and inhibited the membrane lipid peroxidation with the potency correlating to their membrane interactivity. Landiolol is characterized as a drug devoid of the interactivity with membrane lipid rafts relating to β2-adrenergic receptor blockade. The differentiation between β1-blocking selectivity and nonselectivity is compatible with that between membrane noninteractivity and interactivity. The mitochondrial membrane fluidization by landiolol independent of blocking β1-adrenergic receptors is responsible for the antioxidant cardioprotection common to

  16. A high-throughput, nonisotopic, competitive binding assay for kinases using nonselective inhibitor probes (ED-NSIP).

    Science.gov (United States)

    Vainshtein, Inna; Silveria, Scott; Kaul, Poonam; Rouhani, Riaz; Eglen, Richard M; Wang, John

    2002-12-01

    A novel competitive binding assay for protein kinase inhibitors has been developed for high-throughput screening (HTS). Unlike functional kinase assays, which are based on detection of substrate phosphorylation by the enzyme, this novel method directly measures the binding potency of compounds to the kinase ATP binding site through competition with a conjugated binding probe. The binding interaction is coupled to a signal amplification system based on complementation of beta-galactosidase enzyme fragments, a homogeneous, nonisotopic assay technology platform developed by DiscoveRx Corp. In the present study, staurosporine, a potent, nonselective kinase inhibitor, was chemically conjugated to a small fragment of beta-galactosidase (termed ED-SS). This was used as the binding probe to the kinase ATP binding pocket. The binding potencies of several inhibitors with diverse structures were assessed by displacement of ED-SS from the kinase. The assay format was specifically evaluated with GSK3alpha, an enzyme previously screened in a radioactive kinase assay (i.e., measurement of [(33)P]-gamma-ATP incorporation into the kinase peptide substrate). Under optimized assay conditions, nonconjugated staurosporine inhibited ED-SS binding in a concentration-dependent manner with an apparent potency (IC(50)) of 11 nM, which was similar to the IC(50) value determined in a radioactive assay. Furthermore, 9 kinase inhibitors with diverse structures, previously identified from chemical compound library screening, were screened using the competitive binding assay. The potencies in the binding assay were in very good agreement with those obtained previously in the isotopic functional activity assay. The binding assay was adapted for automated HTS using selected compound libraries in a 384-well microtiter plate format. The HTS assay was observed to be highly robust and reproducible (Z' factors > 0.7) with high interassay precision (R(2) > 0.96). Interference of compounds with the beta

  17. The effect of external divalent cations on spontaneous non-selective cation channel currents in rabbit portal vein myocytes.

    Science.gov (United States)

    Albert, A P; Large, W A

    2001-10-15

    1. The effects of external divalent cations on spontaneous single non-selective cation channel currents were studied in outside-out patches from rabbit portal vein smooth muscle cells in K+-free conditions. 2. In an external medium containing 1.5 mM Ca2+ (Ca2+o) the majority of spontaneous channel currents had a unitary conductance of 23 pS, reversal potential (Vr) of +10 mV and a low open probability (Po) at negative patch potentials. Some channels opened to a lower conductance state of about 13 pS suggesting that the cation channels have two conductance states. Open time and burst duration distributions could both be described by two exponentials with time constants of about of 1 ms and 7 ms for open times and 3 ms and 16 ms for burst durations. 3. In 0 Ca2+o the majority of spontaneous cation channels had a unitary conductance of 13 pS and Vr was shifted to +4 mV. Moreover the longer open time and longer burst duration time constants were both reduced to approximately half the values in 1.5 mM Ca2+o. 4. Compared to 0 Ca2+o the single channel currents in 3 microM and 100 microM Ca2+o had a 5- to 6-fold increase in Po which was accompanied by increases in both open times and burst durations. In 3 microM and 100 microM Ca2+o the unitary conductance of the single channel currents was between 22 and 26 pS. 5. At positive membrane potentials the single channel currents had an increased Po compared to negative potentials which was associated with increased open times and burst durations but these values were similar in 3 microM, 100 microM and 1.5 mM Ca2+o. 6. In 1.5 mM Sr2+o and 1.5 mM Ba2+o channels opened to the higher conductance state of about 22-25 pS and had a 3- to 7-fold greater Po than in 0 Ca2+o. 7. In conclusion, external divalent cations have marked effects on the unitary conductance and kinetic behaviour of non-selective cation channels in rabbit portal vein smooth muscle cells.

  18. Epigenomic changes associated with impaired norepinephrine transporter function in postural tachycardia syndrome.

    Science.gov (United States)

    Khan, Abdul Waheed; Corcoran, Susan J; Esler, Murray; El-Osta, Assam

    2017-03-01

    The postural tachycardia syndrome (POTS) is characterised clinically by symptoms of light-headedness, palpitations, fatigue and exercise intolerance occurring with standing and relieved by lying down. Symptoms occur in association with an inappropriate rise in heart rate in the absence of a fall in blood pressure with the assumption of standing. The pathophysiology of POTS is complicated and poorly understood. Plasma norepinephrine (NE) is often elevated in patients with POTS, resulting in consideration of dysfunction of the norepinephrine transporter (NET) encoded by SLC6A2 gene. Whilst some studies have implicated a defect in the SLC6A2 gene, the cause of reduced SLC6A2 expression and function remains unclear. The search to explain the molecular mechanism of NET dysfunction has focused on genetic variation in the SLC6A2 gene and remains inconclusive. More recent studies show epigenetic mechanisms implicated in the regulation of SLC6A2 expression. In this article, we discuss the epigenetic mechanisms involved in SLC6A2 repression and highlight the potential therapeutic application of targeting these mechanisms in POTS.

  19. The Promotion of Human Neural Stem Cells Adhesion Using Bioinspired Poly(norepinephrine Nanoscale Coating

    Directory of Open Access Journals (Sweden)

    Minah Park

    2014-01-01

    Full Text Available The establishment of versatile biomaterial interfaces that can facilitate cellular adhesion is crucial for elucidating the cellular processes that occur on biomaterial surfaces. Furthermore, biomaterial interfaces can provide physical or chemical cues that are capable of stimulating cellular behaviors by regulating intracellular signaling cascades. Herein, a method of creating a biomimetic functional biointerface was introduced to enhance human neural stem cell (hNSC adhesion. The hNSC-compatible biointerface was prepared by the oxidative polymerization of the neurotransmitter norepinephrine, which generates a nanoscale organic thin layer, termed poly(norepinephrine (pNE. Due to its adhesive property, pNE resulted in an adherent layer on various substrates, and pNE-coated biointerfaces provided a highly favorable microenvironment for hNSCs, with no observed cytotoxicity. Only a 2-hour incubation of hNSCs was required to firmly attach the stem cells, regardless of the type of substrate. Importantly, the adhesive properties of pNE interfaces led to micropatterns of cellular attachment, thereby demonstrating the ability of the interface to organize the stem cells. This highly facile surface-modification method using a biomimetic pNE thin layer can be applied to a number of suitable materials that were previously not compatible with hNSC technology.

  20. Insulin modulates norepinephrine-mediated melatonin synthesis in cultured rat pineal gland.

    Science.gov (United States)

    Garcia, Rodrigo Antonio Peliciari; Afeche, Solange Castro; Scialfa, Julieta Helena; do Amaral, Fernanda Gaspar; dos Santos, Sabrina Heloísa José; Lima, Fabio Bessa; Young, Martin Elliot; Cipolla-Neto, José

    2008-01-02

    The mammalian pineal gland synthesizes melatonin in a circadian manner, peaking during the dark phase. This synthesis is primarily regulated by sympathetic innervations via noradrenergic fibers, but is also modulated by many peptidergic and hormonal systems. A growing number of studies reveal a complex role for melatonin in influencing various physiological processes, including modulation of insulin secretion and action. In contrast, a role for insulin as a modulator of melatonin synthesis has not been investigated previously. The aim of the current study was to determine whether insulin modulates norepinephrine (NE)-mediated melatonin synthesis. The results demonstrate that insulin (10(- 8)M) potentiated norepinephrine-mediated melatonin synthesis and tryptophan hydroxylase (TPOH) activity in ex vivo incubated pineal glands. When ex vivo incubated pineal glands were synchronized (12h NE-stimulation, followed by 12h incubation in the absence of NE), insulin potentiated NE-mediated melatonin synthesis and arylalkylamine-N-acetyltransferase (AANAT) activity. Insulin did not affect the activity of hydroxyindole-O-methyltranferase (HIOMT), nor the gene expression of tpoh, aanat, or hiomt, under any of the conditions investigated. We conclude that insulin potentiates NE-mediated melatonin synthesis in cultured rat pineal gland, potentially through post-transcriptional events.

  1. Curcumin promotes browning of white adipose tissue in a norepinephrine-dependent way.

    Science.gov (United States)

    Wang, Shan; Wang, Xiuchao; Ye, Zichen; Xu, Chengming; Zhang, Ming; Ruan, Banjun; Wei, Ming; Jiang, Yinghao; Zhang, Ying; Wang, Li; Lei, Xiaoying; Lu, Zifan

    2015-10-16

    Brown adipose tissue converts energy from food into heat via the mitochondrial uncoupling protein UCP1, defending against cold. In some conditions, inducible 'brown-like' adipocytes, also known as beige adipocytes, can develop within white adipose tissue (WAT). These beige adipocytes have characteristics similar to classical brown adipocytes and thus can burn lipids to produce heat. In the current study, we demonstrated that curcumin (50 or 100 mg/kg/day) decreased bodyweight and fat mass without affecting food intake in mice. We further demonstrated that curcumin improves cold tolerance in mice. This effect was possibly mediated by the emergence of beige adipocytes and the increase of thermogenic gene expression and mitochondrial biogenesis in inguinal WAT. In addition, curcumin promotes β3AR gene expression in inguinal WAT and elevates the levels of plasma norepinephrine, a hormone that can induce WAT browning. Taken together, our data suggest that curcumin can potentially prevent obesity by inducing browning of inguinal WAT via the norepinephrine-β3AR pathway.

  2. Comparison of Nonshivering Thermogenesis Induced by Norepinephrine Stress in Tree Shrews

    Directory of Open Access Journals (Sweden)

    Wan-long Zhu

    2013-11-01

    Full Text Available Nonshivering thermogenesis (NSTis an important thermogenic mechanism for small mammals. Quantitative measurement of NST is usually stimulated by injection of norepinephrine. The injection dosage of norepinephrine (NE is critical for eliciting the maximum NST. Three empirical equations of NE dosages were often referenced in previous studies: (1 NE (mg / kg= 2.53W-0.4; (2 NE(mg/kg = 3.3W-0.458 and (3 NE(mg/kg= 6.6W-0.458. In the present study , we used tree shrews (Tupaia belangeri as experiment subjects to test the effects of the three dosages of NE on NST. Results showed that all the three dosages of NE could induce the maximum NST for T. belangeri. No significant differences were found in NST among groups and the NST was respectively 2.63±0.12 (formula 1, 2.66±0. 11 (formula 2 and 2.78±0.15 (formula 3. However, when injected with NE dosage from formula 3, the increase of body temperatures was significantly higher than the other two NE dosages (increased 1.5±0. 1 oC (formula 3, 0.8±0. 2 oC (formula 2, and 0.6±0. 1 oC (formula 1, respectively. In order to prevent the death because of hyperthermia, formula 1 or 2 is recommended to be used.

  3. Influence of systemically given placebo, trapidil and isosorbide dinitrate on norepinephrine-evoked hand vein constriction in healthy subjects.

    Science.gov (United States)

    Sziegoleit, Werner; Dannenberg, Katrin; Konschak, Ariana; Lautenschläger, Christine; Presek, Peter

    2007-01-01

    Since trapidil (CAS 15421-84-8) is able to dilate human hand veins after local intravenous administration, four studies were carried out in healthy male volunteers using the dorsal hand vein compliance technique to test the influence of common systemic single doses of trapidil (200 mg orally, 100 mg intravenously) and isosorbide dinitrate (CAS 87-33-2, 20 mg orally) on norepinephrine (CAS 51-41-2)-evoked hand vein constriction in comparison with oral placebo. Oral placebo and oral trapidil were studied in a randomized double-blind cross-over design in 10 subjects aged 20 to 30 years, and oral isosorbide dinitrate and intravenous trapidil, in a randomized open cross-over design in 8 subjects aged 22 to 29 years. In the three similar studies with oral medications dose-response curves for venoconstriction by locally infused norepinephrine were established before and 1 h, 2 h and 3 h after oral medication and ED50 values of norepinephrine were calculated. The control dose-response curves and ED50 values of norepinephrine did not differ significantly. After oral placebo administration the dose-response curves of norepinephrine did not change significantly, but the ED50 of norepinephrine increased 3 h after placebo (from 12.1 to 31.7 ng/ min), indicating a lessening in norepinephrine effect at this time. After oral trapidil application the dose-response curves of norepinephrine shifted to the left compared with the pre-treatment curve (significantly 2 h after trapidil) and the corresponding curves after placebo with a significant decrease in the ED50 of norepinephrine 3 h after trapidil compared with placebo (from 31.7 to 12.6 ng/ min). After oral isosorbide dinitrate administration the dose-response curves of norepinephrine did not differ significantly from the pre-treatment curve, but they shifted to the left compared with the corresponding curves after placebo (significantly 3 h after isosorbide dinitrate). The ED50 of norephinephrine decreased significantly 2 h after

  4. Selective serotonin-reuptake inhibitor and norepinephrine dopamine reuptake inhibitor antidepressants do not affect natural killer cell activity in vitro Antidepressivos inibidores seletivos de recaptação da serotonina e inibidores da recaptação de noradrenalina e dopamina não afetam a atividade celular natural killer in vitro

    Directory of Open Access Journals (Sweden)

    Gabriel J. Chittó Gauer

    2009-01-01

    Full Text Available OBJECTIVE: This study aims to evaluate the citotoxic activity of two commonly used anti-depressants: paroxetine and bupropion. We also evaluated the in vitro natural killer activity (NKA after incubating the blood samples with the antidepressants. METHODS: Peripheral blood samples from 15 healthy volunteers were collected and the mononuclear cells (PBMCs were isolated and incubated for 24h with (or without = control cells paroxetine and bupropion, in concentrations of 30, 100 and 1000 ng/ml. After the incubation period in both groups, the amount of dead cells was calculated using trypam blue technique. NKA was evaluated using the classic51Cr release assay. CONCLUSIONS: PBMCs dead cells occurred in both groups and in proportion to all pharmacological concentrations. Nevertheless, the NKA was not affected, even with the reduction in the number of effective cells.OBJETIVO: Avaliar o efeito citotóxico de dois antidepressivos comumente utilizados na prática, a paroxetina e a bupropriona. Além disso, buscou-se avaliar a atividade natural killer (ANK após a incubação dos linfócitos com esses fármacos. MÉTODOS: Sangue venoso de 15 participantes foi coletado e as células mononucleares (PBMCs foram separadas e incubadas por 24h com (ou sem = grupo-controle concentrações de paroxetina e bupropiona em 30, 100 e 1.000 ng/ml. Após a incubação, a quantidade das células mortas foi contada utilizando-se o método trypan blue. Posteriormente foi avaliada a ANK por meio do ensaio clássico de liberação do Cr51. CONCLUSÕES: Ocorreu morte celular de PBMCs proporcionais às doses dos fármacos, no entanto, a ANK não foi afetada, mesmo com a redução do número de células efetoras.

  5. The characteristics of action potential and nonselec-tive cation current of cardiomyocytes in rabbit superior vena cava

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    As a special focus in initiating and maintaining atrial fibrillation (AF), cardiomyocytes in superior vena cava (SVC) have distinctive electrophysiological characters. In this study, we found that comparing with the right atrial (RA) cardiomyoctyes, the SVC cardiomyoctyes had longer APD90 at the different basic cycle lengths; the conduction block could be observed on both RA and SVC cardiomyoctyes. A few of SVC cardiomyoctyes showed slow response action potentials with automatic activity and some others showed early afterdepolarization (EAD) spontaneously. Further more, we found that there are nonselective cation current (INs) in both SVC and RA cardiomyocytes. The peak density of INs in SVC cardiomyocytes was smaller than that in RA cardiomyocytes. Removal of extracellular divalent cation and glucose could increase INs in SVC cardiomyocytes. The agonist or the antagonist of INs may in-crease or decrease APD. To sum up, some SVC cardiomyocytes possess the ability of spontaneous activity; the difference of transmembrane action potentials between SVC and RA cardiomyocytes is partly because of the different density of INs between them; the agonist or the antagonist of INs can in-crease or decrease APD leading to the enhancement or reduction of EAD genesis in SVC cardiomyo-cytes. INs in rabbit myocytes is fairly similar to TRPC3 current in electrophysiological property, which might play an important role in the mechanisms of AF.

  6. Safety of celecoxib and nonselective nonsteroidal anti-inflammatory drugs in juvenile idiopathic arthritis: results of the phase 4 registry

    Science.gov (United States)

    2014-01-01

    Background This study aimed to assess long-term safety and developmental data on juvenile idiopathic arthritis (JIA) patients treated in routine clinical practice with celecoxib or nonselective nonsteroidal anti-inflammatory drugs (nsNSAIDs). Methods Children aged ≥2 to nabumetone were the most frequently used nsNSAIDs. At baseline, the celecoxib group was older, had a numerically longer median time since diagnosis, and a numerically higher proportion of patients with a history of gastrointestinal-related NSAID intolerance. AEs reported were those frequently observed with NSAID treatment and were similar across groups (nsNSAIDs: 52.0%; celecoxib: 52.9%). Twelve unique patients experienced a total of 18 serious AEs; the most frequent were infections, and none was attributed to NSAID use. Conclusions The safety profile of celecoxib and nsNSAIDs appears similar overall. The results from this registry, ongoing pharmacovigilance, and the phase 3 trial that led to the approval of celecoxib for children with JIA provide evidence that the benefit-risk for celecoxib treatment in JIA remains positive. Trial registration ClinicalTrials.gov identifier NCT00688545. PMID:25057265

  7. The inhibitory effect of magnolol on cutaneous permeability in mice is probably mediated by a nonselective vascular hyporeactivity to mediators.

    Science.gov (United States)

    Wang, J P; Raung, S L; Chen, C C; Kuo, J S; Teng, C M

    1993-12-01

    In the present study, we demonstrated the inhibitory effect of magnolol on the plasma leakage in passive cutaneous anaphylactic (PCA) reaction, neurogenic inflammation, dorsal skin and ear edema in mice. Hind-paw skin plasma extravasation caused by antidromic stimulation of the saphenous nerve was reduced in mice pretreated with magnolol, diphenydramine or methysergide, but not with indomethacin. Ear edema formation in the PCA reaction was reduced by magnolol in dose-dependent manner. In addition, histamine-, serotonin-, compound 48/80-, bradykinin- and substance P-induced ear edema in mice was also suppressed by magnolol. A dose- and time-dependency of the inhibitory effect of magnolol was demonstrated in histamine- and compound 48/80-induced dorsal skin edema. The maximal inhibitory effect produced by a single dose of magnolol (10 mg/kg) persisted for 1 h, and significant suppression lasted for at least 3 h. In compound 48/80-pretreated mice, the histamine content of the ear was greatly reduced. Bradykinin- and substance P-induced ear edema in compound 48/80-pretreated mice was less severe than that seen in normal mice, but was still significantly reduced by magnolol pretreatment. Moreover, the inhibitory effect of magnolol was more marked than that of diphenhydramine combined with methysergide. These results suggest that the inhibitory effect of magnolol on local edema formation probably occurs through a nonselective inhibition on vascular tissue to prevent the permeability change caused by various mediators.

  8. Lipid Emulsions Enhance the Norepinephrine-Mediated Reversal of Local Anesthetic-Induced Vasodilation at Toxic Doses

    Science.gov (United States)

    Lee, Soo Hee; Sung, Hui-Jin; Ok, Seong-Ho; Yu, Jongsun; Choi, Mun-Jeoung; Lim, Jin Soo

    2013-01-01

    Purpose Intravenous lipid emulsions have been used to treat the systemic toxicity of local anesthetics. The goal of this in vitro study was to examine the effects of lipid emulsions on the norepinephrine-mediated reversal of vasodilation induced by high doses of levobupivacaine, ropivacaine, and mepivacaine in isolated endothelium-denuded rat aorta, and to determine whether such effects are associated with the lipid solubility of local anesthetics. Materials and Methods The effects of lipid emulsions (0.30, 0.49, 1.40, and 2.61%) on norepinephrine concentration-responses in high-dose local anesthetic (6×10-4 M levobupivacaine, 2×10-3 M ropivacaine, and 7×10-3 M mepivacaine)-induced vasodilation of isolated aorta precontracted with 60 mM KCl were assessed. The effects of lipid emulsions on local anesthetic- and diltiazem-induced vasodilation in isolated aorta precontracted with phenylephrine were also assessed. Results Lipid emulsions (0.30%) enhanced norepinephrine-induced contraction in levobupivacaine-induced vasodilation, whereas 1.40 and 2.61% lipid emulsions enhanced norepinephrine-induced contraction in both ropivacaine- and mepivacaine-induced vasodilation, respectively. Lipid emulsions (0.20, 0.49 and 1.40%) inhibited vasodilation induced by levobupivacaine and ropivacaine, whereas 1.40 and 2.61% lipid emulsions slightly attenuated mepivacaine (3×10-3 M)-induced vasodilation. In addition, lipid emulsions attenuated diltiazem-induced vasodilation. Lipid emulsions enhanced norepinephrine-induced contraction in endothelium-denuded aorta without pretreatment with local anesthetics. Conclusion Taken together, these results suggest that lipid emulsions enhance the norepinephrine-mediated reversal of local anesthetic-induced vasodilation at toxic anesthetic doses and inhibit local anesthetic-induced vasodilation in a manner correlated with the lipid solubility of a particular local anesthetic. PMID:24142661

  9. Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock: The VANISH Randomized Clinical Trial.

    Science.gov (United States)

    Gordon, Anthony C; Mason, Alexina J; Thirunavukkarasu, Neeraja; Perkins, Gavin D; Cecconi, Maurizio; Cepkova, Magda; Pogson, David G; Aya, Hollmann D; Anjum, Aisha; Frazier, Gregory J; Santhakumaran, Shalini; Ashby, Deborah; Brett, Stephen J

    2016-08-02

    Norepinephrine is currently recommended as the first-line vasopressor in septic shock; however, early vasopressin use has been proposed as an alternative. To compare the effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock. A factorial (2×2), double-blind, randomized clinical trial conducted in 18 general adult intensive care units in the United Kingdom between February 2013 and May 2015, enrolling adult patients who had septic shock requiring vasopressors despite fluid resuscitation within a maximum of 6 hours after the onset of shock. Patients were randomly allocated to vasopressin (titrated up to 0.06 U/min) and hydrocortisone (n = 101), vasopressin and placebo (n = 104), norepinephrine and hydrocortisone (n = 101), or norepinephrine and placebo (n = 103). The primary outcome was kidney failure-free days during the 28-day period after randomization, measured as (1) the proportion of patients who never developed kidney failure and (2) median number of days alive and free of kidney failure for patients who did not survive, who experienced kidney failure, or both. Rates of renal replacement therapy, mortality, and serious adverse events were secondary outcomes. A total of 409 patients (median age, 66 years; men, 58.2%) were included in the study, with a median time to study drug administration of 3.5 hours after diagnosis of shock. The number of survivors who never developed kidney failure was 94 of 165 patients (57.0%) in the vasopressin group and 93 of 157 patients (59.2%) in the norepinephrine group (difference, -2.3% [95% CI, -13.0% to 8.5%]). The median number of kidney failure-free days for patients who did not survive, who experienced kidney failure, or both was 9 days (interquartile range [IQR], 1 to -24) in the vasopressin group and 13 days (IQR, 1 to -25) in the norepinephrine group (difference, -4 days [95% CI, -11 to 5]). There was less use of renal replacement therapy in the vasopressin group

  10. Norepinephrine in low to moderate doses may not increase luminal concentrations of L-lactate in the gut in patients with septic shock

    DEFF Research Database (Denmark)

    Ibsen, M; Jørgensen, V L; Perner, A

    2007-01-01

    To investigate the effect of different doses of norepinephrine (noradrenaline) on luminal concentrations of L-lactate in the rectum and stomach in patients with fluid-resuscitated septic shock.......To investigate the effect of different doses of norepinephrine (noradrenaline) on luminal concentrations of L-lactate in the rectum and stomach in patients with fluid-resuscitated septic shock....

  11. Norepinephrine in low to moderate doses may not increase luminal concentrations of L-lactate in the gut in patients with septic shock

    DEFF Research Database (Denmark)

    Ibsen, M; Jørgensen, V L; Perner, A

    2007-01-01

    To investigate the effect of different doses of norepinephrine (noradrenaline) on luminal concentrations of L-lactate in the rectum and stomach in patients with fluid-resuscitated septic shock.......To investigate the effect of different doses of norepinephrine (noradrenaline) on luminal concentrations of L-lactate in the rectum and stomach in patients with fluid-resuscitated septic shock....

  12. Serotonin reuptake inhibitor antidepressants and abnormal bleeding: a review for clinicians and a reconsideration of mechanisms.

    Science.gov (United States)

    Andrade, Chittaranjan; Sandarsh, Surya; Chethan, Kumar B; Nagesh, Koregala S

    2010-12-01

    It is generally believed that selective serotonin reuptake inhibitor (SSRI) drugs increase the risk of abnormal bleeding and decrease the risk of ischemic heart disease events by blocking the uptake of serotonin into platelets, leading to an impairment in the platelet hemostatic response. To perform a detailed qualitative review of existing literature on the association of abnormal bleeding with the use of SSRIs. We conducted a PubMed search during June 2009 using the search terms antidepressants and SSRIs (including the names of individual SSRIs: fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, and escitalopram) in association with bleeding, platelets, hemostasis, nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, antiplatelet drugs, proton pump inhibitors, peptic ulcer, premenstrual dysphoric disorder, menstruation, pregnancy, postpartum hemorrhage, surgery, tooth extraction, dental bleeding, stroke, ischemic heart disease, and other terms related to the field. We then searched the reference lists of identified studies. We provide a qualitative discussion of all studies that would inform clinicians about the mechanisms of bleeding and bleeding risks associated with these drugs in different clinical contexts. Epidemiologic studies show that SSRI use is associated with roughly doubled odds of upper gastrointestinal (GI) bleeding; bleeding at other sites has been less commonly described, as has a possibly increased risk of bleeding associated with surgical procedures. The risk of SSRI-associated GI bleeding is increased with the concurrent use of NSAIDs, anticoagulants, and antiplatelet agents and is decreased by concurrent proton pump inhibitors. The risk of bleeding is increased in patients with cirrhosis of the liver or liver failure. There is, curiously, little literature on use of SSRIs and menstrual or postpartum blood loss. Selective serotonin reuptake inhibitors appear protective against ischemic heart disease events. The data are too

  13. Non-selective regulation of peroxide and superoxide resistance genes by PerR in Campylobacter jejuni

    Directory of Open Access Journals (Sweden)

    Jong-Chul eKim

    2015-02-01

    Full Text Available Campylobacter jejuni is an important foodborne pathogen. The molecular mechanisms for the regulation of oxidative stress resistance have not yet been understood fully in this bacterium. In this study, we investigated how PerR (peroxide stress regulator modulates the transcriptional regulation of both peroxide and superoxide resistance genes in C. jejuni, particularly under oxidative stress conditions. The transcriptional levels of ahpC, katA, and sodB were substantially increased by aeration and oxidant exposure. Interestingly, a perR mutation completely abrogated the transcriptional response of ahpC, katA and sodB to oxidants. Furthermore, we demonstrated that perR transcription was reduced by aeration and oxidant exposure. In contrast to the unique role of PerR homologs in peroxide stress regulation in other bacteria, interestingly, C. jejuni PerR directly regulates the transcription of sodB, the most important gene in superoxide defense, as evidenced by the alteration of sodB transcription by the perR mutation and direct binding of rPerR to the sodB promoter. In addition, we also observed notable morphological changes in C. jejuni from spiral rods to coccoid morphology under aerobic conditions. Based on the intracellular ATP levels, C. jejuni entered a viable-but-non-culturable state under aerobic conditions. These findings clearly demonstrate that C. jejuni possesses a unique regulatory mechanism of oxidative stress defense that does not specifically distinguish between peroxide and superoxide defense, and PerR plays a pivotal role in this non-selective regulation of oxidative stress resistance in C. jejuni.

  14. The incentive amplifying effects of nicotine are reduced by selective and non-selective dopamine antagonists in rats.

    Science.gov (United States)

    Palmatier, Matthew I; Kellicut, Marissa R; Brianna Sheppard, A; Brown, Russell W; Robinson, Donita L

    2014-11-01

    Nicotine is a psychomotor stimulant with 'reinforcement enhancing' effects--the actions of nicotine in the brain increase responding for non-nicotine rewards. We hypothesized that this latter effect of nicotine depends on increased incentive properties of anticipatory cues; consistent with this hypothesis, multiple laboratories have reported that nicotine increases sign tracking, i.e. approach to a conditioned stimulus (CS), in Pavlovian conditioned-approach tasks. Incentive motivation and sign tracking are mediated by mesolimbic dopamine (DA) transmission and nicotine facilitates mesolimbic DA release. Therefore, we hypothesized that the incentive-promoting effects of nicotine would be impaired by DA antagonists. To test this hypothesis, separate groups of rats were injected with nicotine (0.4mg/kg base) or saline prior to Pavlovian conditioning sessions in which a CS (30s illumination of a light or presentation of a lever) was immediately followed by a sweet reward delivered in an adjacent location. Both saline and nicotine pretreated rats exhibited similar levels of conditioned approach to the reward location (goal tracking), but nicotine pretreatment significantly increased approach to the CS (sign tracking), regardless of type (lever or light). The DAD1 antagonist SCH-23390 and the DAD2/3 antagonist eticlopride reduced conditioned approach in all rats, but specifically reduced goal tracking in the saline pretreated rats and sign tracking in the nicotine pretreated rats. The non-selective DA antagonist flupenthixol reduced sign-tracking in nicotine rats at all doses tested; however, only the highest dose of flupenthixol reduced goal tracking in both nicotine and saline groups. The reductions in conditioned approach behavior, especially those by SCH-23390, were dissociated from simple motor suppressant effects of the antagonists. These experiments are the first to investigate the effects of dopaminergic drugs on the facilitation of sign-tracking engendered by

  15. Differential contribution of TRPM4 and TRPM5 nonselective cation channels to the slow afterdepolarization in mouse prefrontal cortex neurons

    Directory of Open Access Journals (Sweden)

    Ya-Ting eLei

    2014-09-01

    Full Text Available In certain neurons from different brain regions, a brief burst of action potentials can activate a slow afterdepolarization (sADP in the presence of muscarinic acetylcholine receptor agonists. The sADP, if suprathreshold, can contribute to persistent non-accommodating firing in some of these neurons. Previous studies have characterized a Ca2+-activated non-selective cation (CAN current (ICAN that is thought to underlie the sADP. ICAN depends on muscarinic receptor stimulation and exhibits a dependence on neuronal activity, membrane depolarization and Ca2+-influx similar to that observed for the sADP. Despite the widespread occurrence of sADPs in neurons throughout the brain, the molecular identity of the ion channels underlying these events, as well as ICAN, remains uncertain. Here we used a combination of genetic, pharmacological and electrophysiological approaches to characterize the molecular mechanisms underlying the muscarinic receptor-dependent sADP in layer 5 pyramidal neurons of mouse prefrontal cortex. First, we confirmed that in the presence of the cholinergic agonist carbachol a brief burst of action potentials triggers a prominent sADP in these neurons. Second, we confirmed that this sADP requires activation of a PLC signaling cascade and intracellular calcium signaling. Third, we obtained direct evidence that the transient receptor potential melastatin 5 channel (TRPM5, which is thought to function as a CAN channel in non-neural cells, contributes importantly to the sADP in the layer 5 neurons. In contrast, the closely related TRPM4 channel may play only a minor role in the sADP.

  16. Chronic Periprosthetic Hip Joint Infection. A Retrospective, Observational Study on the Treatment Strategy and Prognosis in 130 Non-Selected Patients

    DEFF Research Database (Denmark)

    Lange, Jeppe; Troelsen, Anders; Søballe, Kjeld

    2016-01-01

    INTRODUCTION: Limited information is available regarding the treatment strategy and prognosis of non-selected patients treated for chronic periprosthetic hip joint infection. Such information is important as no head-to-head studies on treatment strategies are available. The purpose of this study...... is to report on the treatment strategy and prognosis of a non-selected, consecutive patient population. METHODS: We identified 130 patients in the National Patient Registry, consecutively treated for a chronic periprosthetic hip joint infection between 2003-2008 at 11 departments of orthopaedic surgery. We.......00001). After adjusting for selected confounders, the mortality risk was no longer significantly different. The 5-year re-infection rate after re-implantation was 14.6% (95%CI 8.0-23.1). Re-infections occurred mainly within 3 years of follow-up. The overall 1-year survival rate was 92% (95%CI 86...

  17. Selective serotonin reuptake inhibitor sertraline inhibits voltage-dependent K+ channels in rabbit coronary arterial smooth muscle cells.

    Science.gov (United States)

    Kim, Han Sol; Li, Hongliang; Kim, Hye Won; Shin, Sung Eun; Choi, Il-Whan; Firth, Amy L; Bang, Hyoweon; Bae, Young Min; Park, Won Sun

    2016-12-01

    We examined the effects of the selective serotonin reuptake inhibitor (SSRI) sertraline on voltage-dependent K+ (Kv) channels in freshly isolated rabbit coronary arterial smooth muscle cells using the voltage-clamp technique. Sertraline decreased the Kv channel current in a dose-dependent manner, with an IC50 value of 0.18 mu M and a slope value (Hill coefficient) of 0.61. Although the application of 1 mu M sertraline did not affect the steady-state activation curves, sertraline caused a significant, negative shift in the inactivation curves. Pretreatment with another SSRI, paroxetine, had no significant effect on Kv currents and did not alter the inhibitory effects of sertraline on Kv currents. From these results, we concluded that sertraline dose-dependently inhibited Kv currents independently of serotonin reuptake inhibition by shifting inactivation curves to a more negative potential.

  18. Insulation for daydreams: a role for tonic norepinephrine in the facilitation of internally guided thought.

    Directory of Open Access Journals (Sweden)

    Jonathan Smallwood

    Full Text Available Although consciousness can be brought to bear on both perceptual and internally generated information, little is known about how these different cognitive modes are coordinated. Here we show that between-participant variance in thoughts unrelated to the task being performed (known as task unrelated thought, TUT is associated with longer response times (RT when target presentation occurs during periods when baseline Pupil Diameter (PD is increased. As behavioral interference due to high baseline PD can reflect increased tonic activity in the norepinephrine system (NE, these results might implicate high tonic NE activity in the facilitation of TUTs. Based on these findings, it is hypothesised that high tonic mode NE leads to a generalised de-amplification of task relevant information that prioritses internally generated thought and insulates it from the potentially disruptive events taking place in the external environment.

  19. Norepinephrine transporter (NET) is expressed in cardiac sympathetic ganglia of adult rat

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    The sympathetic nervous system plays a cardinal role in regulating cardiac function through releasing the neurotransmitter norepinephrine (NE). In comparison with central nervous system, the molecular mechanism of NE uptake in myocardium is not clear. In present study, we proved that in rat the CNS type of NE transporter (NET) was also expressed in middle cervical-stellate ganglion complex (MC-SG complex) which is considered to control the activity of heart, but not expressed in myocardium. The results also showed that NET expression level in right ganglion was significantly higher than in the left, rendering the greater capacity of NE uptake in right ventricle, a fact which may contribute to the maintenance of right ventricular function under pathologic state.

  20. Muscle interstitial ATP and norepinephrine concentrations in the human leg during exercise and ATP infusion

    DEFF Research Database (Denmark)

    Mortensen, Stefan P.; Gonzalez-Alonso, Jose; Nielsen, Jens Jung

    2009-01-01

    ATP has been proposed to play multiple roles in local skeletal muscle blood flow regulation by inducing vasodilation and modulating sympathetic vasoconstrictor activity, but the mechanism remain unclear. Here we evaluated the effects of arterial ATP infusion and exercise on limb muscle interstitial...... ATP and NE concentrations to gain insight into the interstitial and intravascular mechanisms by which ATP causes muscle vasodilation and sympatholysis. Leg hemodynamics and muscle interstitial nucleotide and norepinephrine (NE) concentrations were measured during: 1) femoral arterial ATP infusion (0.......42+/-0.04 and 2.26+/-0.52 mumol/min; mean+/-SEM) and 2) one-leg knee-extensor exercise (18+/-0 and 37+/-2W) in 10 healthy, male subjects. Arterial ATP infusion and exercise increased leg blood flow (LBF) in the experimental leg from ~0.3 L/min at baseline to 4.2+/-0.3 and 4.6+/-0.5 L/min, respectively, whereas...

  1. Norepinephrine transporter function and tolerance to hypergravitational stress: A pilot study

    Science.gov (United States)

    Schroeder, Christoph; Strempel, Sebastian; Boese, Andrea; Hemmersbach, Ruth; Tank, Jens; Luft, Friedrich C.; Jordan, Jens

    Pharmacological norepinephrine transporter (NET) inhibition improves orthostatic tolerance on a tilt table while increasing heart rate. We tested the cardiovascular response to NET inhibition during a graded human centrifuge run in seven healthy men. g-Load was increased in 0.5 g steps with 3 g maximal g-load. On two separate days, patients were tested after selective NET inhibition with reboxetine or with placebo in a double-blind, randomized, crossover fashion. Resting diastolic blood pressure increased moderately with NET inhibition. Resting heart rate was profoundly increased by NET inhibition. NET inhibition augmented the heart rate response while attenuating the increase in blood pressure during hypergravitation. NET inhibition could be tested for its potential to improve cardiovascular g-tolerance.

  2. Stress, genotype and norepinephrine in the prediction of mouse behavior using reinforcement learning.

    Science.gov (United States)

    Luksys, Gediminas; Gerstner, Wulfram; Sandi, Carmen

    2009-09-01

    Individual behavioral performance during learning is known to be affected by modulatory factors, such as stress and motivation, and by genetic predispositions that influence sensitivity to these factors. Despite numerous studies, no integrative framework is available that could predict how a given animal would perform a certain learning task in a realistic situation. We found that a simple reinforcement learning model can predict mouse behavior in a hole-box conditioning task if model metaparameters are dynamically controlled on the basis of the mouse's genotype and phenotype, stress conditions, recent performance feedback and pharmacological manipulations of adrenergic alpha-2 receptors. We find that stress and motivation affect behavioral performance by altering the exploration-exploitation balance in a genotype-dependent manner. Our results also provide computational insights into how an inverted U-shape relation between stress/arousal/norepinephrine levels and behavioral performance could be explained through changes in task performance accuracy and future reward discounting.

  3. Mechanisms of Depressor Effect of Norepinephrine Injected into Subnucleus Commissuriu of Nucleus Solitarius Tractus in Rabbits

    Institute of Scientific and Technical Information of China (English)

    ZHANG Yi; SONG Yuanlong; GAO Linlin; LUO Hongyan; LIU Shenghong; YI Zhengrong; LI Ai; HU Xinwu; LIU Changjin; TANG Ming; LIU Lieju

    2005-01-01

    Summary: This experiment aimed to investigate the effect of adrenergic system in the subnucleus commissuriu of nucleus solitrius tractus (CNTS) on renal nerve discharges. Norepinephrine (NE) was microinjected into the CNTS of rabbits and mean arterial blood pressure (MAP) and renal nerve discharges (FRND) were synchronously recorded. The results indicated that (1) microinjection of norepinephine into the CNTS of rabbit could significantly attenuate the frequency of renal nerve discharge, and at the same time decrease markedly the mean arterial pressure. (2) Microinjection of 0.3 nmol yohimbin into CNTS had no significant influence on FRND and MAP, but could attenuate and even reverse the effects of NE on FRND and MAP. These results suggest that microinjection of NE into CNTS may activate the alpha-adrenorecptor located in CNTS and secondarily produce a depressor effect by attenuating the activity of peripheral sympathetic nervous system.

  4. Blood ketone response to norepinephrine-induced free fatty acid in diabetes

    Energy Technology Data Exchange (ETDEWEB)

    Blackard, W.G.; Omori, Yoshiaki

    1963-04-18

    During 90-minute norepinephrine infusions, blood free fatty acid and ketone responses of Japanese nondiabetic and diabetic subjects were determined. Nonobese diabetic subjects with and without fasting hyperglycemia demonstrated significantly greater blood ketone elevations than nondiabetics. An inverse correlation between obesity and blood ketone response to nonrepinephrine was observed in diabetics. This correlation could not be attributed to varying degrees of fasting hyperglycemia or free fatty acid elevation. Nonobese diabetics with mild fasting hyperglycemia (90 to 150 mg%) exhibited an unexpected greater increase in blood ketones than nonobese diabetics with moderate fasting hyperglycemia (150 to 250 mg%). Differences in free fatty acid elevations were not responsible for this apparent paradox. The magnitude of the hyperketonemic response, though dependent on free fatty elevation, seemed more sensitive to the degree of obesity and the fasting blood glucose level. Fractional ketone body measurements attributed the blood ketone elevations predominantly to ..beta..-hydroxybutyric acid increases. 43 references, 6 figures, 1 table.

  5. Norepinephrine and cardiovascular responses to maximal exercise in Parkinson's disease on and off medication.

    Science.gov (United States)

    DiFrancisco-Donoghue, Joanne; Elokda, Ahmed; Lamberg, Eric M; Bono, Nancy; Werner, William G

    2009-09-15

    The aim of this experiment is to understand how Parkinson's disease (PD) medication affects the autonomic responses of individuals during an acute exercise stress test. Fourteen people with PD and fifteen healthy individuals age-matched between 50 and 80 years performed a modified Bruce protocol. Subjects with PD performed the test once off medication (PD-off) and then 1 week later on medication (PD-on). Heart rate (HR), blood pressure (BP), VO(2), and norepinephrine (NE) levels were taken at rest and at peak exercise. At peak exercise HR, BP, and NE values for the PD-on and PD-off group were all significantly lower than healthy controls, regardless of whether subjects were on their medication. Autonomic abnormalities during exercise in this population appear to be disease manifested and not impacted by medications used to treat PD. We can assume, both on and off medication, this population will show markedly lower BP, HR, and NE responses.

  6. Insulation for daydreams: a role for tonic norepinephrine in the facilitation of internally guided thought.

    Science.gov (United States)

    Smallwood, Jonathan; Brown, Kevin S; Baird, Benjamin; Mrazek, Michael D; Franklin, Michael S; Schooler, Jonathan W

    2012-01-01

    Although consciousness can be brought to bear on both perceptual and internally generated information, little is known about how these different cognitive modes are coordinated. Here we show that between-participant variance in thoughts unrelated to the task being performed (known as task unrelated thought, TUT) is associated with longer response times (RT) when target presentation occurs during periods when baseline Pupil Diameter (PD) is increased. As behavioral interference due to high baseline PD can reflect increased tonic activity in the norepinephrine system (NE), these results might implicate high tonic NE activity in the facilitation of TUTs. Based on these findings, it is hypothesised that high tonic mode NE leads to a generalised de-amplification of task relevant information that prioritses internally generated thought and insulates it from the potentially disruptive events taking place in the external environment.

  7. Differential association of traits of fear and anxiety with norepinephrine- and dark-induced pupil reactivity.

    Science.gov (United States)

    White, T L; Depue, R A

    1999-10-01

    The relation between fear and anxiety remains unclear, though psychometric data strongly suggest they are independent emotional systems. Because central norepinephrine (NE) projection systems are at the core of models of both fear and anxiety, the present experiment explored whether this independence extends to NE functioning. Two different aspects of NE functioning were assessed in a healthy young adult sample (N = 18): pupillary reactivity to (a) a specific NE alpha-1 agonist challenge to assess receptor reactivity and (b) a darkness challenge to assess contributions of central NE. Pupillary reactivity to the former was strongly and specifically related to A. Tellegen's (1982) Multidimensional Personality Questionnaire (MPQ) Harm Avoidance scale (i.e., trait fear), whereas the latter was strongly and specifically related to MPQ Negative Emotionality (i.e., trait anxiety). Implications for conceptualizing fear and anxiety as emotional systems are discussed.

  8. Expressions of cardiac sympathetic norepinephrine transporter and β1-adrenergic receptor decreased in aged rats

    Institute of Scientific and Technical Information of China (English)

    He LI; Xiao-qing MA; Fan YE; Jing ZHANG; Xin ZHOU; Zhi-hong WANG; Yu-ming LI; Guo-yuan ZHANG

    2009-01-01

    Evidence suggests that the deterioration of communication between the sympathetic nervous system and cardiovas-cular system always accompanies the aging of human and animals. Cardiac sympathetic norepinephrine (NE) transporter (NET) on presynaptic membrane is a predominant component to eliminate released NE in the synaptic cleff and maintains the sensitivity of the β-adrenergic receptor (β-AR). In the present study, we investigated NET and β1-AR mRNA levels and sympathetic nerve density in cardiac sympathetic ganglion and leff ventricular myocardium in 2- and 16-month-old rats with Northern blot analysis and immunohistochemistry. The expression levels of NET mRNA, NET protein and β1-AR mRNA in the ganglia or myocardia of 16-month-old rats were markedly reduced by 67%, 26%, and 43%, respectively, in comparison with those in 2-month-old rats. Our results also show that aging induces a strong decrease of the catecholaminergic nerve fiber density.

  9. Influence of calcium on the inotropic actions of hyperosmotic agents, norepinephrine, paired electrical stimulation, and treppe.

    Science.gov (United States)

    Willerson, J T; Crie, J S; Adcock, R C; Templeton, G H; Wildenthal, K

    1974-10-01

    To analyze the interaction of calcium ion concentration with hypertonic agents and with other inotropic interventions, isolated right ventricular cat papillary muscles were studied under isometric conditions in Krebs-Ringer bicarbonate solution. Extracellular calcium concentrations were varied between 2.5 and 11.0 mM. Maximal inotropic effects occurred between 5 and 8.0 mM calcium and further elevation to 11.0 mM was without additional influence. The effect of hyperosmotic sucrose and mannitol on papillary muscle performance was compared with that of 10(-6) M norepinephrine at calcium concentrations of 2.5 and 10.0 mM and with paired electrical stimulation in 10.0 mM calcium. Both norepinephrine and the hyperosmotic agents produced significant increases in developed tension and in the maximal rate of tension rise (dT/dt) in Krebs-Ringer in 2.5 and 4.0 mM calcium. In 10 mM calcium norepinephrine increased developed tension and dT/dt, but sucrose and mannitol caused no change or small reductions in both. Paired electrical stimulation, like hyperosmolality, caused no increase in dT/dt in 10 mM calcium. The presence of a potent pharmacological inhibitor of systolic calcium transfer across the cell membrane (D600, 10(-6) M) reduced developed tension and dT/dt by 76+/-2.7 and 74+/-2.0%, respectively, and prevented and in fact reversed the expected increase in dT/dt associated with an increase in rate of stimulation (treppe). However, hypertonic mannitol and paired pacing persisted in causing marked increases in developed tension and dT/dt even in the presence of D600, suggesting that their inotropic effects are not dependent on increased intracellular transfer of calcium during systole through cell membrane channels in which D600 acts as a competitive inhibitor. The results of these studies suggest that apparent functional saturation of intracellular calcium receptor sites eliminates any additional inotropic effect of hyperosmolality or paired pacing. The data are

  10. Importance of calcium in the inotropic effect of hyperosomotic agents, norepinephrine, paired electrical stimulation, and treppe.

    Science.gov (United States)

    Willerson, J T; Crie, J S; Adcock, R C; Templeton, G H; Wildenthal, K

    1975-01-01

    The data obtained from these studies demonstrate that the inotropic effect of hyperosmolar mannitol and sucrose and of paired electrical stimulation is critically influenced by extracellular calcium concentration. The inotropic effect of norepinephrine is not prevented by maximal functional extracellular calcium concentrations. Inhibition of systolic calcium flux at the cell membrane by D600 does not prevent the inotropic effect of hyperosmolar mannitol or of paired electrical stimulation but it does prevent the inotropic effect of hyperosmolar intropic effect of treppe. Thus, intracellular calcium regulation appears to be of major importance in the inotropic effect in isolated cardiac muscle of mannitol and paired pacing while systolic calcium flux at the cell membrane appears to be of major importance in the inotropic effect of treppe.

  11. Norepinephrine turnover in heart and spleen of 7-, 22-, and 34 C-acclimated hamsters

    Science.gov (United States)

    Jones, S. B.; Musacchia, X. J.

    1976-01-01

    The relationship of norepinephrine (NE) concentration and endogenous turnover rates in both myocardial and spleen tissues in the golden hamster is examined as a function of chronic exposure to either high or low ambient temperatures. Changes in myocardial and spleen NE turnover values are discussed in terms of functional alterations in sympathetic nerve activity and the importance of such changes in temperature acclimation. It is found that acclimation of hamsters to 7 C for 7-10 weeks results in decreased myocardial NE concentration and an apparent increase in myocardial NE turnover. In contrast, exposure to 34 C for 6-8 weeks results in increased myocardial NE concentration and an apparent decrease in NE turnover in both myocardial and spleen tissues. The implication of altered NE synthesis is that sympathetic nerve activity is reduced with heat acclimation and is enhanced with cold acclimation.

  12. The norepinephrine transporter gene is associated with the retardation symptoms of major depressive disorder in the Han Chinese population

    Institute of Scientific and Technical Information of China (English)

    Xinrong Li; Ning Sun; Yong Xu; Yanfang Wang; Suping Li; Qiaorong Du; Juyi Peng; Jinxiu Luo; Kerang Zhang

    2012-01-01

    The norepinephrine transporter plays an important role in the pathophysiology and pharmacological treatment of major depressive disorder. Consequently, the norepinephrine transporter gene is an attractive candidate in major depressive disorder research. In the present study, we evaluated the depression symptoms of subjects with major depressive disorder, who were all from the North of China and of Han Chinese origin, using the Hamilton Depression Scale. We examined the relationship between two single nucleotide polymorphisms in the norepinephrine transporter, rs2242446 and rs5569, and the retardation symptoms of major depressive disorder using quantitative trait testing with the UNPHASED program. rs5569 was associated with depressed mood, and the GG genotype may be a risk factor for this; rs2242446 was associated with work and interest, and the TT genotype may be a risk factor for loss of interest. Our findings suggest that rs2242446 and rs5569 in the norepinephrine transporter gene are associated with the retardation symptoms of depression in the Han Chinese population.

  13. The norepinephrine transporter gene is associated with the retardation symptoms of major depressive disorder in the Han Chinese population.

    Science.gov (United States)

    Li, Xinrong; Sun, Ning; Xu, Yong; Wang, Yanfang; Li, Suping; Du, Qiaorong; Peng, Juyi; Luo, Jinxiu; Zhang, Kerang

    2012-09-05

    The norepinephrine transporter plays an important role in the pathophysiology and pharmacological treatment of major depressive disorder. Consequently, the norepinephrine transporter gene is an attractive candidate in major depressive disorder research. In the present study, we evaluated the depression symptoms of subjects with major depressive disorder, who were all from the North of China and of Han Chinese origin, using the Hamilton Depression Scale. We examined the relationship between two single nucleotide polymorphisms in the norepinephrine transporter, rs2242446 and rs5569, and the retardation symptoms of major depressive disorder using quantitative trait testing with the UNPHASED program. rs5569 was associated with depressed mood, and the GG genotype may be a risk factor for this; rs2242446 was associated with work and interest, and the TT genotype may be a risk factor for loss of interest. Our findings suggest that rs2242446 and rs5569 in the norepinephrine transporter gene are associated with the retardation symptoms of depression in the Han Chinese population.

  14. Effects of low-dose dopamine on renal and systemic hemodynamics during incremental norepinephrine infusion in healthy volunteers

    NARCIS (Netherlands)

    Hoogenberg, K; Smit, AJ; Girbes, ARJ

    1998-01-01

    Objectives: To assess the effects of low-dose dopamine on norepinephrine induced renal and systemic vasoconstriction in normotensive healthy subjects. Design: On separate days, either a low-dose dopamine (4 mu g/kg/min) or a placebo (5% glucose) infusion was added in a single, blinded, randomized or

  15. Sevoflurane and propofol anaesthesia differentially modulate the effects of epinephrine and norepinephrine on microcirculatory gastric mucosal oxygenation

    NARCIS (Netherlands)

    Schwarte, L. A.; Schwartges, I.; Schober, P.; Scheeren, T. W. L.; Fournell, A.; Picker, O.

    2010-01-01

    Adequate gastrointestinal mucosal oxygenation is regarded to be crucial in the prevention and therapy of critical illness. Epinephrine and norepinephrine are used for perioperative haemodynamic support. However, their per se effects on gastromucosal haemoglobin oxygenation (mu HbO(2)) remain unclear

  16. Glibenclamide dose response in patients with septic shock: effects on norepinephrine requirements, cardiopulmonary performance, and global oxygen transport.

    Science.gov (United States)

    Morelli, Andrea; Lange, Matthias; Ertmer, Christian; Broeking, Katrin; Van Aken, Hugo; Orecchioni, Alessandra; Rocco, Monica; Bachetoni, Alessandra; Traber, Daniel L; Landoni, Giovanni; Pietropaoli, Paolo; Westphal, Martin

    2007-11-01

    Adenosine triphosphate-sensitive potassium channels are important regulators of arterial vascular smooth muscle tone and are implicated in the pathophysiology of catecholamine tachyphylaxis in septic shock. The present study was designed as a prospective, randomized, double-blinded, clinical pilot study to determine whether different doses of glibenclamide have any effects on norepinephrine requirements, cardiopulmonary hemodynamics, and global oxygen transport in patients with septic shock. We enrolled 30 patients with septic shock requiring invasive hemodynamic monitoring and norepinephrine infusion of 0.5 microg.kg-1.min-1 or greater to maintain MAP between 65 and 75 mmHg. In addition to standard therapy, patients were randomized to receive either 10, 20, or 30 mg of enteral glibenclamide. Systemic hemodynamics, global oxygen transport including arterial lactate concentrations, gas exchange, plasma glucose concentrations, and electrolytes were determined at baseline and after 3, 6, and 12 h after administration of the study drug. Glibenclamide decreased plasma glucose concentrations in a dose-dependent manner but failed to reduce norepinephrine requirements. None of the doses had any effects on cardiopulmonary hemodynamics, global oxygen transport, gas exchange, or electrolytes. These data suggest that oral glibenclamide in doses from 10 to 30 mg fails to counteract arterial hypotension and thus to reduce norepinephrine requirements in catecholamine-dependent human septic shock.

  17. Norepinephrine release in the rat pineal gland : The input from the biological clock measured by in vivo microdialysis

    NARCIS (Netherlands)

    Drijfhout, WJ; vanderLinde, AG; Kooi, SE; Grol, CJ; Westerink, BHC

    1996-01-01

    The sympathetic innervation of the rat pineal gland was investigated, measuring the norepinephrine (NE) release by on-line in vivo microdialysis, NE was assayed using an HPLC method with precolumn derivatization and fluorescence detection. Its high sensitivity and reliability made it very suitable t

  18. Urinary norepinephrine and epinephrine excretion rates are heritable, but not associated with office and ambulatory blood pressure

    NARCIS (Netherlands)

    Bosker, Fokko J.; Wu, Ting; Gladkevich, Anatoliy; Ge, Dongliang; Treiber, Frank A.; Snieder, Harold

    2012-01-01

    Genetic and environmental contributions to urinary excretion rates of norepinephrine (UNEV) and epinephrine (UEV) and their association with blood pressure (BP) were investigated in 91 African American (mean age, 17.3 +/- 2.6 years) and 101 European American (mean age, 18.7 +/- 3.4 years) mono- and

  19. Sevoflurane and propofol anaesthesia differentially modulate the effects of epinephrine and norepinephrine on microcirculatory gastric mucosal oxygenation

    NARCIS (Netherlands)

    Schwarte, L. A.; Schwartges, I.; Schober, P.; Scheeren, T. W. L.; Fournell, A.; Picker, O.

    2010-01-01

    Background: Adequate gastrointestinal mucosal oxygenation is regarded to be crucial in the prevention and therapy of critical illness. Epinephrine and norepinephrine are used for perioperative haemodynamic support. However, their per se effects on gastromucosal haemoglobin oxygenation (mu HbO(2)) re

  20. Stress-related hormone norepinephrine induces interleukin-6 expression in GES-1 cells

    Energy Technology Data Exchange (ETDEWEB)

    Yang, R.; Lin, Q.; Gao, H.B.; Zhang, P. [Department of Biochemistry and Molecular Cell Biology, School of Medicine, Shanghai Jiao Tong University, Shanghai, China, Department of Biochemistry and Molecular Cell Biology, School of Medicine, Shanghai Jiao Tong University, Shanghai (China)

    2014-02-17

    In the current literature, there is evidence that psychological factors can affect the incidence and progression of some cancers. Interleukin 6 (IL-6) is known to be elevated in individuals experiencing chronic stress and is also involved in oncogenesis and cancer progression. However, the precise mechanism of IL-6 induction by the stress-related hormone norepinephrine (NE) is not clear, and, furthermore, there are no reports about the effect of NE on IL-6 expression in gastric epithelial cells. In this study, we examined the effect of NE on IL-6 expression in immortalized human gastric epithelial cells (GES-1 cells). Using real-time PCR and enzyme-linked immunoassay, we demonstrated that NE can induce IL-6 mRNA and protein expression in GES-1 cells. The induction is through the β-adrenergic receptor-cAMP-protein kinase A pathway and mainly at the transcriptional level. Progressive 5′-deletions and site-directed mutagenesis of the parental construct show that, although activating-protein-1 (AP-1), cAMP-responsive element binding protein (CREB), CCAAT-enhancer binding protein-β (C/EBP-β), and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) binding sites are all required in the basal transcription of IL-6, only AP-1 and CREB binding sites in the IL-6 promoter are required in NE-induced IL-6 expression. The results suggest that chronic stress may increase IL-6 secretion of human gastric epithelial cells, at least in part, by the stress-associated hormone norepinephrine, and provides basic data on stress and gastric cancer progression.

  1. Analysis of epinephrine, norepinephrine, and dopamine in urine samples of hospital patients by micellar liquid chromatography.

    Science.gov (United States)

    García Ferrer, Daniel; García García, Aurelio; Peris-Vicente, Juan; Gimeno-Adelantado, José Vicente; Esteve-Romero, Josep

    2015-12-01

    An analytical method based on micellar liquid chromatography was developed to determine the concentration of three catecholamines (epinephrine, norepinephrine, and dopamine) in urine. The detection of these compounds in urine can be useful to diagnose several diseases, related to stress and sympathoadrenal system dysfunction, using a non-invasive collection procedure. The sample pretreatment was a simple dilution in a micellar solution, filtration, and direct injection, thus avoiding time-consuming and tedious extraction steps. Therefore, there is no need to use an internal standard. The three catecholamines were eluted using a C18 column and a mobile phase of 0.055 M sodium dodecyl sulfate-1.5% methanol buffered at pH 3.8 running at 1.5 mL/min under isocratic mode in less than 25 min. The detection was performed by amperometry applying a constant potential of +0.5 V. The procedure was validated following the guidelines of the European Medicines Agency in terms of the following: calibration range (0.09-5 μg/mL), linearity (r(2) > 0.9995), limit of detection (0.02 μg/mL), within- and between-run accuracy (-6.5 to +8.4%) and precision (<10.2%), dilution integrity, matrix effect, robustness (<8.4), and stability. The obtained values were below those required by the guide. The method was rapid, easy-to-handle, eco-friendly, and safe and provides reliable quantitative data, and is thus useful for routine analysis. The procedure was applied to the analysis of epinephrine, norepinephrine, and dopamine in urine samples from patients of a local hospital.

  2. Norepinephrine and dopamine increase motility, biofilm formation and virulence of Vibrio harveyi

    Directory of Open Access Journals (Sweden)

    Qian eYang

    2014-11-01

    Full Text Available Vibrio harveyi is one of the major pathogens of aquatic organisms, affecting both vertebrates and invertebrates, and causes important losses in the aquaculture industry. In order to develop novel methods to control disease caused by this pathogen, we need to obtain a better understanding of pathogenicity mechanisms. Sensing of catecholamines increases both growth and production of virulence-related factors in pathogens of terrestrial animals and humans. However, at this moment, knowledge on the impact of catecholamines on the virulence of pathogens of aquatic organisms is lacking. In the present study, we report that in V. harveyi, norepinephrine and dopamine increased growth in serum-supplemented medium, siderophore production, swimming motility and expression of genes involved in flagellar motility, biofilm formation, and exopolysaccharide production. Consistent with this, pretreatment of V. harveyi with catecholamines prior to inoculation into the rearing water resulted in significantly decreased survival of gnotobiotic brine shrimp larvae, when compared to larvae challenged with untreated V. harveyi. Further, norepinephrine-induced effects could be neutralized by α-adrenergic antagonists or by the bacterial catecholamine receptor antagonist LED209, but not by β-adrenergic or dopaminergic antagonists. Dopamine-induced effects could be neutralized by dopaminergic antagonists or LED209, but not by adrenergic antagonists. Together, our results indicate that catecholamine sensing increases the success of transmission of V. harveyi and that interfering with catecholamine sensing might be an interesting strategy to control vibriosis in aquaculture. We hypothesise that upon tissue and/or hemocyte damage during infection, pathogens come into contact with elevated catecholamine levels, and that this stimulates the expression of virulence factors that are required to colonize a new host.

  3. Benzodiazepines: rat pinealocyte binding sites and augmentation of norepinephrine-stimulated N-acetyltransferase activity

    Energy Technology Data Exchange (ETDEWEB)

    Matthew, E.; Parfitt, A.G.; Sugden, D.; Engelhardt, D.L.; Zimmerman, E.A.; Klein, D.C.

    1984-02-01

    Studies of (/sup 3/H)diazepam binding to intact rat pineal cells were carried out in tissue culture preparations. The binding was saturable, reversible and proportional to the number of cells used. Scatchard analysis resulted in a linear plot (Kd . 23 nM, maximum binding sites (Bmax) . 1.56 pmol/mg of protein for cells in monolayer culture; Kd . 7 nM, Bmax . 1.3 pmol/mg of protein for cells in suspension culture). Inhibition constants (Ki) for clonazepam (500 nM), flunitrazepam (38 nM) and Ro-5-4864 (5 nM) indicated that the binding sites were probably of the ''peripheral'' type. In addition, the effects of diazepam on norepinephrine-stimulated N-acetyltransferase (NAT) activity were studied in organ culture and dissociated cell culture. Diazepam (10-50 microM) both prolonged and increased the magnitude of the norepinephrine-induced increase in NAT activity but did not affect the initial rate of rise of enzyme activity. The effect was dose-dependent and was also seen with clonazepam, flunitrazepam and Ro-5-4864, but not with Ro-15-1788. Diazepam, by itself, at these concentrations, had no effect on NAT, but enzyme activity was increased by higher concentrations (0.1-1 mM). Although a relationship between the (/sup 3/H)diazepam binding sites described here and the effect of benzodiazepines on NAT cannot be established from these studies, the data suggest that the benzodiazepines may alter melatonin levels through their action on NAT.

  4. Selective serotonin reuptake inhibitors and oral bleeding complications after invasive dental treatment.

    Science.gov (United States)

    Napeñas, Joel J; Hong, Catherine H L; Kempter, Eric; Brennan, Michael T; Furney, Scott L; Lockhart, Peter B

    2011-10-01

    The purpose of this study was to examine the frequency of oral bleeding complications after invasive dental procedures in patients taking selective serotonin reuptake inhibitor (SSRI) medications. In this retrospective cohort study, we included dental patients who had invasive dental treatment and were taking an SSRI medication. Data collected included demographics, medical history, dental visits and procedures, and use of adjunctive measures to control bleeding. Primary outcomes included documentation of return visits or phone calls to the dental clinic or emergency department (ED) for oral bleeding, and oral bleeding or use of blood products for inpatients. There were 92 patients taking SSRIs who had 145 invasive procedure visits, consisting of extractions, implant surgery, alveoloplasty, periodontal surgery, subgingival scaling and root planning, and biopsy. There were 110 extraction visits yielding a total of 167 extractions. Among all patients, there was 1 return visit to the clinic and 1 telephone call with a chief complaint of oral bleeding. The frequency of oral bleeding complications after invasive dental treatment is low to negligible in patients on SSRI medications. Copyright © 2011 Mosby, Inc. All rights reserved.

  5. The impact of treatment with selective serotonin reuptake inhibitors on primate cardiovascular disease, behavior, and neuroanatomy.

    Science.gov (United States)

    Shively, Carol A; Silverstein-Metzler, Marnie; Justice, Jamie; Willard, Stephanie L

    2017-03-01

    Selective serotonin reuptake inhibitor (SSRI) use is ubiquitous because they are widely prescribed for a number of disorders in addition to depression. Depression increases the risk of coronary heart disease (CHD). Hence, treating depression with SSRIs could reduce CHD risk. However, the effects of long term antidepressant treatment on CHD risk, as well as other aspects of health, remain poorly understood. Thus, we undertook an investigation of multisystem effects of SSRI treatment with a physiologically relevant dose in middle-aged adult female cynomolgus monkeys, a primate species shown to be a useful model of both depression and coronary and carotid artery atherosclerosis. Sertraline had no effect on depressive behavior, reduced anxious behavior, increased affiliation, reduced aggression, changed serotonin neurotransmission and volumes of neural areas critical to mood disorders, and exacerbated coronary and carotid atherosclerosis. These data suggest that a conservative approach to prescribing SSRIs for cardiovascular or other disorders for long periods may be warranted, and that further study is critical given the widespread use of these medications.

  6. Plasma cytokine profiles in depressed patients who fail to respond to selective serotonin reuptake inhibitor therapy.

    LENUS (Irish Health Repository)

    O'Brien, Sinead M

    2012-02-03

    OBJECTIVE: Approximately 30% of patients with depression fail to respond to a selective serotonin reuptake inhibitor (SSRI). Few studies have attempted to define these patients from a biological perspective. Studies suggest that overall patients with depression show increased production of proinflammatory cytokines. We examined pro- and anti-inflammatory cytokine levels in patients who were SSRI resistant. METHODS: Plasma concentrations of IL-6, IL-8, IL-10, TNF-alpha and sIL-6R were measured with enzyme linked immunosorbent assays (ELISA) in DSM-1V major depressives who were SSRI resistant, in formerly SSRI resistant patients currently euthymic and in healthy controls. RESULTS: Patients with SSRI-resistant depression had significantly higher production of the pro-inflammatory cytokines IL-6 (p=0.01) and TNF-alpha (p=0.004) compared to normal controls. Euthymic patients who were formerly SSRI resistant had proinflammatory cytokine levels which were similar to the healthy subject group. Anti-inflammatory cytokine levels did not differ across the 3 groups. CONCLUSION: Suppression of proinflammatory cytokines does not occur in depressed patients who fail to respond to SSRIs and is necessary for clinical recovery.

  7. Temporal Expression of Mutant LRRK2 in Adult Rats Impairs Dopamine Reuptake

    Directory of Open Access Journals (Sweden)

    Hongxia Zhou, Cao Huang, Jianbin Tong, Weimin C Hong, Yong-Jian Liu, Xu-Gang Xia

    2011-01-01

    Full Text Available Parkinson's disease (PD results from progressive degeneration of dopaminergic neurons. Most PD cases are sporadic, but some have pathogenic mutation in the individual genes. Mutation of the leucine-rich repeat kinase-2 (LRRK2 gene is associated with familial and sporadic PD, as exemplified by G2019S substitution. While constitutive expression of mutant LRRK2 in transgenic mice fails to induce neuron death, transient expression of the disease gene by viral delivery causes a substantial loss of dopaminergic neurons in mice. To further assess LRRK2 pathogenesis, we created inducible transgenic rats expressing human LRRK2 with G2019S substitution. Temporal overexpression of LRRK2G2019S in adult rats impaired dopamine reuptake by dopamine transporter (DAT and thus enhanced locomotor activity, the phenotypes that were not observed in transgenic rats constitutively expressing the gene throughout life time. Reduced DAT binding activity is an early sign of dopaminergic dysfunction in asymptomatic subjects carrying pathogenic mutation in LRRK2. Our transgenic rats recapitulated the initiation process of dopaminergic dysfunction caused by pathogenic mutation in LRRK2. Inducible transgenic approach uncovered phenotypes that may be obscured by developmental compensation in constitutive transgenic rats. Finding in inducible LRRK2 transgenic rats would guide developing effective strategy in transgenic studies: Inducible expression of transgene may induce greater phenotypes than constitutive gene expression, particularly in rodents with short life time.

  8. Selective Serotonin Reuptake Inhibitors in Human Pregnancy: To Treat or Not to Treat?

    Directory of Open Access Journals (Sweden)

    Orna Diav-Citrin

    2012-01-01

    Full Text Available Selective serotonin reuptake inhibitors (SSRIs are increasingly prescribed during pregnancy. The purpose of the present paper is to summarize and evaluate the current evidence for the risk/benefit analysis of SSRI use in human pregnancy. The literature has been inconsistent. Although most studies have not shown an increase in the overall risk of major malformations, several studies have suggested that SSRIs may be associated with a small increased risk for cardiovascular malformations. Others have noted associations between SSRIs and specific types of rare major malformations. In some studies, there appears to be a small increased risk for miscarriages, which may be associated with the underlying maternal condition. Neonatal effects have been described in up to 30% of neonates exposed to SSRIs late in pregnancy. Persistent pulmonary hypertension of the newborn has also been described with an absolute risk of <1%. The risk associated with treatment discontinuation, for example, higher frequency of relapse and increased risk of preterm delivery, should also be considered. The overall benefit of treatment seems to outweigh the potential risks.

  9. The effects of maternal depression and maternal selective serotonin reuptake inhibitor exposure on the offspring

    Directory of Open Access Journals (Sweden)

    Jocelien DA Olivier

    2013-05-01

    Full Text Available It has been estimated that 20% of pregnant women suffer from depression and it is well documented that maternal depression can have long-lasting effects on the child. Currently, common treatment for maternal depression has been the selective serotonin reuptake inhibitor medications (SSRIs which are used by 2-3% of pregnant women in the Nordic countries and by up to 10% of pregnant women in the United States. Antidepressants cross the placenta and are transferred to the fetus, thus, the question arises as to whether children of women taking antidepressants are at risk for altered neurodevelopmental outcomes and, if so, whether the risks are due to SSRI medication exposure or to the underlying maternal depression. This review considers the effects of maternal depression and SSRI exposure on offspring development in both clinical and preclinical populations. As it is impossible in humans to study the effects of SSRIs without taking into account the possible underlying effects of maternal depression (healthy pregnant women do not take SSRIs, animal models are of great value. For example, rodents can be used to determine the effects of maternal depression and/or perinatal SSRI exposure on offspring outcomes. Unraveling the joint (or separate effects of maternal depression and SSRI exposure will provide more insights into the risks or benefits of SSRI exposure during gestation and will help women make informed decisions about using SSRIs during pregnancy.

  10. Time-dependent inhibition of CYP3A4 by sertraline, a selective serotonin reuptake inhibitor.

    Science.gov (United States)

    Masubuchi, Yasuhiro; Kawaguchi, Yuki

    2013-11-01

    Drug-drug interactions associated with selective serotonin reuptake inhibitors (SSRIs) are widely known. A major interaction by SSRIs is the inhibition of cytochrome P450 (P450)-mediated hepatic drug metabolism. The SSRI, sertraline, is also reported to increase the blood concentration of co-administered drugs. The potency of sertraline directly to inhibit hepatic drug metabolism is relatively weak compared with the other SSRIs, implying that additional mechanisms are involved in the interactions. The study examined whether sertraline produces time-dependent inhibition of CYP3A4 and/or other P450 enzymes. Incubation of human liver microsomes with sertraline in the presence of NADPH resulted in marked decreases in testosterone 6β-hydroxylation activities, indicating that sertraline metabolism leads to CYP3A4 inactivation. This inactivation required NADPH and was not protected by glutathione. No significant inactivation was observed for other P450 enzymes. Spectroscopic evaluation revealed that microsomes with and without sertraline in the presence of NADPH gave a Soret peak at 455 nm, suggesting the formation of metabolic intermediate (MI) complexes of sertraline metabolite(s) with the reduced form of P450. This is the first report indicating that sertraline produced time-dependent inhibition of CYP3A4, which may be associated with MI complex formation.

  11. Metabolic interactions of central nervous system medications and selective serotonin reuptake inhibitors.

    Science.gov (United States)

    Naranjo, C A; Sproule, B A; Knoke, D M

    1999-05-01

    Selective serotonin reuptake inhibitors (SSRIs) are prescribed alone and in combination with other psychotropic medications in the treatment of a variety of psychiatric disorders. Such combinations create the potential for pharmacokinetic interactions by affecting the activity of the cytochromes P450 (CYP450), drug metabolizing oxidative enzymes. SSRIs are not equivalent in their potential for interactions when combined with other central nervous system (CNS) medication. Generally citalopram and sertraline are characterized by weaker inhibition of CYP450 enzymes and, therefore, hold less potential for interaction than the other SSRIs. Paroxetine potently inhibits CYP2D6, which can result in increased neuroleptic serum concentrations, accompanied by increased CNS side-effects. Similarly, as a potent inhibitor of CYP2D6, fluoxetine can increase serum concentrations of neuroleptics and antidepressants and numerous case reports have documented concomitant adverse events. Fluoxetine also inhibits CYP3A and CYP2C19, increasing serum concentrations of some benzodiazepines. Fluvoxamine is a potent inhibitor of CYP1A2, a moderate inhibitor of CYP3A and a mild inhibitor of CYP2D6. Therefore, interactions with clozapine and benzodiazepines are evident.

  12. Some selective serotonin reuptake inhibitors inhibit dynamin I guanosine triphosphatase (GTPase).

    Science.gov (United States)

    Otomo, Masahiro; Takahashi, Kiyofumi; Miyoshi, Hiroshi; Osada, Kenichi; Nakashima, Hideki; Yamaguchi, Noboru

    2008-08-01

    Neuronal dynamin I plays a critical role in the recycling of synaptic vesicles, and thus in nervous system function. We expressed and purified dynamin I to explore potentially clinically useful endocytosis inhibitors and to examine the mechanism of their action. We estimated the IC(50) of nineteen psychotropic drugs for dynamin I. The IC(50) values of two selective serotonin reuptake inhibitors (sertraline and fluvoxamine) were 7.3+/-1.0 and 14.7+/-1.6 microM, respectively. Kinetic analyses revealed that fluvoxamine is a noncompetitive inhibitor of dynamin I guanosine triphosphatase (GTPase) with respect to guanosine 5'-triphosphate (GTP) and a competitive inhibitor with respect to L-phosphatidylserine (PS). Fluvoxamine may compete with PS for binding to the pleckstrin homology domain of dynamin I. On the other hand, sertraline was a mixed type inhibitor with respect to both GTP and PS. Our results indicate that sertraline and fluvoxamine may regulate the transportation of neurotransmitters by modulating synaptic vesicle endocytosis via the inhibition of dynamin I GTPase.

  13. The effects of selective serotonin reuptake inhibitors on platelet function in whole blood and platelet concentrates.

    Science.gov (United States)

    Reikvam, Anne-Grete; Hustad, Steinar; Reikvam, Håkon; Apelseth, Torunn Oveland; Nepstad, Ina; Hervig, Tor Audun

    2012-01-01

    Several studies report that patients who are treated with selective serotonin reuptake inhibitors (SSRIs) for depression may have increased risk of bleeding, particularly from the gastrointestinal tract. This may be related to low intraplatelet serotonin concentrations. Several blood banks do not store platelets from donors using SSRIs for transfusion, although the possible effects of SSRIs on platelet storage are not documented. We conducted a case-control pilot study of apheresis platelet concentrates prepared from donors using SSRIs (n=8) and from donors without medication (n=10). The platelet concentrates were stored for 5 days. Light transmission aggregometry (LTA), thrombelastography (TEG), and flow cytometric analyses were preformed for in vitro measurements of platelet function. Platelet function and platelet serotonin content were investigated in whole blood and in platelet concentrates stored for up to 5 days. LTA, TEG, and flow cytometric analysis of glycoprotein expression did not reveal any significant differences between the two groups. All 18 platelet concentrates performed well according to the standards set for platelet quality in relation to transfusion. Blood donors using SSRIs had significantly lower platelet serotonin compared to blood donors without medication. The results from our pilot study indicate that platelets from donors using SSRIs may be suitable for transfusion after storage for 5 days, but further laboratory and clinical studies are necessary to confirm this.

  14. Antiparkinsonian treatment for depression in Parkinson’s disease:Are selective serotonin reuptake inhibitors recommended?

    Institute of Scientific and Technical Information of China (English)

    Philippe De Deurwaerdre; Yuqiang Ding

    2016-01-01

    Depression is a frequent comorbid syndrome in Parkinson’s disease. It is a difficult symptom to manage, as patients continuously receive antiparkinsonian medication and may also have to be treated for the amelioration of the side-effects of antiparkinsonian therapy. The first-line treatment for depression in Parkinson’s disease is the use of selective serotonin reuptake inhibitors (SSRIs). The clinical efficacy of these medications in patients with Parkinson’s disease is questionable. In fact, based on their mechanism of action, which requires at least a functional serotonergic system, it is predicted that SSRIs will have lower efficacy in patients with Parkinson’s disease. Here, we consider the mechanism of action of SSRIs in the context of Parkinson’s disease by investigating the fall in the levels of serotonergic markers and the inhibitory outcomes of antiparkinsonian treatment on serotonergic nerve activity. Because certain classes of antidepressant drugs are widely available, it is necessary to perform translational research to address different strategies used to manage depression in Parkinson’s disease.

  15. Selective serotonin reuptake inhibitor antidepressant use in first trimester pregnancy and risk of congenital anomalies: A European register-based study in 12 European countries

    NARCIS (Netherlands)

    Wemakor, A.; Casson, K.; Garne, E.; Bakker, Marian; Tucker, D.; Khoshnood, B.; Nelen, V.; O'Mahoney, M.; Pierini, A.; Klungsoyr, K.; Gatt, M.; Addor, C.M.; Rissmann, A.; Arriola, L.; Boyle, B.; De Jong-Van Den Berg, L.; Dolk, H.

    2015-01-01

    Objective / Background The Selective Serotonin Reuptake Inhibitor (SSRI) antidepressants are widely prescribed in pregnancy, but there is evidence that they may cause congenital anomalies, particularly congenital heart defects (CHD). Objective: To determine the specificity of association between fir

  16. Selective serotonin reuptake inhibitor antidepressant use in first trimester pregnancy and risk of congenital anomalies: A European register-based study in 12 European countries

    NARCIS (Netherlands)

    Wemakor, A.; Casson, K.; Garne, E.; Bakker, Marian; Tucker, D.; Khoshnood, B.; Nelen, V.; O'Mahoney, M.; Pierini, A.; Klungsoyr, K.; Gatt, M.; Addor, C.M.; Rissmann, A.; Arriola, L.; Boyle, B.; De Jong-Van Den Berg, L.; Dolk, H.

    2015-01-01

    Objective / Background The Selective Serotonin Reuptake Inhibitor (SSRI) antidepressants are widely prescribed in pregnancy, but there is evidence that they may cause congenital anomalies, particularly congenital heart defects (CHD). Objective: To determine the specificity of association between

  17. Partial purification of the 5-hydroxytryptophan-reuptake system from human blood platelets using a citalopram-derived affinity resin

    Energy Technology Data Exchange (ETDEWEB)

    Biessen, E.A.L; Horn, A.S.; Robillard, G.T. (Univ. of Groningen (Netherlands))

    1990-04-03

    This paper describes a procedure for the synthesis and application of a citalopram-derived affinity resin in purifying the 5HT-reuptake system from human blood platelets. A two-step scheme has been developed for partial purification, based on wheat germ agglutinin-lectin (WGA) affinity and citalopram affinity chromatographies. Upon solubilization of the carrier with 1% digitonin, a 50-70-fold increase in specific ({sup 3}H) imipramine binding activity with a 70% recovery could be accomplished through WGA-lectin chromatography. The WGA pool was then subjected to affinity chromatography on citalopram-agarose. At least 90% of the binding capacity adsorbed to the column. Specific elution using 10 {mu}M citalopram resulted in a 22% recovery of binding activity. A 10,000-fold overall purification was obtained by using this two-step procedure. Analysis of the fractions on SDS-PAGE after {sup 125}I labeling revealed specific elution of 78- and 55-kDa proteins concomitant with the appearance of ({sup 3}H) imipramine binding activity. The pharmacological profile of the partially purified reuptake system correlated well with that derived from the crude membrane-bound reuptake system, suggesting a copurification of the 5HT binding activity and ({sup 3}H)imipramine binding activity.

  18. Effects of renal sympathetic nerve radiofrequency ablation on norepinephrine spillover rate and sympathetic nerve activity in dogs with hypertension

    Directory of Open Access Journals (Sweden)

    Hang YU

    2012-11-01

    Full Text Available Objective  To evaluate the validity and explore the mechanism of renal sympathetic denervation (RSD in the treatment of dogs with hypertension reproduced by constriction of abdominal aorta. Methods  The hypertension model was reproduced by constriction of abdominal aorta in 20 adult healthy dogs. These dogs were then randomly divided into the treatment group and control group (10 each. Renal sympathetic nerve radiofrequency ablation was done in treatment group 1 month after modeling. The foreleg blood pressure, sympathetic activity and norepinephrine overflow rate of dogs in two groups were detected before modeling, and 1, 2 and 3 months after modeling, and the trend of the change was also observed. Results  One month after modeling, the systolic blood pressure (SBP, diastolic blood pressure (DBP and mean arterial blood pressure (MAP were elevated significantly in control group (146.7±21.0, 89.0±12.7 and 108.3±14.9mmHg compared with those before modeling (119.5±13.2, 76.5±7.8 and 90.9±8mmHg, P < 0.05. The renal sympathetic activity impulse and norepinephrine spillover rate were also enhanced significantly (P < 0.05. The renal sympathetic nerve activity obviously decreased in the treatment group after the operation, and then increased 2 months after the ablation. The norepinephrine spillover rate in treatment group increased significantly 1 month after modeling (P < 0.05, and decreased after ablation, and it lasted to the end of the experiment (P < 0.05. One and two months after ablation, the norepinephrine spillover rate was lower in treatment group than in control group (P < 0.05. Conclusion  Renal sympathetic nerve radiofrequency ablation significantly inhibits the elevation of norepinephrine spillover rate and sympathetic nerve activity in dogs with hypertension.

  19. 5-HT reuptake inhibitors with 5-HT(1B/1D) antagonistic activity: a new approach toward efficient antidepressants.

    Science.gov (United States)

    Matzen, L; van Amsterdam, C; Rautenberg, W; Greiner, H E; Harting, J; Seyfried, C A; Böttcher, H

    2000-03-23

    As part of our research program toward new, potential antidepressants, a series of unsymmetrical ureas has been prepared and evaluated as 5-HT reuptake inhibitors with 5-HT(1B/1D) antagonistic activities. The design of these compounds was based on coupling of various indole derivatives, previously shown to inhibit 5-HT reuptake, to three different aniline moieties, which are part of known 5-HT(1B/1D) ligands. Binding experiments in rat frontal cortex using [(125)I]iodocyanopindolol, in calf striatum using [(3)H]5-HT, and in rat hippocampus using [(3)H]8-OH-DPAT as radioligands, respectively, revealed significantly higher affinity at the 5-HT(1B) receptor as compared to the affinities for the 5-HT(1A) and 5-HT(1D) receptors for a number of compounds, among them 4-(5-fluoro-1H-indol-3-yl)piperidine-1-carboxylic acid [4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amide (5), the corresponding 4-fluoro-1H-indol-3-yl analogue 21a, and the corresponding 6-fluoro-1H-indol-3-yl analogue 21b. Conformational restriction of the aniline moiety in 5 only slightly enhanced the 5-HT(1B) affinity, whereas introduction of an aniline moiety with higher conformational flexibility resulted in a less potent 5-HT(1B) receptor ligand as compared to 5. The functional 5-HT(1B/1D) antagonistic activity was investigated using the rabbit saphenous vein model as well as the [(3)H]5-HT release from guinea pig cortical slices. All new compounds tested in the rabbit saphenous vein model were shown to antagonize the sumatriptan-evoked contractile responses with pA(2) values ranging from 7.3 to 8.7. These observations were consistent with the results of the cortical slice model, in which the ureas were found to block the sumatriptan-induced inhibition of potassium-evoked [(3)H]5-HT release. The 5-HT reuptake inhibition of the ureas determined in rat brain synaptosomes was found to be either increased or decreased as compared to the uncoupled indole derivatives indicating that the reuptake inhibition

  20. Bioimpedance in monitoring of effects of selective serotonin reuptake inhibitor treatment

    Directory of Open Access Journals (Sweden)

    Kuznecova LV

    2011-06-01

    Full Text Available Vasiliy Grigorievich Alexeev, Ludmila Vasilievna KuznecovaDepartment of Physiology, SP Botkin Moscow City Clinical Hospital, Moscow, RussiaBackground: Bioimpedance has been shown to be a safe technique when used in a number of biomedical applications. In this study, we used the Electro Interstitial Scan (EIS to perform bioimpedance measurements to follow up the efficacy of selective serotonin reuptake inhibitor (SSRI treatment in subjects diagnosed to have major depressive disorder.Methods: We recruited 59 subjects (38 women, 21 men aged 17–76 (mean 47 years diagnosed with major depressive disorder by psychiatric assessment at the Botkin Hospital according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV. Baseline Clinical Global Impression scores and EIS (electrical conductivity and dispersion α parameter measurements were done before starting SSRI therapy. Treatment follow-up was undertaken using EIS bioimpedance measurements and by treatment response based on the Hamilton Depression Scale and Clinical Global Impression, every 15 days for 60 days. At day 45, we classified the patients into two groups, ie, Group 1, including treatment responders, and Group 2, including nonresponders. At day 60, patients were classified into two further groups, ie, Group 3, comprising treatment responders, and Group 4, comprising nonresponders.Results: Comparing Group 1 and Group 2, electrical conductivity measurement of the pathway between the two forehead electrodes had a specificity of 72% and a sensitivity of 85.3% (P < 0.0001, with a cutoff >4.32. Comparing Group 3 and Group 4, electrical conductivity measurements in the same pathway had a specificity of 47.6% and a sensitivity of 76.3% (P < 0.16, with a cutoff >5.92. Comparing Group 1 and Group 2, the electrical dispersion α parameter of the pathway between the two disposable forehead electrodes had a specificity of 80% and a sensitivity of 85.2% (P < 0.0001 with a

  1. [Efficacy of selective serotonin reuptake inhibitor treatment in children and adolescents].

    Science.gov (United States)

    Bailly, Daniel

    2006-09-01

    Selective serotonin reuptake inhibitors (SSRIs) have been used increasingly since the early 1990s to treat anxiety disorders and depression in children and adolescents. Several recent reports, however, cast doubt on their efficacy and especially raise questions about their role in serious adverse effects (increase in suicidal ideation and suicide attempts as well as reactions involving irritability, hostility, self-harm and self-destructive actions). The efficacy of SSRIs (fluoxetine, sertraline, fluvoxamine, paroxetine) in the treatment of obsessive-compulsive disorders in this population is clear today, although their effects are globally relatively modest. SSRIs remain notably less effective than clomipramine for this indication, although a variety of factors (age, family history, and psychiatric comorbidity) are also likely to influence response to treatment. Only several placebo-controlled studies suggest that the SSRIs (fluoxetine, sertraline and fluvoxamine) may have some utility in the treatment of anxiety disorders (generalized anxiety, separation anxiety, social phobias) in children and teens. The additional benefits from SSRIs for this indication nonetheless require confirmation. Imipramine and related tricyclic antidepressants are ineffective in the treatment of depressive disorders in children and adolescents. Among the SSRIs, only fluoxetine has proven its efficacy for this indication, although its effect here too appears relatively modest. The efficacy of sertraline and paroxetine cannot be considered more than probable, requiring confirmation, and that of citalopram has not been demonstrated. Moreover, because of the risk of suicidal behavior observed in some studies, SSRIs are inadvisable for the treatment of depressive disorders in this population. Overall, although the currently available data show SSRIs to be moderately effective and useful in treating anxiety disorders and depression in children and adolescents, future studies must focus on

  2. Selective Serotonin Reuptake Inhibitors and Gastrointestinal Bleeding: A Case-Control Study

    Science.gov (United States)

    Carvajal, Alfonso; Ortega, Sara; Del Olmo, Lourdes; Vidal, Xavier; Aguirre, Carmelo; Ruiz, Borja; Conforti, Anita; Leone, Roberto; López-Vázquez, Paula; Figueiras, Adolfo; Ibáñez, Luisa

    2011-01-01

    Background Selective serotonin reuptake inhibitors (SSRIs) have been associated with upper gastrointestinal (GI) bleeding. Given their worldwide use, even small risks account for a large number of cases. This study has been conducted with carefully collected information to further investigate the relationship between SSRIs and upper GI bleeding. Methods We conducted a case-control study in hospitals in Spain and in Italy. Cases were patients aged ≥18 years with a primary diagnosis of acute upper GI bleeding diagnosed by endoscopy; three controls were matched by sex, age, date of admission (within 3 months) and hospital among patients who were admitted for elective surgery for non-painful disorders. Exposures to SSRIs, other antidepressants and other drugs were defined as any use of these drugs in the 7 days before the day on which upper gastrointestinal bleeding started (index day). Results 581 cases of upper GI bleeding and 1358 controls were considered eligible for the study; no differences in age or sex distribution were observed between cases and controls after matching. Overall, 4.0% of the cases and 3.3% of controls used an SSRI antidepressant in the week before the index day. No significant risk of upper GI bleeding was encountered for SSRI antidepressants (adjusted odds ratio, 1.06, 95% CI, 0.57–1.96) or for whichever other grouping of antidepressants. Conclusions The results of this case-control study showed no significant increase in upper GI bleeding with SSRIs and provide good evidence that the magnitude of any increase in risk is not greater than 2. PMID:21625637

  3. Selective serotonin reuptake inhibitors and gastrointestinal bleeding: a case-control study.

    Directory of Open Access Journals (Sweden)

    Alfonso Carvajal

    Full Text Available BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs have been associated with upper gastrointestinal (GI bleeding. Given their worldwide use, even small risks account for a large number of cases. This study has been conducted with carefully collected information to further investigate the relationship between SSRIs and upper GI bleeding. METHODS: We conducted a case-control study in hospitals in Spain and in Italy. Cases were patients aged ≥18 years with a primary diagnosis of acute upper GI bleeding diagnosed by endoscopy; three controls were matched by sex, age, date of admission (within 3 months and hospital among patients who were admitted for elective surgery for non-painful disorders. Exposures to SSRIs, other antidepressants and other drugs were defined as any use of these drugs in the 7 days before the day on which upper gastrointestinal bleeding started (index day. RESULTS: 581 cases of upper GI bleeding and 1358 controls were considered eligible for the study; no differences in age or sex distribution were observed between cases and controls after matching. Overall, 4.0% of the cases and 3.3% of controls used an SSRI antidepressant in the week before the index day. No significant risk of upper GI bleeding was encountered for SSRI antidepressants (adjusted odds ratio, 1.06, 95% CI, 0.57-1.96 or for whichever other grouping of antidepressants. CONCLUSIONS: The results of this case-control study showed no significant increase in upper GI bleeding with SSRIs and provide good evidence that the magnitude of any increase in risk is not greater than 2.

  4. Serotonin transporter occupancy in rats exposed to serotonin reuptake inhibitors in utero or via breast milk.

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    Capello, Catherine F; Bourke, Chase H; Ritchie, James C; Stowe, Zachary N; Newport, D Jeffrey; Nemeroff, Amanda; Owens, Michael J

    2011-10-01

    Rigorous data regarding fetal central nervous system (CNS) exposure after antidepressant exposure are sparse. The magnitude of serotonin reuptake inhibitor (SRI) CNS exposure was measured in three groups of rats using ex vivo autoradiography of the serotonin transporter (SERT): 1) in utero, 2) postnatal clearance after birth, and 3) exposure through lactation. Rats were exposed to one of five SRI-type antidepressants (escitalopram, fluoxetine, paroxetine, sertraline, and venlafaxine) administered continuously via osmotic minipumps to pregnant or nursing dams. Dam dosing was adjusted to reflect the 50th and 85th percentiles of serum concentrations observed in pregnant women. Embryonic day 21 rat pups exposed in utero exhibited >80% SERT occupancy in brain tissue, which is equivalent to that of the pregnant dam and similar to that reported for human pharmacotherapy. Venlafaxine was the exception with occupancies ranging from 61 to 92% across different litters. The magnitude of SERT occupancy is essentially equivalent between dams and fetuses. By postnatal day 4, high SERT occupancy was observed only in fluoxetine-exposed pups (41-92% occupancy). Significantly less, but measurable, exposure occurred via breast milk exposure even in the absence of detectable drug concentrations in nursing pup sera. Pups exposed to SRIs via breast milk for 3 or 7 days exhibited varying SERT occupancies (0-57% depending on the individual medication and dam dose). These data highlight the need for animal modeling of fetal and nursing infant drug exposure using clinically meaningful dosing strategies and appropriate CNS measures to develop rational treatment guidelines that systematically minimize fetal and neonatal medication exposure in humans.

  5. Selective serotonin reuptake inhibitors to improve outcome in acute ischemic stroke: possible mechanisms and clinical evidence.

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    Siepmann, Timo; Penzlin, Ana Isabel; Kepplinger, Jessica; Illigens, Ben Min-Woo; Weidner, Kerstin; Reichmann, Heinz; Barlinn, Kristian

    2015-10-01

    Several clinical studies have indicated that selective serotonin reuptake inhibitors (SSRIs) administered in patients after acute ischemic stroke can improve clinical recovery independently of depression. Due to small sample sizes and heterogeneous study designs interpretability was limited in these studies. The mechanisms of action whereby SSRI might improve recovery from acute ischemic stroke are not fully elucidated. We searched MEDLINE using the PubMed interface to identify evidence of SSRI mediated improvement of recovery from acute ischemic stroke and reviewed the literature on the potential underlying mechanisms of action. Among identified clinical studies, a well-designed randomized, double-blind, and placebo-controlled study (FLAME - fluoxetine for motor recovery after acute ischemic stroke) demonstrated improved recovery of motor function in stroke patients receiving fluoxetine. The positive effects of SSRIs on stroke recovery were further supported by a meta-analysis of 52 trials in a total of 4060 participants published by the Cochrane collaboration. Based on animal models, the mechanisms whereby SSRIs might ameliorate functional and structural ischemic-brain damage were suggested to include stimulation of neurogenesis with migration of newly generated cells toward ischemic-brain regions, anti-inflammatory neuroprotection, improved regulation of cerebral blood flow, and modulation of the adrenergic neurohormonal system. However, to date, it remains speculative if and to what degree these mechanisms convert into humans and randomized controlled trials in large populations of stroke patients comparing different SSRIs are still lacking. In addition to the need of comprehensive-clinical evidence, further elucidation of the beneficial mechanisms whereby SSRIs may improve structural and functional recovery from ischemic-brain damage is needed to form a basis for translation into clinical practice.

  6. Neuroimaging of the serotonin reuptake site requires high-affinity ligands.

    Science.gov (United States)

    Elfving, Betina; Madsen, Jacob; Knudsen, Gitte M

    2007-11-01

    Numerous attempts have been made to develop suitable radiolabeled tracers for positron emission tomography or single photon emission computed tomography imaging of the serotonin transporter (SERT), but most often, negative outcomes are reported. The aim of this study is to define characteristics of a good SERT radioligand and to investigate species differences. We examined seven different selective serotonin reuptake inhibitors (SSRIs) and that except for one all have been previously tested as emission tomography ligands. The outcome of the ligands as emission tomography tracers was compared in relation with receptor density (Bmax) and/or ligand affinity (Kd) in rat and monkey cerebrum and cerebellum (reference region) membranes. [3H]-(S)-Citalopram and [3H]-(+)-McN5652 display statistically significantly lower affinity, whereas [3H]paroxetine displays statistically significantly higher affinity for SERT in monkey cortex when compared with the rat cerebrum. The affinity of [3H]MADAM, [123I]ADAM, and [11C]DASB for SERT obtained with rat cerebrum and monkey cortex are similar. In monkey cortex, Kd and Bmax could not be determined with [3H]fluoxetine. Of the seven SSRIs, [3H]-(S)-citalopram, [3H]MADAM, and [11C]DASB displayed significant specific binding to SERT in monkey cerebellum, with Bmax cortex:cerebellum ratios being 17, 3, and 4, respectively. In rat brain tissue the ratios were 12, 6, and 3, respectively. In conclusion, it can be estimated that imaging of the human SERT in a high-density region requires radioligands with Kd values between 0.03 and a maximum of 0.3 nM (at 37 degrees C). The differential specific cerebellar binding raises the question of the suitability of cerebellum as a reference region for nonspecific binding.

  7. Serotonin reuptake inhibitor discontinuation syndrome: a hypothetical definition. Discontinuation Consensus panel.

    Science.gov (United States)

    Schatzberg, A F; Haddad, P; Kaplan, E M; Lejoyeux, M; Rosenbaum, J F; Young, A H; Zajecka, J

    1997-01-01

    Adverse events following discontinuation from serotonin reuptake inhibitors (SRIs) are being reported in the literature with increasing frequency; the frequency and severity of these symptoms appear to vary according to the half-life of the SRI, e.g., the incidence appears higher with the shorter half-life agents than with fluoxetine, which has an extended half-life. Yet, there have been no systematic studies of the phenomenon to date. Therefore, a group of experts convened in Phoenix, Arizona, to develop a clear description or definition of the phenomenon based on these reports. The SRI discontinuation syndrome, referred to as "withdrawal symptoms" in many anecdotal case reports, is distinctly different from the classic withdrawal syndrome associated with alcohol and barbiturates. Anti-depressants are not associated with dependence or drug-seeking behavior. SRI discontinuation symptoms tend to be short-lived and self-limiting, but can be troublesome. They may emerge when an SRI is abruptly discontinued, when doses are missed, and less frequently, during dosage reduction. In addition, the symptoms are not attributable to any other cause and can be reversed when the original agent is reinstituted, or one that is pharmacologically similar is substituted. SRI discontinuation symptoms, in most cases, may be minimized by slowly tapering antidepressant therapy, but there have been several case reports where symptoms occurred consistently even through repeated attempts to taper therapy. Physical symptoms include problems with balance, gastrointestinal and flu-like symptoms, and sensory and sleep disturbances. Psychological symptoms include anxiety and/or agitation, crying spells, and irritability. Further analyses of data bases and clinical studies are needed to define this proposed syndrome more clearly.

  8. Response of Vibrio cholerae to the Catecholamine Hormones Epinephrine and Norepinephrine.

    Science.gov (United States)

    Halang, Petra; Toulouse, Charlotte; Geißel, Bernadette; Michel, Bernd; Flauger, Birgit; Müller, Manuel; Voegele, Ralf T; Stefanski, Volker; Steuber, Julia

    2015-12-01

    In Escherichia coli or Salmonella enterica, the stress-associated mammalian hormones epinephrine (E) and norepinephrine (NE) trigger a signaling cascade by interacting with the QseC sensor protein. Here we show that Vibrio cholerae, the causative agent of cholera, exhibits a specific response to E and NE. These catecholates (0.1 mM) enhanced the growth and swimming motility of V. cholerae strain O395 on soft agar in a medium containing calf serum, which simulated the environment within the host. During growth, the hormones were converted to degradation products, including adrenochrome formed by autooxidation with O2 or superoxide. In E. coli, the QseC sensor kinase, which detects the autoinducer AI-3, also senses E or NE. The genome of V. cholerae O395 comprises an open reading frame coding for a putative protein with 29% identity to E. coli QseC. Quantitative reverse transcriptase PCR (qRT-PCR) experiments revealed increased transcript levels of the qseC-like gene and of pomB, a gene encoding a structural component of the flagellar motor complex, under the influence of E or NE. Phentolamine blocks the response of E. coli QseC to E or NE. A V. cholerae mutant devoid of the qseC-like gene retained the phentolamine-sensitive motility in the presence of E, whereas NE-stimulated motility was no longer inhibited by phentolamine. Our study demonstrates that V. cholerae senses the stress hormones E and NE. A sensor related to the histidine kinase QseC from E. coli is identified and is proposed to participate in the sensing of NE. Vibrio cholerae is a Gram-negative bacterium that may cause cholera, a severe illness with high mortality due to acute dehydration caused by diarrhea and vomiting. Pathogenic V. cholerae strains possess virulence factors like the cholera toxin (CTX) and the toxin-coregulated pilus (TCP) produced in response to signals provided by the host. In pathogenic enterobacteria, the stress-associated hormones epinephrine (E) and norepinephrine (NE) of the

  9. Use of selective-serotonin reuptake inhibitors and platelet aggregation inhibitors among individuals with co-occurring atherosclerotic cardiovascular disease and depression or anxiety

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    J Douglas Thornton

    2016-12-01

    Full Text Available Objective: Medications commonly used to treat heart disease, anxiety, and depression can interact resulting in an increased risk of bleeding, warranting a cautious approach in medical decision making. This retrospective, descriptive study examined the prevalence and the factors associated with the use of both selective-serotonin reuptake inhibitor and platelet aggregation inhibitor among individuals with co-occurring atherosclerotic cardiovascular disease and anxiety or depression. Methods: Respondents aged 22 years and older, alive throughout the study period, and diagnosed with co-occurring atherosclerotic cardiovascular disease and anxiety or depression (n = 1507 in years 2007 through 2013 of the Medical Expenditures Panel Survey were included. The use of treatment was grouped as follows: selective-serotonin reuptake inhibitor and platelet aggregation inhibitor, selective-serotonin reuptake inhibitor or platelet aggregation inhibitor, and neither selective-serotonin reuptake inhibitor nor platelet aggregation inhibitor. Results: Overall, 16.5% used both selective-serotonin reuptake inhibitor and platelet aggregation inhibitor, 61.2% used selective-serotonin reuptake inhibitor or platelet aggregation inhibitor, and 22.3% used neither selective-serotonin reuptake inhibitor nor platelet aggregation inhibitor. Respondents aged over 65 years (adjusted odds ratio = 1.93 (95% confidence interval = 1.08–3.45 and having a diagnosis of diabetes (adjusted odds ratio = 1.63 (95% confidence interval = 1.15–2.31 and hypertension (adjusted odds ratio = 1.84 (95% confidence interval = 1.04–3.27 were more likely to be prescribed the combination. Conclusion: The drug interaction was prevalent in patients who are already at higher risk of health disparities and worse outcomes thus requiring vigilant evaluation.

  10. B and C types natriuretic peptides modify norepinephrine uptake and release in the rat adrenal medulla.

    Science.gov (United States)

    Vatta, M S; Presas, M F; Bianciotti, L G; Rodriguez-Fermepin, M; Ambros, R; Fernandez, B E

    1997-01-01

    We have previously reported that atrial natriuretic factor (ANF) modulates adrenomedullar norepinephrine (NE) metabolism. On this basis, the aim of the present work was to study the effects of B and C types natriuretic peptides (BNP and CNP) on the uptake, intracellular distribution and release of 3H-NE. Experiments were carried out in rat adrenal medulla slices incubated "in vitro." Results showed that 100 nM of both, CNP and BNP, enhanced total and neuronal NE uptake. Both peptides (100 nM) caused a rapid increase in NE uptake during the first minute, which was sustained for 60 min. NE intracellular distribution was only modified by CNP (100 nM), which increased the granular fraction and decreased the cytosolic pool. On the other hand, spontaneous as well as evoked (KCl) NE release, was decreased by BNP and CNP (50 and 100 nM for spontaneous release and 1, 10, 50 and 100 nM for evoked output). The present results suggest that BNP and CNP may regulate catecholamine secretion and modulate adrenomedullary biological actions mediated by catecholamines, such as blood arterial pressure, smooth muscle tone, and metabolic activities.

  11. Impact of methylene blue in addition to norepinephrine on the intestinal microcirculation in experimental septic shock.

    Science.gov (United States)

    Nantais, Jordan; Dumbarton, Tristan C; Farah, Nizam; Maxan, Alexander; Zhou, Juan; Minor, Samuel; Lehmann, Christian

    2014-01-01

    Methylene blue (MB) has been used with some success as a treatment for the vasoplegia of vasopressor-refractory septic shock. The putative mechanism of action of MB is the inhibition of endothelial nitric oxide within the microvasculature and improved responsiveness to endogenous catecholamines (norepinephrine (NE)). However, to date, no study has demonstrated the microcirculatory effect of methylene blue in septic shock. The objective of this randomized, controlled, animal study was to show, in an experimentally-induced, septic shock model in rats, the effects of MB and NE on global hemodynamics and the microcirculation. Mean arterial pressure (MAP) was drastically reduced following bacterial endotoxin (lipopolysaccharide, LPS) administration in animals not receiving vasopressors. Only the combination of NE + MB restored MAP to control levels by the end of the three hour experiment. Intravital microscopy of the microcirculation was performed in the terminal ileum in order to examine functional capillary density in intestinal muscle layers and the mucosa, as well as leukocyte activation in venules (rolling, adhesion to the endothelium). Untreated LPS animals showed a significant increase in leukocyte adhesion and a decrease in capillary perfusion in the intestinal microcirculation. In groups receiving NE or NE+MB, we observed a significant decrease in leukocyte adhesion and improved functional capillary density, indicating that microvasculature function was improved. This study suggests that methylene blue may be able to improve hemodynamics while preserving microvascular function in septic shock.

  12. Recurrent hypoglycemia increases anxiety and amygdala norepinephrine release during subsequent hypoglycemia

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    Ewan eMcNay

    2015-11-01

    Full Text Available Recurrent hypoglycemia (RH is a common and debilitating side effect of therapy in patients with both type 1 and, increasingly, type 2 diabetes. Previous studies in rats have shown marked effects of RH on subsequent hippocampal behavioral, metabolic, and synaptic processes. In addition to impaired memory, patients experiencing RH report alterations in cognitive processes that include mood and anxiety, suggesting that RH may also affect amygdala function. We tested the impact of RH on amygdala function using an elevated plus-maze test of anxiety together with in vivo amygdala microdialysis for norepinephrine (NEp, a widely used marker of basolateral amygdala cognitive processes. In contrast to findings in the hippocampus and pre-frontal cortex, neither RH nor acute hypoglycemia alone significantly affected plus-maze performance or NEp release. However, animals tested when hypoglycemic who had previously experienced RH had elevated amygdala NEp during plus-maze testing, accompanied by increased anxiety (i.e. less time spent in the open arms of the plus-maze. The results show that RH has widespread effects on subsequent brain function, which vary by neural system.

  13. Electrochemistry of norepinephrine on carbon-coated nickel magnetic nanoparticles modified electrode and analytical applications.

    Science.gov (United States)

    Bian, Chunli; Zeng, Qingxiang; Xiong, Huayu; Zhang, Xiuhua; Wang, Shengfu

    2010-08-01

    A carbon-coated nickel magnetic nanoparticles modified glassy carbon electrode (C-Ni/GCE) was fabricated. The carbon-coated nickel magnetic nanoparticles were characterized with transmission electron microscopy (TEM). The electrochemical behaviors of norepinephrine (NE) were investigated on the modified electrode by cyclic voltammetry (CV) and differential pulse voltammetry (DPV). The carbon-coated nickel magnetic nanoparticles showed excellent electrocatalytic activity for the electrochemical redox of NE. NE exhibited two couples of well-defined redox peaks on C-Ni/GCE over the potential range from -0.4 to 0.8V in phosphate buffer solution (PBS) (pH=7.0). The redox mechanism for NE was proposed. DPV response of NE on the C-Ni/GCE showed that the catalytic oxidative peak current was linear with the square root concentration of NE in the range of 2.0 x 10(-7) to 8.0 x 10(-5)M, with a detection limit of 6.0 x 10(-8)M. The C-Ni/GCE showed good sensitivity, selectivity and stability for the determination of NE.

  14. Hypothalamic Norepinephrine Mediates Acupunctural Effects on Hypothalamic-Pituitary-Adrenal Axis During Ethanol Withdrawal.

    Science.gov (United States)

    Zhao, Zheng Lin; Kim, Sang Chan; Zhang, Jie; Liu, Hong Feng; Lee, Bong Hyo; Jang, Eun Young; Lee, Chul Won; Cho, Il Je; An, Won G; Yang, Chae Ha; Kim, Young Woo; Zhao, Rong Jie; Wu, Yi Yan

    2016-02-01

    A previous study demonstrated that acupuncture at ST36 (Zu-San-Li) attenuates ethanol withdrawal (EW)-induced hyperactivation of the hypothalamic-pituitary-adrenal axis in rats. The current study investigated the involvement of hypothalamic norepinephrine (NE) in that process. Rats were intraperitoneally treated with 3 g/kg/d of ethanol or saline for 28 days. After 24 hours of EW, acupuncture was applied to rats at bilateral ST36 points or at nonacupoints (tail) for 1 minute. A high-performance liquid chromatography analysis showed that EW significantly increased both the NE and the 3-methoxy-4-hydroxy-phenylglycol (MHPG) levels in the hypothalamic paraventricular nucleus (PVN). Western blot analysis also revealed that EW markedly elevated the phosphorylation rates of tyrosine hydroxylase (TH), but spared TH protein expression in the PVN. However, acupuncture at ST36, but not at nonacupoints, greatly inhibited the increase in the hypothalamic NE, MHPG, and phosphorylation rates of TH. Additionally, postacupuncture infusion of NE into the PVN significantly attenuated the inhibitory effects of acupuncture at ST36 on the oversecretion of plasma corticosterone during EW. These results suggest that acupuncture at ST36 inhibits EW-induced hyperactivation of the hypothalamic NEergic system to produce therapeutic effects on the hypothalamic-pituitary-adrenal axis.

  15. Mutations in the dopamine beta-hydroxylase gene are associated with human norepinephrine deficiency

    Science.gov (United States)

    Kim, Chun-Hyung; Zabetian, Cyrus P.; Cubells, Joseph F.; Cho, Sonhae; Biaggioni, Italo; Cohen, Bruce M.; Robertson, David; Kim, Kwang-Soo

    2002-01-01

    Norepinephrine (NE), a key neurotransmitter of the central and peripheral nervous systems, is synthesized by dopamine beta-hydroxylase (DBH) that catalyzes oxidation of dopamine (DA) to NE. NE deficiency is a congenital disorder of unknown etiology, in which affected patients suffer profound autonomic failure. Biochemical features of the syndrome include undetectable tissue and circulating levels of NE and epinephrine, elevated levels of DA, and undetectable levels of DBH. Here, we report identification of seven novel variants including four potentially pathogenic mutations in the human DBH gene (OMIM 223360) from analysis of two unrelated patients and their families. Both patients are compound heterozygotes for variants affecting expression of DBH protein. Each carries one copy of a T-->C transversion in the splice donor site of DBH intron 1, creating a premature stop codon. In patient 1, there is a missense mutation in DBH exon 2. Patient 2 carries missense mutations in exons 1 and 6 residing in cis. We propose that NE deficiency is an autosomal recessive disorder resulting from heterogeneous molecular lesions at DBH. Copyright 2002 Wiley-Liss, Inc.

  16. Norepinephrine versus dopamine and their interaction in modulating synaptic function in the prefrontal cortex.

    Science.gov (United States)

    Xing, Bo; Li, Yan-Chun; Gao, Wen-Jun

    2016-06-15

    Among the neuromodulators that regulate prefrontal cortical circuit function, the catecholamine transmitters norepinephrine (NE) and dopamine (DA) stand out as powerful players in working memory and attention. Perturbation of either NE or DA signaling is implicated in the pathogenesis of several neuropsychiatric disorders, including attention deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), schizophrenia, and drug addiction. Although the precise mechanisms employed by NE and DA to cooperatively control prefrontal functions are not fully understood, emerging research indicates that both transmitters regulate electrical and biochemical aspects of neuronal function by modulating convergent ionic and synaptic signaling in the prefrontal cortex (PFC). This review summarizes previous studies that investigated the effects of both NE and DA on excitatory and inhibitory transmissions in the prefrontal cortical circuitry. Specifically, we focus on the functional interaction between NE and DA in prefrontal cortical local circuitry, synaptic integration, signaling pathways, and receptor properties. Although it is clear that both NE and DA innervate the PFC extensively and modulate synaptic function by activating distinctly different receptor subtypes and signaling pathways, it remains unclear how these two systems coordinate their actions to optimize PFC function for appropriate behavior. Throughout this review, we provide perspectives and highlight several critical topics for future studies. This article is part of a Special Issue entitled SI: Noradrenergic System. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Aircraft noise exposure affects rat behavior, plasma norepinephrine levels, and cell morphology of the temporal lobe*

    Science.gov (United States)

    Di, Guo-qing; Zhou, Bing; Li, Zheng-guang; Lin, Qi-li

    2011-01-01

    In order to investigate the physiological effects of airport noise exposure on organisms, in this study, we exposed Sprague-Dawley rats in soundproof chambers to previously recorded aircraft-related noise for 65 d. For comparison, we also used unexposed control rats. Noise was arranged according to aircraft flight schedules and was adjusted to its weighted equivalent continuous perceived noise levels (L WECPN) of 75 and 80 dB for the two experimental groups. We examined rat behaviors through an open field test and measured the concentrations of plasma norepinephrine (NE) by high performance liquid chromatography-fluorimetric detection (HPLC-FLD). We also examined the morphologies of neurons and synapses in the temporal lobe by transmission electron microscopy (TEM). Our results showed that rats exposed to airport noise of 80 dB had significantly lower line crossing number (P<0.05) and significantly longer center area duration (P<0.05) than control animals. After 29 d of airport noise exposure, the concentration of plasma NE of exposed rats was significantly higher than that of the control group (P<0.05). We also determined that the neuron and synapsis of the temporal lobe of rats showed signs of damage after aircraft noise of 80 dB exposure for 65 d. In conclusion, exposing rats to long-term aircraft noise affects their behaviors, plasma NE levels, and cell morphology of the temporal lobe. PMID:22135145

  18. Leptin modulates norepinephrine-mediated melatonin synthesis in cultured rat pineal gland.

    Science.gov (United States)

    Peliciari-Garcia, Rodrigo Antonio; Andrade-Silva, Jéssica; Cipolla-Neto, José; Carvalho, Carla Roberta de Oliveira

    2013-01-01

    Pineal melatonin synthesis can be modulated by many peptides, including insulin. Because melatonin appears to alter leptin synthesis, in this work we aimed to investigate whether leptin would have a role on norepinephrine- (NE-)mediated melatonin synthesis in cultured rat pineal glands. According to our data, cultured rat pineal glands express leptin receptor isoform b (Ob-Rb). Pineal expression of Ob-Rb mRNA was also observed in vivo. Administration of leptin (1 nM) associated with NE ( 1 µM) reduced melatonin content as well as arylalkylamine-N-acetyl transferase (AANAT) activity and expression in cultured pineal glands. Leptin treatment per se induced the expression of STAT3 in cultured pineal glands, but STAT3 does not participate in the leptin modulation of NE-mediated pineal melatonin synthesis. In addition, the expression of inducible cAMP early repressor (ICER) was further induced by leptin challenge when associated with NE. In conclusion, leptin inhibition of pineal melatonin synthesis appears to be mediated by a reduction in AANAT activity and expression as well as by increased expression of Icer mRNA. Peptidergic signaling within the pineal gland appears to be one of the most important signals which modulates melatonin synthesis; leptin, as a member of this system, is not an exception.

  19. Leptin Modulates Norepinephrine-Mediated Melatonin Synthesis in Cultured Rat Pineal Gland

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    Rodrigo Antonio Peliciari-Garcia

    2013-01-01

    Full Text Available Pineal melatonin synthesis can be modulated by many peptides, including insulin. Because melatonin appears to alter leptin synthesis, in this work we aimed to investigate whether leptin would have a role on norepinephrine- (NE-mediated melatonin synthesis in cultured rat pineal glands. According to our data, cultured rat pineal glands express leptin receptor isoform b (Ob-Rb. Pineal expression of Ob-Rb mRNA was also observed in vivo. Administration of leptin (1 nM associated with NE (1 µM reduced melatonin content as well as arylalkylamine-N-acetyl transferase (AANAT activity and expression in cultured pineal glands. Leptin treatment per se induced the expression of STAT3 in cultured pineal glands, but STAT3 does not participate in the leptin modulation of NE-mediated pineal melatonin synthesis. In addition, the expression of inducible cAMP early repressor (ICER was further induced by leptin challenge when associated with NE. In conclusion, leptin inhibition of pineal melatonin synthesis appears to be mediated by a reduction in AANAT activity and expression as well as by increased expression of Icer mRNA. Peptidergic signaling within the pineal gland appears to be one of the most important signals which modulates melatonin synthesis; leptin, as a member of this system, is not an exception.

  20. Effect of Uptake-one inhibitors on the uptake of norepinephrine and metaiodobenzylguanidine

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    Tobes, M.C.; Jaques, S. Jr.; Wieland, D.M.; Sisson, J.C.

    1985-08-01

    The mechanisms underlying the uptake of the radiopharmaceutical metaiodobenzylguanidine (MIBG) and the catecholamine norepinephrine (NE) were studied using cultured bovine adrenomedullary cells as an in vitro model system. Sodium-dependent and sodium-independent uptake systems have been identified and characterized for both MIBG and NE. The sodium-dependent uptake of Ne and MIBG was inhibited by the selective Uptake-one inhibitors, desmethylimipramine (DMI) and cocaine, whereas the sodium-independent uptake for NE and MIBG was much less sensitive to inhibition by these agents. The sodium-dependent uptake system fulfills the criteria for the neuronal Uptake-one system, and the sodium-independent uptake system fulfills the criteria for a passive diffusion mechanism. Arterial concentrations proximal to the dog adrenal were very small suggesting that the sodium-dependent (Uptake-one) system is predominant in vivo. Consistent with the in vitro observations, the in vivo uptake of MIBG and NE into dog adrenal medullae was effectively blocked by pretreatment with DMI or cocaine. Therefore, iodine-131 MIBG scintigraphy of the adrenal appears to reflect uptake by way of the Uptake-one system.

  1. Aircraft noise exposure affects rat behavior, plasma norepinephrine levels, and cell morphology of the temporal lobe

    Institute of Scientific and Technical Information of China (English)

    Guo-qing DI; Bing ZHOU; Zheng-guang; LI, Qi-li LIN

    2011-01-01

    In order to investigate the physiological effects of airport noise exposure on organisms,in this study,we exposed Sprague-Dawley rats in soundproof chambers to previously recorded aircraft-related noise for 65 d.For comparison,we also used unexposed control rats.Noise was arranged according to aircraft flight schedules and was adjusted to its weighted equivalent continuous perceived noise levels (LwEcPN) of 75 and 80 dB for the two experimental groups.We examined rat behaviors through an open field test and measured the concentrations of plasma norepinephrine (NE) by high performance liquid chromatography-fluorimetric detection (HPLC-FLD).We also examined the morphologies of neurons and synapses in the temporal lobe by transmission electron microscopy (TEM).Our results showed that rats exposed to airport noise of 80 dB had significantly lower line crossing number (P<0.05) and significantly longer center area duration (P<0.05) than control animals.After 29 d of airport noise exposure,the concentration of plasma NE of exposed rats was significantly higher than that of the control group (P<0.05).We also determined that the neuron and synapsis of the temporal lobe of rats showed signs of damage after aircraft noise of 80 dB exposure for 65 d.In conclusion,exposing rats to long-term aircraft noise affects their behaviors,plasma NE levels,and cell morphology of the temporal lobe.

  2. Desvenlafaxine succinate identifies novel antagonist binding determinants in the human norepinephrine transporter.

    Science.gov (United States)

    Mason, John N; Deecher, Darlene C; Richmond, Rhonda L; Stack, Gary; Mahaney, Paige E; Trybulski, Eugene; Winneker, Richard C; Blakely, Randy D

    2007-11-01

    Desvenlafaxine succinate (DVS) is a recently introduced antagonist of the human norepinephrine and serotonin transporters (hNET and hSERT, respectively), currently in clinical development for use in the treatment of major depressive disorder and vasomotor symptoms associated with menopause. Initial evaluation of the pharmacological properties of DVS (J Pharmacol Exp Ther 318:657-665, 2006) revealed significantly reduced potency for the hNET expressed in membranes compared with whole cells when competing for [(3)H]nisoxetine (NIS) binding. Using hNET in transfected human embryonic kidney-293 cells, this difference in potency for DVS at sites labeled by [(3)H]NIS was found to distinguish DVS, the DVS analog rac-(1-[1-(3-chloro-phenyl)-2-(4-methylpiperazin-1-yl)-ethyl]cyclohexanol (WY-46824), methylphenidate, and the cocaine analog 3beta-(4-iodophenyl)tropane-2beta-carboxylic acid methyl ester (RTI-55) from other hNET antagonists, such as NIS, mazindol, tricyclic antidepressants, and cocaine. These differences seem not to arise from preparation-specific perturbations of ligand intrinsic affinity or antagonist-specific surface trafficking but rather from protein conformational alterations that perturb the relationships between distinct hNET binding sites. In an initial search for molecular features that differentially define antagonist binding determinants, we document that Val148 in hNET transmembrane domain 3 selectively disrupts NIS binding but not that of DVS.

  3. Cortical serotonin and norepinephrine denervation in parkinsonism: preferential loss of the beaded serotonin innervation.

    Science.gov (United States)

    Nayyar, Tultul; Bubser, Michael; Ferguson, Marcus C; Neely, M Diana; Shawn Goodwin, J; Montine, Thomas J; Deutch, Ariel Y; Ansah, Twum A

    2009-07-01

    Parkinson's Disease (PD) is marked by prominent motor symptoms that reflect striatal dopamine insufficiency. However, non-motor symptoms, including depression, are common in PD. It has been suggested that these changes reflect pathological involvement of non-dopaminergic systems. We examined regional changes in serotonin (5-HT) and norepinephrine (NE) systems in mice treated with two different 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment paradigms, at survival times of 3 or 16 weeks after the last MPTP injection. MPTP caused a decrease in striatal dopamine concentration, the magnitude of which depended on the treatment regimen and survival interval after MPTP treatment. There was significant involvement of other subcortical areas receiving a dopamine innervation, but no consistent changes in 5-HT or NE levels in subcortical sites. In contrast, we observed an enduring decrease in 5-HT and NE concentrations in both the somatosensory cortex and medial prefrontal cortex (PFC). Immunohistochemical studies also revealed a decrease in the density of PFC NE and 5-HT axons. The decrease in the cortical serotonergic innervation preferentially involved the thick beaded but not smooth fine 5-HT axons. Similar changes in the 5-HT innervation of post-mortem samples of the PFC from idiopathic PD cases were seen. Our findings point to a major loss of the 5-HT and NE innervations of the cortex in MPTP-induced parkinsonism, and suggest that loss of the beaded cortical 5-HT innervation is associated with a predisposition to the development of depression in PD.

  4. Molecular cloning and structural analysis of human norepinephrine transporter gene(NETHG)

    Institute of Scientific and Technical Information of China (English)

    GUOLIHE; LIHUAZHU; 等

    1995-01-01

    A cDNA molecule encoding a major part of the human Norepinephrine transporter(hNET) was synthesized by means of Polymerase Chain Reaction(PCR) technique and used as a probe for selecting the human genomic NET gene.A positive clone harbouring the whole gene was obtained from a human lymphocyte genomic library through utilizing the “genomic walking” technique.The clone,designated as phNET,harbours a DNA fragment of about 59 kd in length inserted into BamH I site in cosmid pWE15.The genomic clone contains 14 exons encoding all amino acid residues in the protein.A single exon encodes a distinct transmembrane domain,except for transmembrane domain 10 and 11,which are encoded by part of two exons respectively,and exon 12,which encodes part of domain 11 and all of domain 12.These results imply that there is a close relationship between exon splicing of a gene and structureal domains of the protein,as is the case for the human γ-aminobutyric acid transporter(hGAT) and a number of other membrane proteins.

  5. Mechanistic insight into the norepinephrine-induced fibrosis in systemic sclerosis

    Science.gov (United States)

    Uehara, Akihito; Motegi, Sei-ichiro; Yamada, Kazuya; Uchiyama, Akihiko; Perera, Buddhini; Toki, Sayaka; Ogino, Sachiko; Yokoyama, Yoko; Takeuchi, Yuko; Ishikawa, Osamu

    2016-01-01

    Raynaud’s phenomenon is frequently observed in systemic sclerosis (SSc) patients, and cold- or stress-induced norepinephrine (NE) has been speculated to be associated with vasoconstriction. Objective was to elucidate the role of NE in fibrosis in SSc. IL-6 is a potent stimulator of collagen production in fibroblasts. NE enhanced IL-6 production and proliferation more significantly in SSc fibroblasts than in normal fibroblasts. Furthermore, the production of IL-6 and phosphorylation of p38 in SSc fibroblasts was enhanced by adrenergic receptor (AR)β agonist, isoproterenol, but not ARα agonist, oxymetazoline. ARβ blocker, propranolol, inhibited NE-induced IL-6 production and phosphorylation of p38 in SSc fibroblasts. NE-induced IL-6 was significantly inhibited by p38 inhibitor, SB203580, suggesting that NE-induced phosphorylation of p38 via ARβ enhances IL-6 production in SSc fibroblasts. NE-induced phosphorylation of ERK1/2 via ARα inhibited IL-6 production in SSc fibroblasts. Combined treatment with NE and endothelin-1 resulted in an additive increase in IL-6 production in SSc fibroblasts. NE-induced IL-6/IL-6 receptor trans-signaling increased the production of collagen type I in SSc fibroblasts, and both propranolol and SB203580 inhibited NE-induced collagen production. These results suggest that cold exposure and/or emotional stress-induced NE might contribute to the skin fibrosis via potentiation of IL-6 production from fibroblasts in SSc. PMID:27650973

  6. Cerebrospinal fluid norepinephrine and cognition in subjects across the adult age span.

    Science.gov (United States)

    Wang, Lucy Y; Murphy, Richard R; Hanscom, Brett; Li, Ge; Millard, Steven P; Petrie, Eric C; Galasko, Douglas R; Sikkema, Carl; Raskind, Murray A; Wilkinson, Charles W; Peskind, Elaine R

    2013-10-01

    Adequate central nervous system noradrenergic activity enhances cognition, but excessive noradrenergic activity may have adverse effects on cognition. Previous studies have also demonstrated that noradrenergic activity is higher in older than younger adults. We aimed to determine relationships between cerebrospinal fluid (CSF) norepinephrine (NE) concentration and cognitive performance by using data from a CSF bank that includes samples from 258 cognitively normal participants aged 21-100 years. After adjusting for age, gender, education, and ethnicity, higher CSF NE levels (units of 100 pg/mL) are associated with poorer performance on tests of attention, processing speed, and executive function (Trail Making A: regression coefficient 1.5, standard error [SE] 0.77, p = 0.046; Trail Making B: regression coefficient 5.0, SE 2.2, p = 0.024; Stroop Word-Color Interference task: regression coefficient 6.1, SE 2.0, p = 0.003). Findings are consistent with the earlier literature relating excess noradrenergic activity with cognitive impairment.

  7. Individual differences in the locus coeruleus-norepinephrine system: Relevance to stress-induced cardiovascular vulnerability.

    Science.gov (United States)

    Wood, Christopher S; Valentino, Rita J; Wood, Susan K

    2017-04-01

    Repeated exposure to psychosocial stress is a robust sympathomimetic stressor and as such has adverse effects on cardiovascular health. While the neurocircuitry involved remains unclear, the physiological and anatomical characteristics of the locus coeruleus (LC)-norepinephrine (NE) system suggest that it is poised to contribute to stress-induced cardiovascular vulnerability. A major theme throughout is to review studies that shed light on the role that the LC may play in individual differences in vulnerability to social stress-induced cardiovascular dysfunction. Recent findings are discussed that support a unique plasticity in afferent regulation of the LC, resulting in either excitatory or inhibitory input to the LC during establishment of different stress coping strategies. This contrasting regulation of the LC by either afferent regulation, or distinct differences in stress-induced neuroinflammation would translate to differences in cardiovascular regulation and may serve as the basis for individual differences in the cardiopathological consequences of social stress. The goal of this review is to highlight recent developments in the interplay between the LC-NE and cardiovascular systems during repeated stress in an effort to advance therapeutic treatments for the development of stress-induced cardiovascular vulnerability.

  8. Increase in norepinephrine-induced formation of phosphatidic acid in rat vas deferens after denervation.

    Science.gov (United States)

    Takenawa, T; Masaki, T; Goto, K

    1983-01-01

    Surgical denervation of rat vas deferens causes supersensitivity in that the tissue sensitivity and the maximum response to a variety of agonists increase. To understand the molecular mechanism of supersensitivity in smooth muscle, norepinephrine(NE)-induced alteration in phospholipid metabolism was studied using control and denervated vasa deferentia. When the tissue was stimulated by NE, only [32P]Pi incorporation into phosphatidic acid(PA) was increased in proportion to the increase in NE concentration without any significant effect on that into other phospholipids. This PA labeling was significantly accelerated by denervation. In the denervated tissue, PA labeling was stimulated by lower concentrations of NE and the maximum response to NE was increased compared to the control. The breakdown of phosphatidylinositol 4-monophosphate(DPI) and phosphatidylinositol 4,5-diphosphate (TPI) was also accelerated by NE. But the influence of denervation on this NE-induced DPI and TPI was not marked. Therefore, it is likely that denervation clearly enhanced NE-induced PA labeling without an appreciable effect on that of the other phospholipids. Furthermore, the absolute amount of PA was also increased by NE, and this increase was exaggerated by denervation. Considering that PA can behave as a Ca2+ ionophore in the plasma membrane, these results suggest that the stimulated accumulation of PA plays an important role in receptor-linked supersensitivity in smooth muscle.

  9. High-performance liquid chromatographic assay of free norepinephrine, epinephrine, dopamine, vanillylmandelic acid and homovanillic acid.

    Science.gov (United States)

    Gerlo, E; Malfait, R

    1985-09-13

    A procedure is described for the concurrent assay of free norepinephrine, epinephrine, dopamine, vanillylmandelic acid and homovanillic acid in physiological fluids using high-performance liquid chromatography with electrochemical detection. The column packing is an octadecyl-bonded silica. A single mobile phase containing 1-octanesulphonate is used for the assay of catecholamines and for the assay of the acidic metabolites. An efficient sample preparation scheme is presented for the isolation of the catecholamines and their acidic metabolites from the same sample aliquot. Catecholamines are extracted by ion exchange on small columns and adsorption on alumina, using dihydroxybenzylamine as an internal standard. Vanillylmandelic acid and homovanillic acid are recovered from the combined loading and washing effluents of the ion-exchange column by a solvent extraction procedure. Recovery of catecholamines averages 67%. The limit of detection for individual catecholamines is ca. 30 pg. Recoveries of vanillylmandelic acid and homovanillic acid average 77% and 87%, respectively. The use of the same mobile phase for the concurrent assay of catecholamines and their acidic metabolites considerably increases the throughput of samples in the chromatographic system by eliminating the time-consuming column-equilibration periods.

  10. Characterisation of PDO olive oil Chianti Classico by non-selective (UV-visible, NIR and MIR spectroscopy) and selective (fatty acid composition) analytical techniques

    Energy Technology Data Exchange (ETDEWEB)

    Casale, M., E-mail: monica@dictfa.unige.it [Universita degli Studi di Genova, Department of Chemistry and Food and Pharmaceutical Technologies, Via Brigata Salerno 13, I-16147, Genoa (Italy); Oliveri, P.; Casolino, C. [Universita degli Studi di Genova, Department of Chemistry and Food and Pharmaceutical Technologies, Via Brigata Salerno 13, I-16147, Genoa (Italy); Sinelli, N. [Universita degli Studi di Milano, Department of Food Science and Technology, Via Celoria, 2 - I-20133 Milan (Italy); Zunin, P.; Armanino, C.; Forina, M.; Lanteri, S. [Universita degli Studi di Genova, Department of Chemistry and Food and Pharmaceutical Technologies, Via Brigata Salerno 13, I-16147, Genoa (Italy)

    2012-01-27

    Highlights: Black-Right-Pointing-Pointer Characterisation of the Italian PDO extra virgin olive oil Chianti Classico. Black-Right-Pointing-Pointer Comparison between non-selective (UV-vis, NIR and MIR spectroscopy) and selective (fatty acid composition) analytical techniques. Black-Right-Pointing-Pointer Synergy among spectroscopic techniques, by the fusion of the respective spectra. Black-Right-Pointing-Pointer Prediction of the content of oleic and linoleic acids in the olive oils. - Abstract: An authentication study of the Italian PDO (protected designation of origin) extra virgin olive oil Chianti Classico was performed; UV-visible (UV-vis), Near-Infrared (NIR) and Mid-Infrared (MIR) spectroscopies were applied to a set of samples representative of the whole Chianti Classico production area. The non-selective signals (fingerprints) provided by the three spectroscopic techniques were utilised both individually and jointly, after fusion of the respective profile vectors, in order to build a model for the Chianti Classico PDO olive oil. Moreover, these results were compared with those obtained by the gas chromatographic determination of the fatty acids composition. In order to characterise the olive oils produced in the Chianti Classico PDO area, UNEQ (unequal class models) and SIMCA (soft independent modelling of class analogy) were employed both on the MIR, NIR and UV-vis spectra, individually and jointly, and on the fatty acid composition. Finally, PLS (partial least square) regression was applied on the UV-vis, NIR and MIR spectra, in order to predict the content of oleic and linoleic acids in the extra virgin olive oils. UNEQ, SIMCA and PLS were performed after selection of the relevant predictors, in order to increase the efficiency of both classification and regression models. The non-selective information obtained from UV-vis, NIR and MIR spectroscopy allowed to build reliable models for checking the authenticity of the Italian PDO extra virgin olive oil

  11. [Cost-effectiveness analysis of celecoxib versus non-selective non-steroidal anti-inflammatory drug therapy for the treatment of osteoarthritis in Spain: A current perspective].

    Science.gov (United States)

    De Lossada, A; Oteo-Álvaro, Á; Giménez, S; Oyagüez, I; Rejas, J

    2016-01-01

    To assess the cost-effectiveness of celecoxib and non-selective non-steroidal anti-inflammatory drugs for the treatment of osteoarthritis in clinical practice in Spain. A decision-tree model using distribution, doses, treatment duration and incidence of GI and CV events observed in the pragmatic PROBE-designed «GI-Reasons» trial was used for cost-effectiveness. Effectiveness was expressed in terms of event averted and quality-adjusted life-years (QALY) gained. QALY were calculated based on utility decrement in case of any adverse events reported in GI-Reasons trial. The National Health System perspective in Spain was applied; cost calculations included current prices of drugs plus cost of adverse events occurred. The analysis was expressed as an incremental cost-effectiveness ratio per QALY gained and per event averted. One-way and probabilistic analyses were performed. Compared with non-selective non-steroidal anti-inflammatory drugs, at current prices, celecoxib treatment had higher overall treatment costs €201 and €157, respectively. However, celecoxib was associated with a slight increase in QALY gain and significantly lower incidence of gastrointestinal events (pcost-effectiveness ratio of €13,286 per QALY gained and €4,471 per event averted. Sensitivity analyses were robust, and confirmed the results of the base case. Celecoxib at current price may be considered as a cost-effective alternative vs. non-selective non-steroidal anti-inflammatory drugs in the treatment of osteoarthritis in daily practice in the Spanish NHS. Copyright © 2015 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España, S.L.U. All rights reserved.

  12. Role of nonselective cation channels as Ca2+ entry pathway in endothelin-1-induced contraction and their suppression by nitric oxide.

    Science.gov (United States)

    Zhang, X F; Komuro, T; Miwa, S; Minowa, T; Iwamuro, Y; Okamoto, Y; Ninomiya, H; Sawamura, T; Masaki, T

    1998-07-10

    The present study was carried out to clarify the role of nonselective cation channels as a Ca2+ entry pathway in the contraction and the increase in [Ca2+]i induced by endothelin- in endothelium-denuded rat thoracic aorta rings, and their suppression by nitric oxide (NO). In Ca2+-free medium, the endothelin-1-induced contraction was suppressed to about 20% of control values, although the increase in [Ca2+]i became negligible. The contraction and the increase in [Ca2+]i monitored by fura 2 fluorescence were unaffected by a blocker of L-type voltage-operated Ca2+ channels nifedipine. A blocker of nonselective cation channels 1-[beta-[3-(4-methoxyphenyl)propoxyl]-4-methoxyphenethyl]-1H-imida zole . HCl(SK&F 96365) suppressed the endothelin-1-induced contraction and increase in [Ca2+]i to the level similar to that after removal of extracellular Ca2+. SK&F 96365 had no further effect on the endothelin-1-induced contraction in the absence of extracellular Ca2+. The endothelin-1-induced contraction and increase in [Ca2+]i were abolished by a donor of NO sodium nitroprusside. The effects of another NO donor 3-morpholinosydnonimine (SIN-1) were also tested and yielded essentially similar results to those for sodium nitroprusside on the endothelin-1-induced contraction. Furthermore, the inhibitory effects of sodium nitroprusside could be blocked with a guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ) at 30 microM. These findings suggest that Ca2+ entry through nonselective cation channels but not voltage-operated Ca2+ channels plays a critical role in the endothelin-1-induced increase in [Ca2+]i and the resulting contraction and that inhibition by NO of the endothelin-1-induced contraction is mainly the result of blockade of Ca2+ entry through these channels.

  13. Tramadol: Effects on sexual behavior in male rats are mainly caused by its 5-HT reuptake blocking effects.

    Science.gov (United States)

    Olivier, Jocelien D A; Esquivel Franco, Diana C; Oosting, Ronald; Waldinger, Marcel; Sarnyai, Zoltan; Olivier, Berend

    2017-04-01

    Tramadol is a well-known and effective analgesic. Recently it was shown that tramadol is also effective in human premature ejaculation. The inhibitory effect of tramadol on the ejaculation latency is probably due to its mechanism of action as a μ-opioid receptor agonist and noradrenaline/serotonin (5-HT) reuptake inhibitor. In order to test this speculation, we tested several doses of tramadol in a rat model of male sexual behavior and investigated two types of drugs interfering with the μ-opioid and the 5-HT system. First the μ-opioid receptor agonist properties of tramadol were tested with naloxone, a μ-opioid receptor antagonist. Second, the effects of WAY100,635, a 5-HT1A receptor antagonist, were tested on the behavioral effects of tramadol. Finally the effects of paroxetine, a selective serotonin reuptake inhibitor, combined with naloxone or WAY100,635 treatment, were compared to the effects of tramadol combined with these drugs. Results showed that naloxone, at a sexually inactive dose, could only partially antagonize the inhibitory effect of tramadol. Moreover, low and behaviorally inactive doses of WAY100,635, strongly decreased sexual behavior when combined with a behaviorally inactive dose of tramadol. Finally we showed that the effects of paroxetine on sexual behavior resembled the effects of tramadol, indicating that tramadol's inhibitory effects on sexual behavior are primarily and mainly caused by its SSRI properties and that its μ-opioid receptor agonistic activity only contributes marginally. These findings support the hypothesis that tramadol exerts inhibition of premature ejaculations in men by its 5-HT reuptake inhibiting properties. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. Further evidence for differences between non-selective and BZ-1 (omega 1) selective, benzodiazepine receptor ligands in murine models of "state" and "trait" anxiety.

    Science.gov (United States)

    Griebel, G; Sanger, D J; Perrault, G

    1996-01-01

    The behavioural effects of several BZ (omega) receptor ligands were compared in mice using the light/dark choice task, an animal model of "state" anxiety, and the free-exploration test, which has been proposed as an experimental model of "trait" anxiety. The drugs used included non-selective full (alprazolam, clorazepate, chlordiazepoxide and diazepam), partial agonists (bretazenil, imidazenil and Ro 19-8022) and BZ-1 (omega 1) selective receptor ligands (abecarnil, CL 218,872 and zolpidem). In the light/dark choice task, non-selective full agonists elicited clear anxiolytic-like effects increasing time spent in the lit box and simultaneously reducing attempts at entry into the illuminated cage followed by withdrawal responses, a measure of risk assessment. With the exception of abecarnil, both non-selective partial agonists and BZ-1 (omega 1) selective receptor ligands displayed reduced efficacy compared to the full agonists as they decreased risk assessment responses without altering time in the lit box. In addition, the weak anxiolytic-like actions displayed by selective BZ-1 (omega 1) agents were evident only at doses which reduced locomotor activity, indicating that this effect may be non-specific. In the free-exploration test, non-selective BZ (omega) receptor agonists markedly increased the percentage of time spent in the novel compartment and reduced the number of attempts to enter whereas selective BZ-1 (omega 1) receptor ligands displayed a weaker neophobia-reducing effect as they reduced risk assessment responses only. As was the case in the light/dark choice task, this latter effect was observed at locomotor depressant doses. These findings indicate that while both full and partial BZ (omega) receptor agonists are equally effective against "trait" anxiety, full agonists may be superior in reducing "state" anxiety. In addition, the lack of specific effects of selective BZ-1 (omega 1) receptor ligands in reducing both types of anxiety suggests that the BZ

  15. Effects of selective serotonin reuptake inhibitors on glaucoma: A nationwide population-based study

    Science.gov (United States)

    Chen, Vincent Chin-Hung; McIntyre, Roger S.; Lee, Yena; Lin, Tsang-Yaw; Weng, Jun-Cheng; Chen, Pau-Chung; Hsu, Chung-Yao

    2017-01-01

    Background Selective serotonin reuptake inhibitors (SSRIs) are one of the most commonly prescribed classes of antidepressants. Glaucoma is the second leading cause of blindness globally and iatrogenic glaucoma has been implicated across disparate medication classes. Available studies that have sought to determine the association between SSRI exposure and glaucoma have provided mixed results. The aim of the study herein was to investigate whether an association exists between SSRI exposure and glaucoma incidence. Methods Glaucoma cases were identified from Taiwan’s National Health Insurance Research Database with a new primary diagnosis of glaucoma between 1997 and 2009. The date wherein the cases were diagnosed with glaucoma was operationalized as the index date. The control group was comprised of individuals within the database who were not diagnosed with glaucoma. 15,865 glaucoma cases were compared to 77,014 sex-, age-, residence- and insurance premium-matched controls on measures of prescribed duration and dosage of SSRIs up to 365 days before index date to proxy SSRIs exposure. Results Individuals receiving SSRIs were at greater risk of glaucoma incidence (OR = 1.39; 95% CI = 1.29–1.50); the foregoing increased likelihood was reduced after adjusting for confounding variables (aOR = 1.09; 95% CI = 1.00,1.18). SSRI treatment of longer duration (i.e. >365 days) and higher doses (≥1 defined daily dose) were associated with greater risk of glaucoma incidence (aOR = 1.36; 95% CI = 1.08–1.71). Subgroup analysis showed that the effect of SSRIs on glaucoma was limited to individuals younger than 65 years of age (aOR = 1.37; 95% CI = 1.25–1.50), without diabetes (aOR = 1.39; 95% CI = 1.27–1.52), without hypertension (aOR = 1.46; 95% CI = 1.31–1.63) or hypercholesterolemia (aOR = 1.35; 95% CI = 1.23–1.48). Conclusion Treatment with SSRIs was associated with greater risk of having a diagnosis of glaucoma, particularly in individuals with longer duration

  16. An analysis of psychotropic drug sales. Increasing sales of selective serotonin reuptake inhibitors anre closely related to number of products

    DEFF Research Database (Denmark)

    Nielsen, Margrethe; Gøtzsche, Peter C.

    2011-01-01

    by changes in sales of the benzodiazepines and SSRIs. We found a decline in the sales of benzodiazepines after a peak in 1986, likely due to the recognition that they cause dependence. From a low level in 1992, we found that the sales of SSRIs increased almost linearly by a factor of 18, up to 44 DDD per......BACKGROUND: Prescribing of selective serotonin reuptake inhibitors (SSRIs) has increased dramatically. OBJECTIVE: To compare the sales of benzodiazepines and SSRIs within the primary care sector in Denmark and relate changes in usage to number of indications and products on the market. METHODS: We...

  17. Voltammetric determination of norepinephrine in the presence of acetaminophen using a novel ionic liquid/multiwall carbon nanotubes paste electrode

    Energy Technology Data Exchange (ETDEWEB)

    Salmanpour, Sadegh [Department of Chemistry, Sari Branch, Islamic Azad University, Sari (Iran, Islamic Republic of); Tavana, Toktam [Department of Chemistry, Qaemshahr Branch, Islamic Azad University, Qaemshahr (Iran, Islamic Republic of); Pahlavan, Ali [Department of Physics, Science and Research Branch, Islamic Azad University, Mazandaran (Iran, Islamic Republic of); Khalilzadeh, Mohammad A., E-mail: khalilzadeh73@yahoo.com [Department of Chemistry, Science and Research Branch, Islamic Azad University, Mazandaran (Iran, Islamic Republic of); Ensafi, Ali A. [Department of Chemistry, Isfahan University of Technology, Isfahan (Iran, Islamic Republic of); Karimi-Maleh, Hassan, E-mail: h.karimi.maleh@gmail.com [Department of Chemistry, Science and Research Branch, Islamic Azad University, Mazandaran (Iran, Islamic Republic of); Beitollahi, Hadi [Environment Department, Research Institute of Environmental Sciences, International Center for Science, High Technology and Environmental Sciences, Kerman (Iran, Islamic Republic of); Kowsari, Elaheh [Department of Chemistry, Amirkabir University of Technology, No. 424, Hafez Avenue, Tehran (Iran, Islamic Republic of); Zareyee, Daryoush [Department of Chemistry, Qaemshahr Branch, Islamic Azad University, Qaemshahr (Iran, Islamic Republic of)

    2012-10-01

    A novel multiwall carbon nanotubes (MWCNTs) modified carbon ionic liquid electrode (CILE) was fabricated and used to investigate the electrochemical behavior of norepinephrine (NP). MWCNTs/CILE was prepared by mixing hydrophilic ionic liquid, 1-methyl-3-butylimidazolium bromide (MBIDZBr), with graphite powder, MWCNTs, and liquid paraffin. The fabricated MWCNTs/CILE showed great electrocatalytic ability to the oxidation of NE. The electron transfer coefficient, diffusion coefficient, and charge transfer resistant (R{sub ct}) of NE at the modified electrode were calculated. Differential pulse voltammetry of NE at the modified electrode exhibited two linear dynamic ranges with slopes of 0.0841 and 0.0231 {mu}A/{mu}M in the concentration ranges of 0.3 to 30.0 {mu}M and 30.0 to 450.0 {mu}M, respectively. The detection limit (3{sigma}) of 0.09 {mu}M NP was achieved. This modified electrode exhibited a good ability for well separated oxidation peaks of NE and acetaminophen (AC) in a buffer solution, pH 7.0. The proposed sensor was successfully applied for the determination of NE in human urine, pharmaceutical, and serum samples. Highlights: Black-Right-Pointing-Pointer Electrochemical behavior of norepinephrine study using carbon ionic liquid electrode Black-Right-Pointing-Pointer This sensor resolved the overlap response of norepinephrine and acetaminophen. Black-Right-Pointing-Pointer This sensor is also used for the determination of above compounds in real samples.

  18. Age dependence of the levels of plasma norepinephrine, aldosterone, renin activity and urinary vanillylmandelic acid in normal and essential hypertensives.

    Science.gov (United States)

    Abd-Allah, Nadia M; Hassan, Fayeza H; Esmat, Amr Y; Hammad, Somaya A

    2004-01-01

    In the present study the upper reference limits (URLs) for resting plasma norepinephrine, epinephrine, serum aldosterone, plasma renin activity, aldosterone/renin activity ratio, as well as urinary vanillylmandelic acid in healthy Egyptian normotensive subjects over a range of ages (5-60 yr) were established. There was a significant age effect on plasma norepinephrine, UVMA, serum aldosterone and PRA, whereas a single URL for plasma epinephrine level is satisfactory. In uncomplicated untreated essential hypertensive subjects (5-60 yr), the average prevalence of elevation in the plasma norepinephrine, epinephrine and urinary vanillylmandelic acid above their corresponding URLs was 85.10, 62.15 and 83.20%, respectively. This suggests that elevation in plasma catecholamine concentrations is more likely a common consequence than playing a possible role in the pathogenesis of hypertension, supported by insignificant correlation coefficients between the plasma catecholamine levels and resting systolic and diastolic blood pressure values (SBP & DBP) in all hypertensive age groups. Primary hyperaldosteronism was not detected among the normokalemic essential hypertensives at any age using aldosterone/plasma renin activity ratio as a primary screening method. In the present study, 7 statistically significant positive coefficient correlations are reported for SBP or DBP values with UVMA levels in hypertensive children and adolescents, serum aldosterone in old hypertensives, and PRA in adult hypertensives.

  19. Arterial pressure allows monitoring the changes in cardiac output induced by volume expansion but not by norepinephrine.

    Science.gov (United States)

    Monnet, Xavier; Letierce, Alexia; Hamzaoui, Olfa; Chemla, Denis; Anguel, Nadia; Osman, David; Richard, Christian; Teboul, Jean-Louis

    2011-06-01

    To evaluate to which extent the systemic arterial pulse pressure could be used as a surrogate of cardiac output for assessing the effects of a fluid challenge and of norepinephrine. Observational study. Medical intensive care unit. Patients with an acute circulatory failure who received a fluid challenge (228 patients, group 1) or in whom norepinephrine was introduced or increased (145 patients, group 2). We measured the systolic, diastolic, and mean arterial pressure, pulse pressure, and the transpulmonary thermodilution cardiac output before and after the therapeutic interventions. In group 1, the fluid challenge significantly increased cardiac output by 24% ± 25%. It significantly increased cardiac output by ≥15% (+35% ± 27%) in 142 patients ("responders"). The fluid-induced changes in cardiac output were correlated with the changes in pulse pressure (r = .56, p arterial pressure (r = .55, p arterial pressure (r = .37, p arterial pressure (r = .52, p pressure were significantly related to changes in stroke volume (multiple r = .52) and to age (r = .12). A fluid-induced increase in pulse pressure of ≥17% allowed detecting a fluid-induced increase in cardiac output of ≥15% with a sensitivity of 65[56-72]% and a specificity of 85[76-92]%. The area under the receiver operating characteristic curves for the fluid-induced changes in mean arterial pressure and in diastolic arterial pressure was significantly lower than for pulse pressure. In group 2, the introduction/increase of norepinephrine significantly increased cardiac output by 14% ± 18%. The changes in cardiac output induced by the introduction/increase in the dose of norepinephrine were correlated with the changes in pulse pressure and systolic arterial pressure (r = .21 and .29, respectively, p = .001) but to a significantly lesser extent than in group 1. Pulse pressure and systolic arterial pressure could be used for detecting the fluid-induced changes in cardiac output, in spite of a significant

  20. Effects of electro-acupuncture on brain tissue norepinephrine contents in a morphine withdrawal anxiety mouse model

    Institute of Scientific and Technical Information of China (English)

    Qizhi Zhou; Yuxing Liu; Xuguang Liu; Jiaolu Wei; Yong Tang; Junmei Wu; Yi Pu

    2008-01-01

    BACKGROUND: Following morphine withdrawal, anxiety is associated with abnormal norepinephrine content change. However, increasing blood lactic acid content can induce anxiety or panic in patients with anxiety disorder or endogenous opioid peptide functional disorder. OBJECTIVE: This study was designed to observe the effects of electro-acupuncture, at the "Sanyinjiao" point (SP 6), on brain tissue norepinephrine and blood lactic acid content in anxiety-model mice after morphine withdrawal.DESIGN: A randomized controlled animal experiment. SETTING: This study was performed in the Laboratory of Acupuncture, Electro-acupuncture & Tuina College, Chengdu University of Traditional Chinese Medicine, from June to September 2001.MATERIALS: A total of 50 healthy Kunming male mice were provided by the Laboratory Animal Center of Chengdu University of Traditional Chinese Medicine. The protocol was performed in accordance with ethical guidelines stated in the Guide for the use and care of laboratory animals, approved by the Committee on the Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources Commission on Life Sciences, National Research Council, China (1985). Experimental reagents and equipment used were as follows: morphine hydrochloride (Lot No. 930503, Shenyang No.1 Pharmaceutical Factory, China), norepinephrine (Sigma Chemical Company, USA), fluorospectrophotometer (RF-510, Shimadzu Corporation, Japan), Han electro-acupuncture apparatus (WQ 1002, No. zun (91)-227270-588, Beijing Anlong Photoelectricity-Technique Company, China), and T-maze (self-made). METHODS: A total of 50 mice were randomly divided into 5 groups, with 10 mice in each group: blank control, T-maze, model, model + electro-acupuncture, and electro-acupuncture groups. Establishment of anxiety model after morphine withdrawal: the mouse hot plate assay was used to detect the activity of morphine. The median effective dose of morphine, 2.95 mg/kg, was defined as the base. Mice were

  1. Characterisation of PDO olive oil Chianti Classico by non-selective (UV-visible, NIR and MIR spectroscopy) and selective (fatty acid composition) analytical techniques.

    Science.gov (United States)

    Casale, M; Oliveri, P; Casolino, C; Sinelli, N; Zunin, P; Armanino, C; Forina, M; Lanteri, S

    2012-01-27

    An authentication study of the Italian PDO (protected designation of origin) extra virgin olive oil Chianti Classico was performed; UV-visible (UV-vis), Near-Infrared (NIR) and Mid-Infrared (MIR) spectroscopies were applied to a set of samples representative of the whole Chianti Classico production area. The non-selective signals (fingerprints) provided by the three spectroscopic techniques were utilised both individually and jointly, after fusion of the respective profile vectors, in order to build a model for the Chianti Classico PDO olive oil. Moreover, these results were compared with those obtained by the gas chromatographic determination of the fatty acids composition. In order to characterise the olive oils produced in the Chianti Classico PDO area, UNEQ (unequal class models) and SIMCA (soft independent modelling of class analogy) were employed both on the MIR, NIR and UV-vis spectra, individually and jointly, and on the fatty acid composition. Finally, PLS (partial least square) regression was applied on the UV-vis, NIR and MIR spectra, in order to predict the content of oleic and linoleic acids in the extra virgin olive oils. UNEQ, SIMCA and PLS were performed after selection of the relevant predictors, in order to increase the efficiency of both classification and regression models. The non-selective information obtained from UV-vis, NIR and MIR spectroscopy allowed to build reliable models for checking the authenticity of the Italian PDO extra virgin olive oil Chianti Classico. Copyright © 2011 Elsevier B.V. All rights reserved.

  2. Selective serotonin re-uptake inhibitors potentiate gene blunting induced by repeated methylphenidate treatment: Zif268 versus Homer1a.

    Science.gov (United States)

    Van Waes, Vincent; Vandrevala, Malcolm; Beverley, Joel; Steiner, Heinz

    2014-11-01

    There is a growing use of psychostimulants, such as methylphenidate (Ritalin; dopamine re-uptake inhibitor), for medical treatments and as cognitive enhancers in the healthy. Methylphenidate is known to produce some addiction-related gene regulation. Recent findings in animal models show that selective serotonin re-uptake inhibitors (SSRIs), including fluoxetine, can potentiate acute induction of gene expression by methylphenidate, thus indicating an acute facilitatory role for serotonin in dopamine-induced gene regulation. We investigated whether repeated exposure to fluoxetine, in conjunction with methylphenidate, in adolescent rats facilitated a gene regulation effect well established for repeated exposure to illicit psychostimulants such as cocaine-blunting (repression) of gene inducibility. We measured, by in situ hybridization histochemistry, the effects of a 5-day repeated treatment with methylphenidate (5 mg/kg), fluoxetine (5 mg/kg) or a combination on the inducibility (by cocaine) of neuroplasticity-related genes (Zif268, Homer1a) in the striatum. Repeated methylphenidate treatment alone produced minimal gene blunting, while fluoxetine alone had no effect. In contrast, fluoxetine added to methylphenidate robustly potentiated methylphenidate-induced blunting for both genes. This potentiation was widespread throughout the striatum, but was most robust in the lateral, sensorimotor striatum, thus mimicking cocaine effects. For illicit psychostimulants, blunting of gene expression is considered part of the molecular basis of addiction. Our results thus suggest that SSRIs, such as fluoxetine, may increase the addiction liability of methylphenidate.

  3. Lamotrigine Augmentation of Serotonin Reuptake Inhibitors in Severe and Long-Term Treatment-Resistant Obsessive-Compulsive Disorder

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    Manuel Arrojo-Romero

    2013-01-01

    Full Text Available The treatment recommendations in obsessive-compulsive disorder (OCD after lack of response to selective serotonin reuptake inhibitors (SSRIs include augmentation with other drugs, particularly clomipramine, a more potent serotonin reuptake inhibitor (SRI, or antipsychotics. We present two cases of response to lamotrigine augmentation in treatment-refractory OCD; each received multiple SRI trials over a >10-year period. The first patient had eleven years of treatment with multiple combinations including clomipramine and SSRIs. She had a >50% decrease of Y-BOCS (from 29 to 14 by augmenting paroxetine (60 mg/day with lamotrigine (100 mg/day. The second patient had 22 years of treatment with multiple combinations, including combinations of SSRIs with clomipramine and risperidone. She had an almost 50% decrease of Y-BOCS (from 30 to 16 and disappearance of tics by augmenting clomipramine (225 mg/d with lamotrigine (200 mg/day. These two patients were characterized by lack of response to multiple treatments, making a placebo response to lamotrigine augmentation unlikely. Prospective randomized trials in treatment-resistant OCD patients who do not respond to combinations of SSRIs with clomipramine and/or antipsychotics are needed, including augmentation with lamotrigine. Until these trials are available, our cases suggest that clinicians may consider lamotrigine augmentation in such treatment-resistant OCD patients.

  4. Neurotensin releases norepinephrine differentially from perfused hypothalamus of sated and fasted rat

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    Lee, T.F.; Rezvani, A.H.; Hepler, J.R.; Myers, R.D.

    1987-01-01

    The central injection of neurotensin (NT) has been reported to attenuate the intake of food in the fasted animal. To determine whether endogenous norepinephrine (NE) is involved in the satiating effect of NT, the in vivo activity of NE in circumscribed sites in the hypothalamus of the unanesthetized rat was examined. Bilateral guide tubes for push-pull perfusion were implanted stereotaxically to rest permanently above one of several intended sites of perfusion, which included the paraventricular nucleus (PVN), ventromedial nucleus (VMN), and the lateral hypothalamic (LH) area. After endogenous stores of NE at a specific hypothalamic locus were radiolabeled by microinjection of 0.02-0.5 ..mu..Ci of (/sup 3/H)NE, an artificial cerebrospinal fluid was perfused at the site at a rate of 20 ..mu..l/min over successive intervals of 5.0 min. When 0.05 or 0.1 ..mu..g/..mu..l NT was added to the perfusate, the peptide served either to enhance or educe the local release of NE at 50% of the sites of perfusion. In these experiments, the circumscribed effect of NT on the characteristics of catecholamine efflux depended entirely on the state of hunger or satiety of the rat. That is, when NT was perfused in the fully satiated rat, NE release was augmented within the PVn or VMN; conversely, NE release was inhibited in the LH. in the animal fasted for 18-22 h, NT exerted an opposite effect on the activity of NE within the same anatomical loci in that the efflux of NE was enhanced in the LH but attenuated or unaffected in the PVN or VMN. Taken together, these observations provide experimental support for the view-point that NT could act as a neuromodulator of the activity of hypothalamic noradrenergic neurons that are thought to play a functional role in the regulation of food intake.

  5. Curcumin suppresses gelatinase B mediated norepinephrine induced stress in H9c2 cardiomyocytes.

    Directory of Open Access Journals (Sweden)

    Shrey Kohli

    Full Text Available BACKGROUND: Extracellular matrix (ECM remodeling facilitates biomechanical signals in response to abnormal physiological conditions. This process is witnessed as one of the major effects of the stress imposed by catecholamines, such as epinephrine and norepinephrine (NE, on cardiac muscle cells. Matrix metalloproteinases (MMPs are the key proteases involved in degradation of the ECM in heart. OBJECTIVES: The present study focuses on studying the effect of curcumin on Gelatinase B (MMP-9, an ECM remodeling regulatory enzyme, in NE-induced cardiac stress. Curcumin, a bioactive polyphenol found in the spice turmeric, has been studied for its multi-fold beneficial properties. This study focuses on investigating the role of curcumin as a cardio-protectant. METHODS: H9c2 cardiomyocytes were subjected to NE and curcumin treatments to study the response in stress conditions. Effect on total collagen content was studied using Picrosirus red staining. Gelatinase B activity was assessed through Gel-Diffusion Assay and Zymographic techniques. RT-PCR, Western Blotting and Immunocytochemistry were performed to study effect on expression of gelatinase B. Further, the effect of curcumin on the localization of NF-κB, known to regulate gelatinase B, was also examined. RESULTS: Curcumin suppressed the increase in the total collagen content under hypertrophic stress and was found to inhibit the in-gel and in-situ gelatinolytic activity of gelatinase B. Moreover, it was found to suppress the mRNA and protein expression of gelatinase B. CONCLUSIONS: The study provides an evidence for an overall inhibitory effect of curcumin on Gelatinase B in NE-induced hypertrophic stress in H9c2 cardiomyocytes which may contribute in the prevention of ECM remodeling.

  6. B and C types natriuretic peptides modulate norepinephrine uptake and release in the rat hypothalamus.

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    Vatta, M S; Presas, M; Bianciotti, L G; Zarrabeitia, V; Fernández, B E

    1996-09-16

    We previously reported that atrial natriuretic factor (ANF) regulates catecholamine metabolism in the central nervous system. ANF, B and C types natriuretic peptides (BNP and CNP) also play a regulatory role in body fluid homeostasis, cardiovascular activity and hormonal and neuro-hormonal secretions. The aim of the present work was to investigate BNP and CNP effects on the uptake and release of norepinephrine (NE) in rat hypothalamic slices incubated in vitro. Results showed that BNP (100 nM) and CNP (1, 10 and 100 nM) enhanced total and neuronal [3H]NE uptake but did not modify non-neuronal uptake. BNP (100 nM) and CNP (1 nM) caused a rapid increase in NE uptake (1 min), which was sustained for 60 min. BNP (100 nM) did not modify the intracellular distribution of NE; however, 1 nM CNP increased the granular store and decreased the cytosolic pool of NE. BNP (100 nM) and CNP (1, 10 and 100 nM), diminished spontaneous NE release. In addition, BNP (1, 10, 100 nM) and CNP (1, 10 and 100 pM, as well as 1, 10 and 100 nM) reduced NE output induced by 25 mM KCl. These results suggest that BNP and CNP may be involved in the regulation of several central as well as peripheral physiological functions through the modulation of noradrenergic neurotransmission at the presynaptic neuronal level. Present results provide evidence to consider CNP as the brain natriuretic peptide since physiological concentrations of this peptide (pM) diminished NE evoked release.

  7. The norepinephrine system and its relevance for multi-component behavior.

    Science.gov (United States)

    Mückschel, Moritz; Gohil, Krutika; Ziemssen, Tjalf; Beste, Christian

    2017-02-01

    The ability to execute several actions in a specific temporal order to achieve an overarching goal, a process often termed action cascading or multi-component behavior, is essential for everyday life requirements. We are only at the beginning to understand the neurobiological mechanisms important for these cognitive processes. However, it is likely that the locus coeruleus-norepinephrine (LC-NE) system may be of importance. In the current study we examine the relevance of the LC-NE system for action cascading processes using a system neurophysiological approach combining high-density EEG recordings and source localization to analyze event-related potentials (ERPs) with recordings of pupil diameter as a proximate of LC-NE system activity. N=25 healthy participants performed an action cascading stop-change paradigm. Integrating ERPs and pupil diameter using Pearson correlations, the results show that the LC-NE system is important for processes related to multi-component behavior. However, the LC-NE system does not seem to be important during the time period of response selection processes during multi-component behavior (reflected in the P3) as well as during perceptual and attentional selection (P1 and N1 ERPs). Rather, it seems that the neurophysiological processes in the fore period of a possibly upcoming imperative stimulus to initiate multi-component behavior are correlated with the LC-NE system. It seems that the LC-NE system facilitates responses to task-relevant processes and supports task-related decision and response selection processes by preparing cognitive control processes in case these are required during multi-component behavior rather than modulating these processes once they are operating. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. A kinetic study of the ouabain-induced efflux of norepinephrine from the dog saphenous vein

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    Monteiro, J.G. (Laboratorio de Farmacologia, Faculdade de Medicina, Porto (Portugal))

    1991-07-01

    Dog saphenous vein strips were incubated with (3H)norepinephrine ((3H)NE), 1.4 microM, after inhibition of the NE-metabolizing enzymes and extraneuronal uptake, and superfused for up to 290 min. From the 70th min onwards the strips were exposed to 10 microM ouabain, some of them being subject to electrical stimulation from the 140th min onwards. Other strips were exposed to either 1, 10 or 100 microM ouabain from the 70th min onwards. The spontaneous efflux of (3H)NE had a long half-time (156 min), and over 90% of the (3H)NE accumulated did not participate in efflux (bound fraction). Ouabain, 10 microM, induced a pronounced increase of the rate of efflux of (3H)NE, which was delayed in its onset and reached a maximum at t = 135 min of superfusion. Increasing the concentration of ouabain decreased both the delay to the beginning of the overflow and the time to maximum efflux and increased the maximum rate of efflux. In Ca(++)-free medium (during the superfusion period), the maximum rate of efflux was lower than in Ca(++)-containing medium, but was attained earlier. The bound fraction amounted to 22% when the efflux was induced by 10 microM ouabain in Ca(++)-containing medium, a value unnaffected by electrical stimulation but reduced markedly by omitting calcium. The results support the view that the efflux of (3H)NE induced by ouabain is delayed and that it is both carrier-mediated and due to exocytosis.

  9. Norepinephrine-induced nerve growth factor depletion causes cardiac sympathetic denervation in severe heart failure.

    Science.gov (United States)

    Kimura, Kensuke; Kanazawa, Hideaki; Ieda, Masaki; Kawaguchi-Manabe, Haruko; Miyake, Yoshiko; Yagi, Takashi; Arai, Takahide; Sano, Motoaki; Fukuda, Keiichi

    2010-08-25

    In severe congestive heart failure (CHF), sympathetic overactivity correlates with the exacerbation of cardiac performance. To test the hypothesis that the cardiac sympathetic nerve density dramatically changes with the acceleration of circulating norepinephrine (NE) concentration, we investigated the temporal association of nerve growth factor (NGF) expression in the heart and cardiac sympathetic nerve density during the development of CHF in the continuous NE-infused rats. The animals were analyzed at 0-, 1-, 3-, 7-, 14-, and 28-day after implantation of osmotic pump at a rate of 0.05 mg/kg/hr. The cardiac performance was temporally facilitated in NE-exposed rats at 3-day in accordance with the sympathetic hyper-innervation induced by the augmentation of NGF mRNA expression in the heart. In NE-treated rats, left ventricular end-diastolic pressure was significantly increased after 7-day and marked left ventricular hypertrophy and systemic fluid retention were observed at 28-day. CHF-induced sympathetic overactivity further increased plasma NE concentration in NE-treated rats and finally reached to 16.1+/-5.6 ng/ml at 28-day (control level was 0.39+/-0.1 ng/ml, pcardiac performance. The cardiac sympathetic fiber loss was also confirmed in NE-exposed DBH (dopamine beta-hydroxylase)-Cre/Floxed-EGFP (enhanced green fluorescent protein) mice with severe CHF, in which sympathetic nerve could be traced by EGFP. Our results suggest that the cardiac sympathetic nerve density is strictly regulated by the NGF expression in the heart and long-exposure of high plasma NE concentration caused myocardial NGF reduction, following sympathetic fiber loss in severe CHF animals.

  10. Dynamic arterial elastance predicts mean arterial pressure decrease associated with decreasing norepinephrine dosage in septic shock.

    Science.gov (United States)

    Guinot, Pierre-Grégoire; Bernard, Eugénie; Levrard, Mélanie; Dupont, Hervé; Lorne, Emmanuel

    2015-01-19

    Gradual reduction of the dosage of norepinephrine (NE) in patients with septic shock is usually left to the physician's discretion. No hemodynamic indicator predictive of the possibility of decreasing the NE dosage is currently available at the bedside. The respiratory pulse pressure variation/respiratory stroke volume variation (dynamic arterial elastance (Eadyn)) ratio has been proposed as an indicator of vascular tone. The purpose of this study was to determine whether Eadyn can be used to predict the decrease in arterial pressure when decreasing the NE dosage in resuscitated sepsis patients. A prospective study was carried out in a university hospital intensive care unit. All consecutive patients with septic shock monitored by PICCO2 for whom the intensive care physician planned to decrease the NE dosage were enrolled. Measurements of hemodynamic and PICCO2 variables were obtained before/after decreasing the NE dosage. Responders were defined by a >15% decrease in mean arterial pressure (MAP). In total, 35 patients were included. MAP decreased by >15% after decreasing the NE dosage in 37% of patients (n = 13). Clinical characteristics appeared to be similar between responders and nonresponders. Eadyn was lower in responders than in nonresponders (0.75 (0.69 to 0.85) versus 1 (0. 83 to 1.22), P decrease in arterial pressure, with an area under the receiver-operating characteristic curve of 0.87 (95% confidence interval (95% CI): 0.72 to 0.96; P decrease in arterial pressure in response to NE dose reduction. Eadyn may constitute an easy-to-use functional approach to arterial-tone assessment, which may be helpful to identify patients likely to benefit from NE dose reduction.

  11. Norepinephrine activates dopamine D4 receptors in the rat lateral habenula.

    Science.gov (United States)

    Root, David H; Hoffman, Alexander F; Good, Cameron H; Zhang, Shiliang; Gigante, Eduardo; Lupica, Carl R; Morales, Marisela

    2015-02-25

    The lateral habenula (LHb) is involved in reward and aversion and is reciprocally connected with dopamine (DA)-containing brain regions, including the ventral tegmental area (VTA). We used a multidisciplinary approach to examine the properties of DA afferents to the LHb in the rat. We find that >90% of VTA tyrosine hydroxylase (TH) neurons projecting to the LHb lack vesicular monoamine transporter 2 (VMAT2) mRNA, and there is little coexpression of TH and VMAT2 protein in this mesohabenular pathway. Consistent with this, electrical stimulation of LHb did not evoke DA-like signals, assessed with fast-scan cyclic voltammetry. However, electrophysiological currents that were inhibited by L741,742, a DA-D4-receptor antagonist, were observed in LHb neurons when DA uptake or degradation was blocked. To prevent DA activation of D4 receptors, we repeated this experiment in LHb slices from DA-depleted rats. However, this did not disrupt D4 receptor activation initiated by the dopamine transporter inhibitor, GBR12935. As the LHb is also targeted by noradrenergic afferents, we examined whether GBR12935 activation of DA-D4 receptors occurred in slices depleted of norepinephrine (NE). Unlike DA, NE depletion prevented the activation of DA-D4 receptors. Moreover, direct application of NE elicited currents in LHb neurons that were blocked by L741,742, and GBR12935 was found to be a more effective blocker of NE uptake than the NE-selective transport inhibitor nisoxetine. These findings demonstrate that NE is released in the rat LHb under basal conditions and that it activates DA-D4 receptors. Therefore, NE may be an important regulator of LHb function.

  12. Insulin and norepinephrine regulate ghrelin secretion from a rat primary stomach cell culture.

    Science.gov (United States)

    Gagnon, Jeffrey; Anini, Younes

    2012-08-01

    Ghrelin is a peptide hormone primarily produced in the previously unidentified X/A endocrine cells of the stomach. Extensive studies have focused on the effects of ghrelin on growth hormone release and appetite regulation. However, the mechanisms regulating ghrelin secretion are less understood. In the present study, we developed a primary culture of newborn rat stomach cells to investigate the mechanisms regulating ghrelin synthesis and secretion. We demonstrated that this cell preparation secretes ghrelin in a regulated manner through the increase of cAMP, intracellular calcium, and activation of protein kinase C. Norepinephrine (NE) (0.1-10 μm) stimulated ghrelin secretion through the β1-adrenergic receptor via increased cAMP and protein kinase A activity, whereas acetylcholine had no effect. Because circulating ghrelin levels were previously shown to be inversely correlated with insulin levels, we investigated the effect of insulin on ghrelin secretion. We first demonstrated that ghrelin cells express the insulin receptor α- and β-subunits. Next, we determined that insulin (1-10 nm) inhibited both basal and NE-stimulated ghrelin secretion, caused an increase in phosphorylated serine-threonine kinase (AKT) and a reduction in intracellular cAMP, but did not alter proghrelin mRNA levels. The inhibitory effect of insulin was blocked by inhibiting phospho-inositol-3 kinase and AKT but not MAPK. Higher dose insulin (100 nm) did not suppress ghrelin secretion, which prompted the investigation of cellular insulin resistance by pretreating the cells with 100 nm insulin for 24 h. This caused a reduction in insulin receptor expression and prevented the insulin-mediated AKT activation and the suppression of ghrelin secretion with no impact on NE-stimulated ghrelin secretion. Our findings highlight the role of the sympathetic nervous system, insulin, and insulin resistance in the regulation of ghrelin secretion.

  13. Role of calcium and EPAC in norepinephrine-induced ghrelin secretion.

    Science.gov (United States)

    Mani, Bharath K; Chuang, Jen-Chieh; Kjalarsdottir, Lilja; Sakata, Ichiro; Walker, Angela K; Kuperman, Anna; Osborne-Lawrence, Sherri; Repa, Joyce J; Zigman, Jeffrey M

    2014-01-01

    Ghrelin is an orexigenic hormone secreted principally from a distinct population of gastric endocrine cells. Molecular mechanisms regulating ghrelin secretion are mostly unknown. Recently, norepinephrine (NE) was shown to enhance ghrelin release by binding to β1-adrenergic receptors on ghrelin cells. Here, we use an immortalized stomach-derived ghrelin cell line to further characterize the intracellular signaling pathways involved in NE-induced ghrelin secretion, with a focus on the roles of Ca(2+) and cAMP. Several voltage-gated Ca(2+) channel (VGCC) family members were found by quantitative PCR to be expressed by ghrelin cells. Nifedipine, a selective L-type VGCC blocker, suppressed both basal and NE-stimulated ghrelin secretion. NE induced elevation of cytosolic Ca(2+) levels both in the presence and absence of extracellular Ca(2+). Ca(2+)-sensing synaptotagmins Syt7 and Syt9 were also highly expressed in ghrelin cell lines, suggesting that they too help mediate ghrelin secretion. Raising cAMP with the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine also stimulated ghrelin secretion, although such a cAMP-mediated effect likely does not involve protein kinase A, given the absence of a modulatory response to a highly selective protein kinase A inhibitor. However, pharmacological inhibition of another target of cAMP, exchange protein-activated by cAMP (EPAC), did attenuate both basal and NE-induced ghrelin secretion, whereas an EPAC agonist enhanced basal ghrelin secretion. We conclude that constitutive ghrelin secretion is primarily regulated by Ca(2+) influx through L-type VGCCs and that NE stimulates ghrelin secretion predominantly through release of intracellular Ca(2+). Furthermore, cAMP and its downstream activation of EPAC are required for the normal ghrelin secretory response to NE.

  14. Curcumin Suppresses Gelatinase B Mediated Norepinephrine Induced Stress in H9c2 Cardiomyocytes

    Science.gov (United States)

    Kohli, Shrey; Chhabra, Aastha; Jaiswal, Astha; Rustagi, Yashika; Sharma, Manish; Rani, Vibha

    2013-01-01

    Background Extracellular matrix (ECM) remodeling facilitates biomechanical signals in response to abnormal physiological conditions. This process is witnessed as one of the major effects of the stress imposed by catecholamines, such as epinephrine and norepinephrine (NE), on cardiac muscle cells. Matrix metalloproteinases (MMPs) are the key proteases involved in degradation of the ECM in heart. Objectives The present study focuses on studying the effect of curcumin on Gelatinase B (MMP-9), an ECM remodeling regulatory enzyme, in NE-induced cardiac stress. Curcumin, a bioactive polyphenol found in the spice turmeric, has been studied for its multi-fold beneficial properties. This study focuses on investigating the role of curcumin as a cardio-protectant. Methods H9c2 cardiomyocytes were subjected to NE and curcumin treatments to study the response in stress conditions. Effect on total collagen content was studied using Picrosirus red staining. Gelatinase B activity was assessed through Gel-Diffusion Assay and Zymographic techniques. RT-PCR, Western Blotting and Immunocytochemistry were performed to study effect on expression of gelatinase B. Further, the effect of curcumin on the localization of NF-κB, known to regulate gelatinase B, was also examined. Results Curcumin suppressed the increase in the total collagen content under hypertrophic stress and was found to inhibit the in-gel and in-situ gelatinolytic activity of gelatinase B. Moreover, it was found to suppress the mRNA and protein expression of gelatinase B. Conclusions The study provides an evidence for an overall inhibitory effect of curcumin on Gelatinase B in NE-induced hypertrophic stress in H9c2 cardiomyocytes which may contribute in the prevention of ECM remodeling. PMID:24116115

  15. Significance of matrix metalloproteinases in norepinephrine-induced remodelling of rat hearts.

    Science.gov (United States)

    Briest, Wilfried; Hölzl, Alexander; Rassler, Beate; Deten, Alexander; Baba, Hideo A; Zimmer, Heinz-Gerd

    2003-02-01

    Norepinephrine (NE) induced hypertrophy and remodelling of the extracellular matrix (ECM) in the left ventricle (LV) of the rat heart with resulting fibrosis. However, there was no increased collagen deposition in the right ventricle (RV). To test the hypothesis that lack of RV fibrosis is the result of elevated cleavage of collagens we inhibited the activity of matrix metalloproteinases (MMP) by doxycycline (Doxy) and then measured function and collagen metabolism in the RV as compared to the LV. Female Sprague-Dawley rats were treated with 30 mg/kg per day doxycycline alone or in combination with i.v. infusion of NE (0.1 mg/kg per h). The activity of MMP-2 was increased both in the LV and RV after 3 days of NE infusion and reduced after concomitant doxycycline treatment which also caused inhibition when given alone. After 14 days of NE infusion in combination with doxycycline there was an additional increase in the NE-induced elevation of collagen accumulation in the LV (interstitial collagen fraction: NE-Doxy 1.797%, PDoxy: 36.4 mmHg) and RV dP/dt(max) (NE: 5500 mmHg/s, PDoxy: 2550 mmHg/s). Also in the NE-stimulated LV, the doxycycline-induced collagen accumulation was associated with reduced LV dP/dt(max) (NE-Doxy: 13169 mmHg/s; NE: 18849 mmHg/s, P<0.05). MMP inhibition leads to myocardial stiffness with negative functional consequences for the RV and LV in NE-treated rat hearts.

  16. Modulatory effect of endothelin-1 and -3 on neuronal norepinephrine release in the rat posterior hypothalamus.

    Science.gov (United States)

    Di Nunzio, Andrea S; Legaz, Guillermina; Rodano, Valeria; Bianciotti, Liliana G; Vatta, Marcelo S

    2004-04-15

    Based upon the existence of high density of ET-receptors on catecholaminergic neurons of the hypothalamus, we studied the effects of endothelin-1 (ET-1) and endothelin-3 (ET-3) on neuronal norepinephrine (NE) release in the rat posterior hypothalamus. The intracellular pathways and receptors involved were also investigated. Neuronal NE release was enhanced by ET-1 and ET-3 (10 etaM). The selective antagonists of subtype A and B ET receptors (ETA, ETB) (100 etaM BQ-610 and 100 etaM BQ-788, respectively) abolished the increase induced by ET-1 but not by ET-3. The PLC inhibitor, U73122 (10 microM), abolished ET-1 and ET-3 response. GF-109203X (100 etaM) (PKC inhibitor) blocked the increase in NE release produced by ET-3 and partially blocked ET-1 response. The inositol 1,4,5-trisphosphate-induced calcium release inhibitor, 42 microM 2-APB, inhibited the stimulatory effect induced by ET-3 but not by ET-1. The PKA inhibitor, 500 etaM H-89, blocked the increase in neuronal NE release evoked by ET-1 but not by ET-3. Our results showed that ET-1 as well as ET-3 displayed an excitatory neuromodulatory effect on neuronal NE release in the rat posterior hypothalamus. ET-1 through an atypical ETA or ETB receptor activated the PLC/PKC signalling pathway as well as the cAMP pathway, whereas ET-3 through a non-ETA/non-ETB receptor activated the phosphoinositide pathway. Both ETs would enhance the sympathoexcitatory response elicited by the posterior hypothalamus and thus participate in cardiovascular regulation.

  17. Reserpine-induced reduction in norepinephrine transporter function requires catecholamine storage vesicles.

    Science.gov (United States)

    Mandela, Prashant; Chandley, Michelle; Xu, Yao-Yu; Zhu, Meng-Yang; Ordway, Gregory A

    2010-01-01

    Treatment of rats with reserpine, an inhibitor of the vesicular monoamine transporter (VMAT), depletes norepinephrine (NE) and regulates NE transporter (NET) expression. The present study examined the molecular mechanisms involved in regulation of the NET by reserpine using cultured cells. Exposure of rat PC12 cells to reserpine for a period as short as 5min decreased [(3)H]NE uptake capacity, an effect characterized by a robust decrease in the V(max) of the transport of [(3)H]NE. As expected, reserpine did not displace the binding of [(3)H]nisoxetine from the NET in membrane homogenates. The potency of reserpine for reducing [(3)H]NE uptake was dramatically lower in SK-N-SH cells that have reduced storage capacity for catecholamines. Reserpine had no effect on [(3)H]NE uptake in HEK-293 cells transfected with the rat NET (293-hNET), cells that lack catecholamine storage vesicles. NET regulation by reserpine was independent of trafficking of the NET from the cell surface. Pre-exposure of cells to inhibitors of several intracellular signaling cascades known to regulate the NET, including Ca(2+)/Ca(2+)-calmodulin dependent kinase and protein kinases A, C and G, did not affect the ability of reserpine to reduce [(3)H]NE uptake. Treatment of PC12 cells with the catecholamine depleting agent, alpha-methyl-p-tyrosine, increased [(3)H]NE uptake and eliminated the inhibitory effects of reserpine on [(3)H]NE uptake. Reserpine non-competitively inhibits NET activity through a Ca(2+)-independent process that requires catecholamine storage vesicles, revealing a novel pharmacological method to modify NET function. Further characterization of the molecular nature of reserpine's action could lead to the development of alternative therapeutic strategies for treating disorders known to be benefitted by treatment with traditional competitive NET inhibitors.

  18. Tricyclic isoxazolines: identification of R226161 as a potential new antidepressant that combines potent serotonin reuptake inhibition and alpha2-adrenoceptor antagonism.

    Science.gov (United States)

    Andrés, J Ignacio; Alcázar, Jesús; Alonso, José M; Alvarez, Rosa M; Bakker, Margot H; Biesmans, Ilse; Cid, José M; De Lucas, Ana I; Drinkenburg, Wilhelmus; Fernández, Javier; Font, Luis M; Iturrino, Laura; Langlois, Xavier; Lenaerts, Ilse; Martínez, Sonia; Megens, Anton A; Pastor, Joaquín; Pullan, Shirley; Steckler, Thomas

    2007-06-01

    In previous articles we have described the discovery of a new series of tricyclic isoxazolines combining central serotonin (5-HT) reuptake inhibition with alpha(2)-adrenoceptor antagonistic activity. We report now on the synthesis, the in vitro binding potency and the primary in vivo activity of six enantiomers within this series, one of which was selected for further pharmacological evaluation and assigned as R226161. Some additional in vivo studies in rats are described with this compound, which proved to be centrally and orally active as a combined 5-HT reuptake inhibitor and alpha(2)-adrenoceptor antagonist.

  19. Green tea catechins enhance norepinephrine-induced lipolysis via a protein kinase A-dependent pathway in adipocytes.

    Science.gov (United States)

    Chen, Shu; Osaki, Noriko; Shimotoyodome, Akira

    2015-05-22

    Green tea catechins have been shown to attenuate obesity in animals and humans. The catechins activate adenosine monophosphate-activated protein kinase (AMPK), and thereby increase fatty acid oxidation in liver and skeletal muscles. Green tea catechins have also been shown to reduce body fat in humans. However, the effect of the catechins on lipolysis in adipose tissue has not been fully understood. The aim of this study was to clarify the effect of green tea catechins on lipolysis in adipocytes and to elucidate the underlying mechanism. Differentiated mouse adipocyte cell line (3T3-L1) was stimulated with green tea catechins in the presence or absence of norepinephrine. Glycerol and free fatty acids in the media were measured. Phosphorylation of hormone-sensitive lipase (HSL) was determined by Western blotting, and the mRNA expression levels of HSL, adipose triglyceride lipase (ATGL), and perilipin were determined by quantitative RT-PCR. The cells were treated with inhibitors of protein kinase A (PKA), protein kinase C (PKC), protein kinase G (PKG), or mitogen-activated protein kinase (MAPK) to determine the responsible pathway. Treatment of 3T3-L1 adipocytes with green tea catechins increased the level of glycerol and free fatty acids released into the media in the presence, but not absence, of norepinephrine, and increased the level of phosphorylated HSL in the cells. The catechins also increased mRNA and protein levels of HSL and ATGL. PKA inhibitor (H89) attenuated the catechin-induced increase in glycerol release and HSL phosphorylation. The results demonstrate that green tea catechins enhance lipolysis in the presence of norepinephrine via a PKA-dependent pathway in 3T3-L1 adipocytes, providing a potential mechanism by which green tea catechins could reduce body fat.

  20. Cardioprotection Afforded by Norepinephrine-mediated Postconditioning in Isolated Rat Hearts

    Institute of Scientific and Technical Information of China (English)

    Xinhua Huang; Dai Li; Yishuai Zhang; Nianshen Li; Benmei Chen; Jun Peng; Yuanjian Li

    2008-01-01

    Objectives Previous studies have demonstrated that endogenous norepinephrine (NE) plays an important role in the mediation of ischemic preconditioning. The present study is designed to determine whether NE is also involved in medi-ation of the protective effects of postconditioning. Methods The rat hearts were rapidly excised under anesthesia and attached to a Langendorff apparatus via the aorta for retrograde perfusion with Krebs-Henseleit buffer solution. All hearts were subjected to 30 min of left coronary artery occlusion followed by 60 rain of reperfusion, except the control group. Animals were randomly divided into 5 groups as follows: ① control group, the hearts were underwent same procedures without ischemic insult; ② ischemia reperfusion group, the left coronary artery was occluded for 30 min and followed by 60 min of reperfusion;③ ischemic postconditioning (Ipost) group, immediately at the onset of reperfusion, the heart was initiated with 1 min of full coronary flow, followed by 1 min of re-occlusion, repeated for a total of three cycles; ④ Ipost plus prazosin group, the heart was perfused with prazosin for 10 min before ischemia; ⑤ Ipost plus reserpine group, a single dose of reserpine was administered by I.m. Injection, 24 hours before the experiment. Coronary flow was measured by timed collection of coronary effluent and sample of coronary effluent at 5 rain of reperfusion were collected for the measurement of ereatine kinase (CK). Infarct size and risk area were determined at the end of experiments. Results 30 rain of ischemia and followed by 60 min of reperfusion caused a significant decrease in cardiac function and a significant increase in CK release and infarct size. Postconditioning with three cycles of 1-min ischemia and 1-min reperfusion markedly improved cardiac function and reduced CK release and infarct size. However,the cardioprotection afforded by postconditioning was abolished by prazosin (10-6M), a selective α1 adrenergic

  1. Selective binding of 2-[{sup 125}I]iodo-nisoxetine to norepinephrine transporters in the brain

    Energy Technology Data Exchange (ETDEWEB)

    Kung, M.-P.; Choi, Seok-Rye; Hou, Catherine; Zhuang, Z.-P.; Foulon, Catherine; Kung, Hank F. E-mail: kunghf@sunmac.spect.upenn.edu

    2004-07-01

    A radioiodinated ligand, (R)-N-methyl-(2-[{sup 125}I]iodo-phenoxy)-3-phenylpropylamine, [{sup 125}I]2-INXT, targeting norepinephrine transporters (NET), was successfully prepared. A no-carrier-added product, [{sup 125}I]2-INXT, displayed a saturable binding with a high affinity (K{sub d}=0.06 nM) in the homogenates prepared from rat cortical tissues as well as from LLC-PK{sub 1} cells expressing NET. A relatively low number of binding sties (B{sub max}=55 fmol/mg protein) measured with [{sup 125}I]2-INXT in rat cortical homogenates is consistent with the value reported for a known NET ligand, [{sup 3}H]nisoxetine. Competition studies with various compounds on [{sup 125}I]2-INXT binding clearly confirmed the pharmacological specificity and selectivity for NET binding sites. Following a tail-vein injection of [{sup 125}I]2-INXT in rats, a good initial brain uptake was observed (0.56% dose at 2 min) followed by a slow washout from the brain (0.2% remained at 3 hours post-injection). The hypothalamus (a NET-rich region) to striatum (a region devoid of NET) ratio was 1.5 at 3 hours post-i.v. injection. Pretreatment of rats with nisoxetine significantly inhibited the uptake of [{sup 125}I]2-INXT (70-100% inhibition) in locus coeruleus, hypothalamus and raphe nuclei, regions known to have a high density of NET; whereas escitalopram, a serotonin transporter ligand, did not show a similar effect. Ex vivo autoradiography of rat brain sections of [{sup 125}I]2-INXT (at 3 hours after an i.v. injection) displayed an excellent regional brain localization pattern corroborated to the specific NET distribution in the brain. The specific brain localization was significantly reduced by a dose of nisoxetine pretreatment. Taken together, the data suggest that [{sup 123}I]2-INXT may be useful for mapping NET binding sites in the brain.

  2. Locus Ceruleus Norepinephrine Release: A Central Regulator of CNS Spatio-Temporal Activation?

    Science.gov (United States)

    Atzori, Marco; Cuevas-Olguin, Roberto; Esquivel-Rendon, Eric; Garcia-Oscos, Francisco; Salgado-Delgado, Roberto C; Saderi, Nadia; Miranda-Morales, Marcela; Treviño, Mario; Pineda, Juan C; Salgado, Humberto

    2016-01-01

    Norepinephrine (NE) is synthesized in the Locus Coeruleus (LC) of the brainstem, from where it is released by axonal varicosities throughout the brain via volume transmission. A wealth of data from clinics and from animal models indicates that this catecholamine coordinates the activity of the central nervous system (CNS) and of the whole organism by modulating cell function in a vast number of brain areas in a coordinated manner. The ubiquity of NE receptors, the daunting number of cerebral areas regulated by the catecholamine, as well as the variety of cellular effects and of their timescales have contributed so far to defeat the attempts to integrate central adrenergic function into a unitary and coherent framework. Since three main families of NE receptors are represented-in order of decreasing affinity for the catecholamine-by: α2 adrenoceptors (α2Rs, high affinity), α1 adrenoceptors (α1Rs, intermediate affinity), and β adrenoceptors (βRs, low affinity), on a pharmacological basis, and on the ground of recent studies on cellular and systemic central noradrenergic effects, we propose that an increase in LC tonic activity promotes the emergence of four global states covering the whole spectrum of brain activation: (1) sleep: virtual absence of NE, (2) quiet wake: activation of α2Rs, (3) active wake/physiological stress: activation of α2- and α1-Rs, (4) distress: activation of α2-, α1-, and β-Rs. We postulate that excess intensity and/or duration of states (3) and (4) may lead to maladaptive plasticity, causing-in turn-a variety of neuropsychiatric illnesses including depression, schizophrenic psychoses, anxiety disorders, and attention deficit. The interplay between tonic and phasic LC activity identified in the LC in relationship with behavioral response is of critical importance in defining the short- and long-term biological mechanisms associated with the basic states postulated for the CNS. While the model has the potential to explain a large

  3. Comparison under a simulated sun of two black-nickel-coated flat-plate solar collectors with a nonselective black-paint-coated collector

    Science.gov (United States)

    Simon, F. F.

    1975-01-01

    A performance evaluation was made of two, black nickel coated, flat plate solar collectors. Collector performance was determined under a simulated sun for a wide range of inlet temperatures, including the temperature required for solar powered absorption air conditioning. For a basis of comparison a performance test was made on a traditional, two glass, nonselective, black paint coated, flat plate collector. Performance curves and performance parameters are presented to point out the importance of the design variables which determine an efficient collector. A black nickel coated collector was found to be a good performer at the conditions expected for solar powered absorption air conditioning. This collector attained a thermal efficiency of 50 percent at an inlet temperature of 366 K (200 F) and an incident flux of 946 watts/sq m (300 Btu/hr-sq ft).

  4. Selective serotonin reuptake inhibitor sertraline inhibits voltage-dependent K+ channels in rabbit coronary arterial smooth muscle cells

    Indian Academy of Sciences (India)

    HAN SOL KIM; HONGLIANG LI; HYE WON KIM; SUNG EUN SHIN; IL-WHAN CHOI; AMY L FIRTH; HYOWEON BANG; YOUNG MIN BAE; WON SUN PARK

    2016-12-01

    We examined the effects of the selective serotonin reuptake inhibitor (SSRI) sertraline on voltage-dependent K+ (Kv)channels in freshly isolated rabbit coronary arterial smooth muscle cells using the voltage-clamp technique. Sertralinedecreased the Kv channel current in a dose-dependent manner, with an IC50 value of 0.18 μM and a slope value (Hillcoefficient) of 0.61. Although the application of 1 μM sertraline did not affect the steady-state activation curves,sertraline caused a significant, negative shift in the inactivation curves. Pretreatment with another SSRI, paroxetine,had no significant effect on Kv currents and did not alter the inhibitory effects of sertraline on Kv currents. From theseresults, we concluded that sertraline dose-dependently inhibited Kv currents independently of serotonin reuptakeinhibition by shifting inactivation curves to a more negative potential.

  5. Prediction of clinical response based on pharmacokinetic/pharmacodynamic models of 5-hydroxytryptamine reuptake inhibitors in mice

    DEFF Research Database (Denmark)

    Kreilgaard, Mads; Smith, D. G.; Brennum, L. T.

    2008-01-01

    Bridging the gap between preclinical research and clinical trials is vital for drug development. Predicting clinically relevant steady-state drug concentrations (Css) in serum from preclinical animal models may facilitate this transition. Here we used a pharmacokinetic/pharmacodynamic (PK/PD) mod....../PD) modelling approach to evaluate the predictive validity of 5-hydroxytryptamine (5-HT; serotonin) transporter (SERT) occupancy and 5-hydroxytryptophan (5-HTP)-potentiated behavioral syndrome induced by 5-HT reuptake inhibitor (SRI) antidepressants in mice.......Bridging the gap between preclinical research and clinical trials is vital for drug development. Predicting clinically relevant steady-state drug concentrations (Css) in serum from preclinical animal models may facilitate this transition. Here we used a pharmacokinetic/pharmacodynamic (PK...

  6. Prenatal exposure to selective serotonin reuptake inhibitors (SSRI) increases aggression and modulates maternal behavior in offspring mice.

    Science.gov (United States)

    Svirsky, Natali; Levy, Sigal; Avitsur, Ronit

    2016-01-01

    Selective serotonin reuptake inhibitors (SSRI) are commonly prescribed antidepressant drugs in pregnant women. SSRIs cross the placental barrier and affect serotonergic neurotransmission in the fetus. Although no gross SSRI-related teratogenic effects were reported, infants born following prenatal exposure to SSRIs are at higher risk for various developmental abnormalities. The aim of this study was to examine the effects of prenatal SSRI on social and maternal behavior in mice. To this end, pregnant female dams were exposed to saline or fluoxetine (FLX) throughout pregnancy, and the behavior of the offspring was examined. The results indicate that in utero FLX increased aggression in adult males and delayed emergence of maternal behavior in adult females. Social exploration and recognition memory were not affected by prenatal FLX exposure. These findings support the notion that alterations in the development of serotonergic pathways following prenatal exposure to SSRIs are associated with changes in social and maternal behavior throughout life.

  7. Dependence and withdrawal reactions to benzodiazepines and sellective serotonin reuptake inhibitors: How did the health authorities react?

    DEFF Research Database (Denmark)

    Nielsen, Margrethe

    2013-01-01

    AIM: Our objective was to explore communications from drug agencies about benzodiazepine dependence and selective serotonin reuptake inhibitors (SSRIs) withdrawal reactions over time. METHODS: Documentary study. We searched the web-sites of the European Medicines Agency and the drug agencies in USA......, UK, and Denmark for documents mentioning benzodiazepines or SSRIs. We supplemented with other relevant literature that could contribute to our study. The searches were performed in 2009 in PubMed, Google, BMJ and JAMA. RESULTS: It took many years before the drug regulators acknowledged benzodiazepine...... the problems. CONCLUSION: Given the experience with the benzodiazepines, we believe the regulatory bodies should have required studies from the manufacturers that could have elucidated the dependence potential of the SSRIs before marketing authorization was granted....

  8. Effect of the selective serotonin reuptake inhibitor paroxetine on platelet function is modified by a SLC6A4 serotonin transporter polymorphism

    NARCIS (Netherlands)

    Abdelmalik, N.; Ruhé, H.G.; Barwari, K.; Van Den Dool, E.-J.; Meijers, J.C.M.; Middeldorp, S.; Büller, H.R.; Schene, A.H.; Kamphuisen, P.W.

    2008-01-01

    Background: Selective serotonin reuptake inhibitors (SSRIs) have been associated with an increased bleeding tendency. Objectives: To prospectively quantify the dose-response effects of paroxetine and the influence of the serotonin transporter gene (SLC6A4) promoter polymorphism (5-HTTLPR) on platele

  9. Effect of selective serotonin re-uptake inhibitors (SSRIs) on functional outcome in patients with acute ischemic stroke treated with tPA

    NARCIS (Netherlands)

    Miedema, I; Horvath, K M; Uyttenboogaart, M; Koopman, K; Lahr, Maarten; De Keyser, J; Luijckx, G J

    2010-01-01

    Background: Selective serotonin re-uptake inhibitors (SSRIs) may have therapeutic potential in the treatment of ischemic stroke by effects on neuronal cell survival and the plasticity of brain processes. In the present study, we investigated whether prior treatment with a SSRI is associated with mor

  10. Disturbed development of the enteric nervous system after in utero exposure of selective serotonin re-uptake inhibitors and tricyclic antidepressants. Part 1 : Literature review

    NARCIS (Netherlands)

    Nijenhuis, C.M.; Ter Horst, P.G.; de Jong-van den Berg, L.T.; Wilffert, B.

    2012-01-01

    The increase in selective serotonin re-uptake inhibitor (SSRI) use during pregnancy, questions concerning abnormal development of the enteric nervous system (ENS), increase in laxative use in children and the association of fluoxetine with infantile hypertrophic pyloric stenosis (IHPS) gave rise to

  11. Effect of selective serotonin re-uptake inhibitors (SSRIs) on functional outcome in patients with acute ischemic stroke treated with tPA

    NARCIS (Netherlands)

    Miedema, I; Horvath, K M; Uyttenboogaart, M; Koopman, K; Lahr, Maarten; De Keyser, J; Luijckx, G J

    2010-01-01

    Background: Selective serotonin re-uptake inhibitors (SSRIs) may have therapeutic potential in the treatment of ischemic stroke by effects on neuronal cell survival and the plasticity of brain processes. In the present study, we investigated whether prior treatment with a SSRI is associated with

  12. Selective serotonin reuptake inhibitor antidepressant use in first trimester pregnancy and risk of specific congenital anomalies : a European register-based study

    NARCIS (Netherlands)

    Wemakor, Anthony; Casson, Karen; Garne, Ester; Bakker, Marian; Addor, Marie-Claude; Arriola, Larraitz; Gatt, Miriam; Khoshnood, Babak; Klungsoyr, Kari; Nelen, Vera; O'Mahoney, Mary; Pierini, Anna; Rissmann, Anke; Tucker, David; Boyle, Breidge; de Jong-van den Berg, Lolkje; Dolk, Helen

    2015-01-01

    Evidence of an association between early pregnancy exposure to selective serotonin reuptake inhibitors (SSRI) and congenital heart defects (CHD) has contributed to recommendations to weigh benefits and risks carefully. The objective of this study was to determine the specificity of association betwe

  13. Use of dihydro-isobenzofuran in combination with serotonin reuptake inhibitors for CNS disease e.g. depression, anxiety, bipolar disorder, obsessive compulsory disorder

    DEFF Research Database (Denmark)

    2013-01-01

    NOVELTY - For treatment of a CNS disease in a patient, dihydro-isobenzofuran compound (I) in combination with serotonin reuptake inhibitor, is used. USE - For treatment of CNS disease (claimed) including depression, anxiety, bipolar disorder, obsessive compulsory disorder, post traumatic stress...

  14. Slimmer or fertile? Pharmacological mechanisms involved in reduced sperm quality and fertility in rats exposed to the anorexigen sibutramine.

    Directory of Open Access Journals (Sweden)

    Cibele S Borges

    Full Text Available Sperm acquire motility and fertility capacity during epididymal transit, under the control of androgens and sympathetic innervations. It is already known that the acceleration of epididymal sperm transit time can lead to lower sperm quality. In a previous work we showed that rats exposed to the anorexigen sibutramine, a non-selective serotonin-norepinephrine reuptake inhibitor, presented faster sperm transit time, lower epididymal sperm reserves and potentiation of the tension of epididymal duct to norepinephrine exposed acutely in vitro to sibutramine. In the present work we aimed to further investigate pharmacological mechanisms involved in these alterations and the impact on rat sperm quality. For this, adult male Wistar rats were treated with sibutramine (10 mg/kg/day or vehicle for 30 days. Sibutramine decreased final body, seminal vesicle, ventral prostate and epididymal weights, as well as sperm transit time in the epididymal cauda. On the contrary of the in vitro pharmacological assays, in which sibutramine was added directly to the bath containing strips of distal epididymal cauda, the ductal tension was not altered after in vivo sub-chronic exposure to sibutramine. However, there is pharmacological evidence that the endogenous epididymal norepinephrine reserves were reduced in these animals. It was also shown that the decrease in prostate weight can be related to increased tension developed of the gland, due to sibutramine sympathomimetic effects. In addition, our results showed reduced sperm quality after in utero artificial insemination, a more sensitive procedure to assess fertility in rodents. The epididymal norepinephrine depletion exerted by sibutramine, associated with decreases in sperm transit time, quantity and quality, leading to reduced fertility in this experimental model, reinforces the concerns about the possible impact on fertility of man taking sibutramine as well as other non-selective serotonin-norepinephrine

  15. Modulation of the release of norepinephrine by gamma-aminobutyric acid and morphine in the frontal cerebral cortex of the rat

    Energy Technology Data Exchange (ETDEWEB)

    Peoples, R.W.

    1989-01-01

    Agents that enhance gamma-aminobutyric acid, or GABA, neurotransmission modulate certain effects of opioids, such as analgesia. Opioid analgesia is mediated in part by norepinephrine in the forebrain. In this study, the interactions between morphine and GABAergic agents on release of ({sup 3}H) norepinephrine from rat frontal cerebral cortical slices were examined. GABA, 5 {times} 10{sup {minus}5}-10{sup {minus}3} M, enhanced potassium stimulated ({sup 3}H) norepinephrine release and reversed the inhibitory effect of morphine in a noncompetitive manner. GABA did not enhance release of ({sup 3}H) norepinephrine stimulated by the calcium ionophore A23187. The effect of GABA was reduced by the GABA{sub A} receptor antagonists bicuculline methiodide or picrotoxin, and by the selective inhibitor of GABA uptake SKF 89976A, but was blocked completely only when bicuculline methiodide and SKF 89976A were used in combination. The GABA{sub A} agonist muscimol, 10{sup {minus}4} M, mimicked the effect of GABA, but the GABA{sub B} agonist ({plus minus})baclofen, 10{sup {minus}4} M, did not affect the release of ({sup 3}H) norepinephrine in the absence or the presence of morphine. Thus GABA appears to produce this effect by stimulating GABA uptake and GABA{sub A}, but not GABA{sub B}, receptors. In contrast to the results that would be predicted for an event involving GABA{sub A} receptors, however, the effect of GABA did not desensitize, and benzodiazepine agonists did not enhance the effect of GABA at any concentration tested between 10{sup {minus}8} and 10{sup {minus}4} M. Thus these receptors may constitute a subclass of GABA{sub A} receptors. These results support a role of GABA uptake and GABA{sub A} receptors in enhancing the release of norepinephrine and modulating its inhibition by opioids in the frontal cortex of the rat.

  16. Dietary supplement increases plasma norepinephrine, lipolysis, and metabolic rate in resistance trained men

    Directory of Open Access Journals (Sweden)

    Schilling Brian K

    2009-01-01

    Full Text Available Abstract Background Dietary supplements targeting fat loss and increased thermogenesis are prevalent within the sport nutrition/weight loss market. While some isolated ingredients have been reported to be efficacious when used at high dosages, in particular in animal models and/or via intravenous delivery, little objective evidence is available pertaining to the efficacy of a finished product taken by human subjects in oral form. Moreover, many ingredients function as stimulants, leading to increased hemodynamic responses. The purpose of this investigation was to determine the effects of a finished dietary supplement on plasma catecholamine concentration, markers of lipolysis, metabolic rate, and hemodynamics. Methods Ten resistance trained men (age = 27 ± 4 yrs; BMI = 25 ± 3 kg· m-2; body fat = 9 ± 3%; mean ± SD ingested a dietary supplement (Meltdown®, Vital Pharmaceuticals or a placebo, in a random order, double blind cross-over design, with one week separating conditions. Fasting blood samples were collected before, and at 30, 60, and 90 minutes post ingestion and were assayed for epinephrine (EPI, norepinephrine (NE, glycerol, and free fatty acids (FFA. Area under the curve (AUC was calculated for all variables. Gas samples were collected from 30–60 minutes post ingestion for measurement of metabolic rate. Heart rate and blood pressure were recorded at all blood collection times. Results AUC was greater for the dietary supplement compared to the placebo for NE (1332 ± 128 pg·mL-1·90 min-1 vs. 1003 ± 133 pg·mL-1·90 min-1; p = 0.03, glycerol (44 ± 3 μg·mL-1·90 min-1 vs. 26 ± 2 μg·mL-1·90 min-1; p -1·90 min-1 vs. 0.88 ± 0.12 mmol·L-1·90 min-1; p = 0.0003. No difference between conditions was noted for EPI AUC (p > 0.05. For all variables, values were highest at 90 minutes post ingestion. Total kilocalorie expenditure during the 30 minute collection period was 29.6% greater (p = 0.02 for the dietary supplement (35 ± 3

  17. Incremental cost-effectiveness of cyclooxygenase 2-selective versus nonselective nonsteroidal, anti-inflammatory drugs in a cohort of coumarin users : A pharmacoeconomic analysis linked to a case-control study

    NARCIS (Netherlands)

    Knijff-Dutmer, EAJ; Postma, MJ; van der Palen, J; Brouwers, JRBJ; van de Laar, MAFJ

    2004-01-01

    Background: A previous case-control study involving concomitant users of coumarin and nonsteroidal anti-inflammatory drugs (NSAIDs) found that cyclooxygenase 2 (COX-2)-selective NSAIDs were associated with fewer bleeding complications than nonselective NSAIDs. Objective: The goal of this study was t

  18. Incremental cost-effectiveness of cyclooxygenase 2-selective versus nonselective nonsteroidal anti-inflammatory drugs in a cohort of coumarin users: A pharmacoeconomic analysis linked to a case-control study

    NARCIS (Netherlands)

    Knijff-Dutmer, Ellen A.J.; Postma, Maarten J.; Palen, van der Job; Brouwers, Jacobus R.B.J.; Laar, van de Martin A.F.J.

    2004-01-01

    Background: A previous case-control study involving concomitant users of coumarin and nonsteroidal anti-inflammatory drugs (NSAIDs) found that cyclooxygenase 2 (COX-2)-selective NSAIDs were associated with fewer bleeding complications than nonselective NSAIDs. Objective: The goal of this study was

  19. Norepinephrine transporter expression is inversely associated with glycaemic indices: a pilot study in metabolically diverse persons with overweight and obesity

    Science.gov (United States)

    Guo, L.; Corcoran, S. J.; Esler, M. D.; Phillips, S. E.; Sari, C. I.; Grima, M. T.; Karapanagiotidis, S.; Wong, C. Y.; Eikelis, N.; Mariani, J. A.; Kobayashi, D.; Dixon, J. B.; Lambert, G. W.; Lambert, E. A.

    2016-01-01

    Summary Objective The objective of this study was to examine the cross‐sectional relationship between the expression of norepinephrine transporter (NET), the protein responsible for neuronal uptake‐1, and indices of glycaemia and hyperinsulinaemia, in overweight and obese individuals. Methods Thirteen non‐medicated, non‐smoking subjects, aged 58 ± 1 years (mean ± standard error of the mean), body mass index (BMI) 31.4 ± 1.0 kg m−2, with wide‐ranging plasma glucose and haemoglobin A1c (HbA1c, range 5.1% to 6.5%) participated. They underwent forearm vein biopsy to access sympathetic nerves for the quantification of NET by Western blot, oral glucose tolerance test (OGTT), euglycaemic hyperinsulinaemic clamp, echocardiography and assessments of whole‐body norepinephrine kinetics and muscle sympathetic nerve activity. Results Norepinephrine transporter expression was inversely associated with fasting plasma glucose (r = −0.62, P = 0.02), glucose area under the curve during OGTT (AUC0–120, r = −0.65, P = 0.02) and HbA1c (r = −0.67, P = 0.01), and positively associated with steady‐state glucose utilization during euglycaemic clamp (r = 0.58, P = 0.04). Moreover, NET expression was inversely related to left ventricular posterior wall dimensions (r = −0.64, P = 0.02) and heart rate (r = −0.55, P = 0.05). Indices of hyperinsulinaemia were not associated with NET expression. In stepwise linear regression analysis adjusted for age, body mass index and blood pressure, HbA1c was an independent inverse predictor of NET expression, explaining 45% of its variance. Conclusions Hyperglycaemia is associated with reduced peripheral NET expression. Further studies are required to identify the direction of causality.

  20. Pharmacokinetics and tolerability of DA-8031, a novel selective serotonin reuptake inhibitor for premature ejaculation in healthy male subjects

    Directory of Open Access Journals (Sweden)

    Shin D

    2017-03-01

    Full Text Available Dongseong Shin,1 SeungHwan Lee,2 Sojeong Yi,2 Seo Hyun Yoon,2 Joo-Youn Cho,2 Mi Young Bahng,3 In-Jin Jang,2 Kyung-Sang Yu2 1Clinical Trials Center, Gachon University Gil Medical Center, Incheon, 2Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, 3Department of Product Development, Dong-A ST, Seoul, Korea Objective: DA-8031 is a selective serotonin reuptake inhibitor under development for the treatment of premature ejaculation. This is the first-in-human study aimed at evaluating the pharmacokinetics and tolerability of DA-8031 and its metabolites (M1, M2, M4, and M5 in the plasma and urine after administration of a single oral dose in healthy male subjects.Methods: A dose block-randomized, double-blind, placebo-controlled, single ascending dose study was conducted. Subjects received either placebo or a single dose of DA-8031 at 5, 10, 20, 40, 60, 80, or 120 mg. DA-8031 and its four metabolites were analyzed in the plasma and urine for pharmacokinetic evaluation. The effect of genetic polymorphisms of cytochrome-P450 (CYP enzymes on the pharmacokinetics of DA-8031 was evaluated.Results: After a single dose, plasma DA-8031 reached the maximum concentration at a median of 2–3 h and was eliminated with terminal elimination half-life of 17.9–28.7 h. The mean renal clearance was 3.7–5.6 L/h. Dose-proportional pharmacokinetics was observed over the dose range of 20–80 mg. Among the metabolites, M4 had the greatest plasma concentration, followed by M5 and M1. Subjects with CYP2D6 intermediate metabolizer had significantly greater dose-normalized Cmax and AUC0–t of DA-8031 as well as smaller metabolic ratios than those subjects with CYP2D6 extensive metabolizer. The most common adverse events were nausea, dizziness, and headache, and no serious adverse events were reported.Conclusion: In conclusion, the systemic exposure of DA-8031 was increased proportionally to the dose within 20

  1. High expression of organic cation transporter 3 in human BAT-like adipocytes. Implications for extraneuronal norepinephrine uptake

    DEFF Research Database (Denmark)

    Breining, Peter; Pedersen, Steen Bønløkke; Pikelis, Arunas;

    2016-01-01

    with known markers of thermogenic function, e.g. UCP1. When examining neck AT biopsies from 57 individuals we found that OCT3 was expressed at 2.5 ± 0.16 fold higher level in the deep-neck AT compared with subcutaneous AT. UCP1 was found extensively expressed in the deep-neck AT depot and the correlation...... between UCP1 and OCT3 within the deep-neck AT was found highly significant (r(2) = 0.4012, P-value 3-blocker. In conclusion, we found that OCT3 may......Brown adipose tissue (BAT) is activated by extracellular norepinephrine (NE) released by the sympathetic nervous system. The extracellular concentration of NE is additionally regulated by the disappearance/degradation of NE. Recent studies have introduced the organic cation transporter 3 (OCT3...

  2. Dopamine and norepinephrine responses to film-induced sexual arousal in sexually functional and sexually dysfunctional women.

    Science.gov (United States)

    Meston, C M; McCall, K M

    2005-01-01

    This study was designed to assess potential differences between sexually functional and dysfunctional women in dopamine (DA) and norepinephrine (NE) responses to erotic stimuli. Blood levels of homovanillic acid (HVA; the major metabolite of DA) and NE were taken during the showing of a nonsexual and a sexual film from 9 women with female sexual arousal disorder and hypoactive sexual desire disorder and from 13 sexually functional women. We assessed sexual arousal subjectively using a self-report scale and physiologically using a vaginal photoplethysmograph. HVA levels significantly decreased in sexually functional and dysfunctional women during the erotic versus during the neutral film. NE levels were not significantly different for either group of women during the neutral and erotic films. Sexually dysfunctional women had significantly higher levels of NE during both the neutral and erotic films compared with functional women. Subjective or physiological arousal differences between neutral and erotic films were not significantly different between functional and dysfunctional women.

  3. PET quantification of the norepinephrine transporter in human brain with (S,S)-18F-FMeNER-D2.

    Science.gov (United States)

    Moriguchi, Sho; Kimura, Yasuyuki; Ichise, Masanori; Arakawa, Ryosuke; Takano, Harumasa; Seki, Chie; Ikoma, Yoko; Takahata, Keisuke; Nagashima, Tomohisa; Yamada, Makiko; Mimura, Masaru; Suhara, Tetsuya

    2016-12-15

    Norepinephrine transporter (NET) in the brain plays important roles in human cognition and the pathophysiology of psychiatric disorders. Two radioligands, (S,S)-(11)C-MRB and (S,S)-(18)F-FMeNER-D2, have been used for imaging NETs in the thalamus and midbrain (including locus coeruleus) using positron emission topography (PET) in humans. However, NET density in the equally important cerebral cortex has not been well quantified because of unfavorable kinetics with (S,S)-(11)C-MRB and defluorination with (S,S)-(18)F-FMeNER-D2, which can complicate NET quantification in the cerebral cortex adjacent to the skull containing defluorinated (18)F radioactivity. In this study, we have established analysis methods of quantification of NET density in the brain including cerebral cortex using (S,S)-(18)F-FMeNER-D2 PET.

  4. Effects of morphine on hypothalamic corticotropin-releasing factor (CRF, norepinephrine and dopamine in non-stressed and stressed rats.

    Directory of Open Access Journals (Sweden)

    Suemaru,Shuso

    1985-12-01

    Full Text Available The effects of morphine on the hypothalamic corticotropin-releasing factor (CRF, norepinephrine (NE and dopamine (DA concentrations were investigated in non-stressed and stressed rats. Acutely administered morphine stimulated both the synthesis and release of CRF in the hypothalamus, thereby activating the pituitary-adrenocortical system in non-stressed rats, but inhibited the stress-induced CRF synthesis and ACTH-corticosterone secretion. Either a morphine or ether-laparotomy stress reduced NE and DA concentrations in the hypothalamus. A pretreatment with morphine inhibited the stress-induced reduction in the hypothalamic NE and DA concentrations, and induced a significant increase in the DA concentration. These observations suggest that hypothalamic NE and DA are involved in morphine-induced changes in hypothalamo-pituitary-adrenocortical (HPA activity and that endogenous opiates have a role in regulating CRF secretion by interacting with hypothalamic biogenic amines.

  5. [Role of the sympathetic nervous system in vasovagal syncope and rationale for beta-blockers and norepinephrine transporter inhibitors].

    Science.gov (United States)

    Márquez, Manlio F; Gómez-Flores, Jorge Rafael; González-Hermosillo, Jesús A; Ruíz-Siller, Teresita de Jesús; Cárdenas, Manuel

    2016-12-29

    Vasovagal or neurocardiogenic syncope is a common clinical situation and, as with other entities associated with orthostatic intolerance, the underlying condition is a dysfunction of the autonomic nervous system. This article reviews various aspects of vasovagal syncope, including its relationship with orthostatic intolerance and the role of the autonomic nervous system in it. A brief history of the problem is given, as well as a description of how the names and associated concepts have evolved. The response of the sympathetic system to orthostatic stress, the physiology of the baroreflex system and the neurohumoral changes that occur with standing are analyzed. Evidence is presented of the involvement of the autonomic nervous system, including studies of heart rate variability, microneurography, cardiac innervation, and molecular genetic studies. Finally, we describe different studies on the use of beta-blockers and norepinephrine transporter inhibitors (sibutramine, reboxetine) and the rationality of their use to prevent this type of syncope.

  6. Fear extinction can be made state-dependent on peripheral epinephrine: role of norepinephrine in the nucleus tractus solitarius.

    Science.gov (United States)

    Rosa, Jessica; Myskiw, Jociane C; Furini, Cristiane R G; Sapiras, Gerson G; Izquierdo, Ivan

    2014-09-01

    We investigate whether the extinction of inhibitory avoidance (IA) learning can be subjected to endogenous state-dependence with systemic injections of epinephrine (E), and whether endogenous norepinephrine (NE) and the nucleus tractus solitarius (NTS)→locus coeruleus→hippocampus/amygdala (HIPP/BLA) pathway participate in this. Rats trained in IA were submitted to two sessions of extinction 24 h apart: In the first, the animals were submitted to a training session of extinction, and in the second they were tested for the retention of extinction. Saline or E were given i.p. immediately after the extinction training (post-extinction training injections) and/or 6 min before the extinction test (pre-extinction test). Post-extinction training E (50 or 100 μg/kg) induced a poor retrieval of extinction in the test session of this task unless an additional E injection (50 μg/kg) was given prior to the extinction test. This suggested state-dependence. Muscimol (0.01 μg/side) microinfused into the NTS prior to the extinction test session blocked E-induced state-dependence. Norepinephrine (NE, 1 μg/side) infused bilaterally into NTS restores the extinction impairment caused by post-extinction training i.p. E. In animals with bilateral NTS blockade induced by muscimol, NE (1 μg/side) given prior to the extinction test into the CA1 region of the dorsal hippocampus or into the basolateral amygdala restored the normal extinction levels that had been impaired by muscimol. These results suggest a role for the NTS→locus coeruleus→HIPP/BLA pathway in the retrieval of extinction, as it has been shown to have in the consolidation of inhibitory avoidance and of object recognition learning.

  7. Glucagon stimulates ghrelin secretion through the activation of MAPK and EPAC and potentiates the effect of norepinephrine.

    Science.gov (United States)

    Gagnon, Jeffrey; Anini, Younes

    2013-02-01

    Ghrelin is a stomach-derived orexigenic hormone whose levels in circulation are altered by energy availability. Like ghrelin, the glucotropic hormone glucagon increases in the fasting state and serves to normalize energy levels. We hypothesized that glucagon can directly stimulate stomach ghrelin production. To verify this hypothesis, we used a primary culture of dispersed rat stomach cells. We first demonstrated that stomach ghrelin cells express the glucagon receptor (GluR). Glucagon (1-100 nM) significantly stimulated ghrelin secretion and proghrelin mRNA expression, and co-incubation with a GluR inhibitor prevented glucagon's action. The MAP kinase inhibitor (PD98058) reduced the glucagon-stimulated ghrelin secretion and proghrelin mRNA expression. Furthermore, glucagon treatment increased the phosphorylation of ERK1/2. Glucagon also increased intracellular cAMP levels, and inhibition of adenylate cyclase reduced glucagon's effect on ghrelin secretion. Surprisingly, inhibiting protein kinase A (PKA) (using H89 and phosphorothioate [Rp]-cAMP) did not prevent glucagon-stimulated ghrelin secretion. Instead, inhibiting the exchange protein activated by cAMP (EPAC) with Brefeldin-A was able to significantly reduce glucagon-stimulated ghrelin secretion. Furthermore, the EPAC agonist (8-pCPT) significantly stimulated ghrelin secretion. Depleting endoplasmic reticulum calcium stores or blocking voltage-dependant calcium channels prevented glucagon stimulated ghrelin secretion. Finally, co-incubation with the sympathetic neurotransmitter norepinephrine potentiated the glucagon stimulation of ghrelin secretion. Our findings are the first to show a direct link between glucagon and stomach ghrelin production and secretion and highlight the role of MAPK, the PKA-independent EPAC pathway, and the synergy between norepinephrine and glucagon in ghrelin release.

  8. Possible association of norepinephrine transporter -3081(A/T polymorphism with methylphenidate response in attention deficit hyperactivity disorder

    Directory of Open Access Journals (Sweden)

    Shin Min-Sup

    2010-10-01

    Full Text Available Abstract Background Attention-deficit/hyperactivity disorder (ADHD is a heritable disorder characterized by symptoms of inattention and/or hyperactivity/impulsivity. Methylphenidate (MPH has been shown to block the norepinephrine transporter (NET, and genetic investigations have demonstrated that the norepinephrine transporter gene (SLC6A2 is associated with ADHD. The aims of this study were to examine the association of the SLC6A2 -3081(A/T and G1287A polymorphisms with MPH response in ADHD. Methods This study enrolled 112 children and adolescents with ADHD. A response criterion was defined based on the Clinical Global Impression-Improvement (CGI-I score, and the ADHD Rating Scale-IV (ARS score was also assessed at baseline and 8 weeks after MPH treatment. Results We found that the subjects who had the T allele as one of the alleles (A/T or T/T genotypes at the -3081(A/T polymorphism showed a better response to MPH treatment than those with the A/A genotype as measured by the CGI-I. We also found a trend towards a difference in the change of the total ARS scores and hyperactivity/impulsivity subscores between subjects with and without the T allele. No significant association was found between the genotypes of the SLC6A2 G1287A polymorphism and response to ADHD treatment. Conclusion Our findings provide evidence for the involvement of the -3081(A/T polymorphism of SLC6A2 in the modulation of the effectiveness of MPH treatment in ADHD.

  9. Effect of Selective Serotonin Reuptake Inhibitors and Immunomodulator on Cytokines Levels: An Alternative Therapy for Patients with Major Depressive Disorder

    Science.gov (United States)

    Hernandez, María Eugenia; Mendieta, Danelia; Pérez-Tapia, Mayra; Bojalil, Rafael; Estrada-Parra, Sergio; Pavón, Lenin

    2013-01-01

    Major depressive disorder (MDD) is a psychiatric illness that presents as a deficit of serotonergic neurotransmission in the central nervous system. MDD patients also experience alterations in cortisol and cytokines levels. Treatment with selective serotonin reuptake inhibitors (SSRIs) is the first-line antidepressant regimen for MDD. The aim of this study was to determine the effect of a combination of SSRIs and an immunomodulator—human dialyzable leukocyte extract (hDLE)—on cortisol and cytokines levels. Patients received SSRIs or SSRIs plus hDLE. The proinflammatory cytokines IL-1β, IL-2, and IFN-γ; anti-inflammatory cytokines IL-13 and IL-10; and 24-h urine cortisol were measured at weeks (W) 0, 5, 20, 36, and 52 of treatment. The reduction in cortisol levels in the SSRI-treated group was 30% until W52, in contrast, the combined treatment induced a 54% decrease at W36. The decline in cortisol in patients who were treated with SSRI plus hDLE correlated with reduction of anti-inflammatory cytokines and increases levels of proinflammatory cytokines at the study conclusion. These results suggest that the immune-stimulating activity of hDLE, in combination with SSRIs, restored the pro- and anti-inflammatory cytokine balance and cortisol levels in depressed patients versus those who were given SSRIs alone. PMID:24348675

  10. Anti-inflammatory drugs as moderators of antidepressant effects, especially those of the selective serotonin-reuptake inhibitor class.

    Science.gov (United States)

    Kronenberg, Sefi

    2011-09-01

    Large studies examining remission rates obtained by antidepressants have yielded somewhat dismal results. In the well-reported Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, only 36.8% of patients exhibited remission with the selective serotonin-reuptake inhibitor (SSRI) citalopram and the cumulative remission rate was 67% after multiple treatments were attempted. Warner-Schmidt et al. recently published an interesting paper that suggests specific mechanisms by which anti-inflammatory drugs inhibit the antidepressant effects of SSRIs. They employed well-established mouse models of depression: the tail suspension test and the forced swim test. In their experiment, ibuprofen significantly attenuated the antidepressant-like effects of SSRIs in both tests. The authors also presented data from the STAR*D study itself. These data - demonstrating higher remission rates for depressed patients receiving citalopram without concomitant NSAIDs (55.2%) than those receiving citalopram with NSAIDs (44.5%) - serve to illustrate the potential hindering effects of anti-inflammatory drugs.

  11. Differences in the dynamics of serotonin reuptake transporter occupancy may explain superior clinical efficacy of escitalopram versus citalopram.

    Science.gov (United States)

    Kasper, Siegfried; Sacher, Julia; Klein, Nikolas; Mossaheb, Nilufar; Attarbaschi-Steiner, Trawat; Lanzenberger, Rupert; Spindelegger, Christoph; Asenbaum, Susanne; Holik, Alexander; Dudczak, Robert

    2009-05-01

    Escitalopram the S-enantiomer of the racemate citalopram, is clinically more effective than citalopram in the treatment of major depressive disorder. However, the precise mechanism by which escitalopram achieves superiority over citalopram is yet to be determined. It has been hypothesized that the therapeutically inactive R-enantiomer competes with the serotonin-enhancing S-enantiomer at a low-affinity allosteric site on serotonin reuptake transporters (SERTs), and reduces the effectiveness of the S-enantiomer at the primary, high-affinity serotonin-binding site. This study summarizes the results of two recent single-photon emission computerized tomography studies measuring SERT occupancy in citalopram-treated and escitalopram-treated healthy volunteers, after a single dose and multiple doses (i.e. under steady-state conditions). The single-dose study showed no attenuating effect of R-citalopram. After multiple dosing, however, SERT occupancy was significantly reduced in the presence of R-citalopram. Under steady-state conditions, R-enantiomer concentrations were greater than for the S-enantiomer because of slower clearance of R-citalopram. A pooled analysis suggests that build-up of the R-enantiomer after repeated citalopram dosing may lead to increased inhibition of S-enantiomer occupancy of SERT. This review adds to the growing body of evidence regarding differences in the dynamics of SERT occupancy, that is, molecular mechanisms underlying the often-observed superior clinical efficacy of escitalopram compared with citalopram in major depressive disorder.

  12. Comparison of paroxetine and dapoxetine, a novel selective serotonin reuptake inhibitor in the treatment of premature ejaculation

    Institute of Scientific and Technical Information of China (English)

    Abdulmuttalip Simsek; Sinan Levent Kirecci; Onur Kucuktopcu; Faruk Ozgor; Mehmet Fatih Akbulut; Omer Sarilar; Unsal Ozkuvanci; Zafer Gokhan Gurbuz

    2014-01-01

    Dapoxetine hydrochloride is a selective serotonin reuptake inhibitor and the ifrst drug approved for the on‑demand treatment of premature ejaculation(PE). Our objective in this study was to characterize the efifcacy of on‑demand dapoxetine(30 and 60mg) and daily paroxetine(20mg) usage in treating PE. We conducted a 1 month study involving a total of 150patients. Patients were divided into three groups of 50. Group1 were treated with on‑demand dapoxetine(30mg), Group2 with on‑demand dapoxetine(60mg) and Group3 with daily paroxetine(20mg). Our outcome measurement was increased from baseline intravaginal ejaculatory latency time(IELT) after treatment. The IELT increased from baseline to posttreatment by 117%, 117% and 170% in the paroxetine group(P0.05), while the 60mg dapoxetine group had a larger posttreatment IELT increase compared with the 30mg dapoxetine(P<0.05) and paroxetine(P<0.01) groups. Dapoxetine(60mg) 1–3h before planned intercourse is a very effective treatment modality for PE. However, an on‑demand dose of 30mg dapoxetine is no more effective than the currently prescribed paroxetine treatment.

  13. The gender difference of selective serotonin reuptake inhibitor, fluoxetine in adult rats with stress-induced gastric ulcer.

    Science.gov (United States)

    Abdel-Sater, Khaled A; Abdel-Daiem, Wafaa M; Sayyed Bakheet, Mohamad

    2012-08-01

    We investigated the gender difference of selective serotonin reuptake inhibitor, fluoxetine in adult rats with stress-induced gastric ulcer. The rats were randomly divided into six groups: Group I, control males and group II, control females; group III, acute cold restraint stressed males and group IV, acute cold restraint stressed females; group V, fluoxetine-treated stressed males and group VI, fluoxetine-treated stressed females. Acute cold restraint stress was established by fixing the four limbs of the rat and placing it in a refrigerator at 4°C for 3h. Fluoxetine was given intraperitoneal in a single dose of 10mg/kg/day. After 2 weeks, stomach and brain tissues were collected for the assay of gastric malonaldehyde (MDA), catalase, nitric oxide (NO) and cortical gamma aminobutyric acid (GABA). Stressed animals exhibited increased total acidity in association with decreased gastric secretion volume. Gastric MDA was increased while gastric catalase, NO, and cortical GABA were decreased in stressed male rats when compared to stressed females. However, fluoxetine administration attenuated these stress-induced changes especially in stressed male animals. Stressed male rats were more responsive to the antiulcer effect of fluoxetine more than stressed females. However, fluoxetine might be considered to be the first-choice drug in depressive patients with gastric ulcers in the future.

  14. Effects of selective serotonin reuptake inhibitor on treating tinnitus in patients stratified for presence of depression or anxiety.

    Science.gov (United States)

    Oishi, Naoki; Kanzaki, Sho; Shinden, Seiichi; Saito, Hideyuki; Inoue, Yasuhiro; Ogawa, Kaoru

    2010-01-01

    We evaluated the effects of a selective serotonin reuptake inhibitor, paroxetine, on treating tinnitus.Tinnitus patients stratified for the presence of depression and anxiety were studied retrospectively. Fifty-six patients were observed for more than 6 months. They were initially treated with paroxetine only at a dose of 10 mg/day for 2-4 weeks; thereafter, the dose was increased to 20 mg/day. Tinnitus distress was evaluated with the Tinnitus Handicap Inventory (THI) and with visual analog scales (VASs) for tinnitus loudness and annoyance. Depression and anxiety were measured with the Self-Rating Depression Scale (SDS) and the trait section of the State-Trait Anxiety Inventory (STAI). The patients were grouped according to their SDS and STAI scores, and each variable was compared at baseline and the 6-month follow-up. Changes among these variables were also examined to determine whether reduced tinnitus distress was related to the improvement of depression or anxiety. Patients with both depression and anxiety showed better results (decrease in THI, VASs, SDS and STAI scores) than patients with anxiety alone, or patients without depression and anxiety. In patients with depression and anxiety, changes in tinnitus variables and changes in depression and anxiety scores were strongly correlated. In other patients, however, changes in tinnitus variables and changes in depression and anxiety scores were not correlated. These results suggest that paroxetine is effective in treating distressed tinnitus patients with depression and anxiety by reducing their tinnitus severity as well as their depression and anxiety.

  15. The effects of combining serotonin reuptake inhibition and 5-HT7 receptor blockade on circadian rhythm regulation in rodents.

    Science.gov (United States)

    Westrich, Ligia; Sprouse, Jeffrey; Sánchez, Connie

    2013-02-17

    Disruption of circadian rhythms may lead to mood disorders. The present study investigated the potential therapeutic utility of combining a 5-HT7 antagonist with a selective serotonin (5-HT) reuptake inhibitor (SSRI), the standard of care in depression, on circadian rhythm regulation. In tissue explants of the suprachiasmatic nucleus (SCN) from PER2::LUC mice genetically modified to report changes in the expression of a key clock protein, the period length of PER2 bioluminescence was shortened in the presence of AS19, a 5-HT7 partial agonist. This reduction was blocked by SB269970, a selective 5-HT7 antagonist. The SSRI, escitalopram, had no effect alone on period length, but a combination with SB269970, yielded significant increases. Dosed in vivo, escitalopram had little impact on the occurrence of activity onsets in rats given access to running wheels, whether the drug was given acutely or sub-chronically. However, preceding the escitalopram treatment with a single acute dose of SB269970 produced robust phase delays, in keeping with the in vitro explant data. Taken together, these findings suggest that the combination of an SSRI and a 5-HT7 receptor antagonist has a greater impact on circadian rhythms than that observed with either agent alone, and that such a multimodal approach may be of therapeutic value in treating patients with poor clock function.

  16. Comparison of paroxetine and dapoxetine, a novel selective serotonin reuptake inhibitor in the treatment of premature ejaculation

    Directory of Open Access Journals (Sweden)

    Abdulmuttalip Simsek

    2014-10-01

    Full Text Available Dapoxetine hydrochloride is a selective serotonin reuptake inhibitor and the first drug approved for the on-demand treatment of premature ejaculation (PE. Our objective in this study was to characterize the efficacy of on-demand dapoxetine (30 and 60 mg and daily paroxetine (20 mg usage in treating PE. We conducted a 1 month study involving a total of 150 patients. Patients were divided into three groups of 50. Group 1 were treated with on-demand dapoxetine (30 mg, Group 2 with on-demand dapoxetine (60 mg and Group 3 with daily paroxetine (20 mg. Our outcome measurement was increased from baseline intravaginal ejaculatory latency time (IELT after treatment. The IELT increased from baseline to posttreatment by 117%, 117% and 170% in the paroxetine group (P 0.05, while the 60 mg dapoxetine group had a larger posttreatment IELT increase compared with the 30 mg dapoxetine (P < 0.05 and paroxetine (P < 0.01 groups. Dapoxetine (60 mg 1-3 h before planned intercourse is a very effective treatment modality for PE. However, an on-demand dose of 30 mg dapoxetine is no more effective than the currently prescribed paroxetine treatment.

  17. Effect of Selective Serotonin Reuptake Inhibitors and Immunomodulator on Cytokines Levels: An Alternative Therapy for Patients with Major Depressive Disorder

    Directory of Open Access Journals (Sweden)

    María Eugenia Hernandez

    2013-01-01

    Full Text Available Major depressive disorder (MDD is a psychiatric illness that presents as a deficit of serotonergic neurotransmission in the central nervous system. MDD patients also experience alterations in cortisol and cytokines levels. Treatment with selective serotonin reuptake inhibitors (SSRIs is the first-line antidepressant regimen for MDD. The aim of this study was to determine the effect of a combination of SSRIs and an immunomodulator—human dialyzable leukocyte extract (hDLE—on cortisol and cytokines levels. Patients received SSRIs or SSRIs plus hDLE. The proinflammatory cytokines IL-1β, IL-2, and IFN-γ; anti-inflammatory cytokines IL-13 and IL-10; and 24-h urine cortisol were measured at weeks (W 0, 5, 20, 36, and 52 of treatment. The reduction in cortisol levels in the SSRI-treated group was 30% until W52, in contrast, the combined treatment induced a 54% decrease at W36. The decline in cortisol in patients who were treated with SSRI plus hDLE correlated with reduction of anti-inflammatory cytokines and increases levels of proinflammatory cytokines at the study conclusion. These results suggest that the immune-stimulating activity of hDLE, in combination with SSRIs, restored the pro- and anti-inflammatory cytokine balance and cortisol levels in depressed patients versus those who were given SSRIs alone.

  18. Dependence and withdrawal reactions to benzodiazepines and selective serotonin reuptake inhibitors. How did the health authorities react?

    Science.gov (United States)

    Nielsen, Margrethe; Hansen, Ebba Holme; Gøtzsche, Peter C

    2013-01-01

    Our objective was to explore communications from drug agencies about benzodiazepine dependence and selective serotonin reuptake inhibitors (SSRIs) withdrawal reactions over time. Documentary study. We searched the web-sites of the European Medicines Agency and the drug agencies in USA, UK, and Denmark for documents mentioning benzodiazepines or SSRIs. We supplemented with other relevant literature that could contribute to our study. The searches were performed in 2009 in PubMed, Google, BMJ and JAMA. It took many years before the drug regulators acknowledged benzodiazepine dependence and SSRI withdrawal reactions and before the prescribers and the public were informed. Drug regulators relied mainly on the definitions of dependence and withdrawal reactions from the diagnostic psychiatric manuals, which contributed to the idea that SSRIs do not cause dependence, although it is difficult for many patients to stop treatment. In the perspective of a precautionary principle, drug agencies have failed to acknowledge that SSRIs can cause dependence and have minimised the problem with regard to its frequency and severity. In the perspective of a risk management principle, the drug agencies have reacted in concordance with the slowly growing knowledge of adverse drug reactions and have sharpened the information to the prescribers and the public over time. However, solely relying on spontaneous reporting of adverse effects leads to underestimation and delayed information about the problems. Given the experience with the benzodiazepines, we believe the regulatory bodies should have required studies from the manufacturers that could have elucidated the dependence potential of the SSRIs before marketing authorization was granted.

  19. Early malnourished rats are not affected by anorexia induced by a selective serotonin reuptake inhibitor in adult life.

    Science.gov (United States)

    Barreto Medeiros, J M; Cabral Filho, J E; De Souza, S L; Freitas Silva, S R; Mendes Da Silva, C; Deiró, T C B J; Monteiro, J M; Guedes, R C A; De Castro, C M M B; Manhães De Castro, R

    2002-06-01

    The effect of early postnatal malnutrition upon food intake and its modulation by the selective serotonin reuptake inhibitor (SSRI) citalopram, was investigated in adult rats. Sixty four Wistar rats were allocated to two groups, according to their mother's diet during lactation. Mothers receiving a 23% protein diet fed the well-nourished group; mothers receiving 8% protein diet fed the malnourished. After weaning, all rats received the 23% protein diet ad libitum. On the 120th day after birth, each nutritional group was divided in two subgroups (each one, n = 16) which received a single daily injection of citalopram (10 mg/kg) or saline (0.9% NaCl) for 14 days. Chronic treatment with citalopram decreased both the food intake and weight gain in the well-nourished rats, but not in the malnourished ones. These data are consistent with findings concerning the nutritional manipulation of the nervous system during its higher vulnerable phase, suggesting that early malnutrition alters the effect of treatment of SSRI in adult rats, and that malnutrition during the critical period of brain development affects the serotoninergic system.

  20. The Risk of Congenital Heart Anomalies Following Prenatal Exposure to Serotonin Reuptake Inhibitors—Is Pharmacogenetics the Key?

    Science.gov (United States)

    Daud, Aizati N. A.; Bergman, Jorieke E. H.; Kerstjens-Frederikse, Wilhelmina S.; Groen, Henk; Wilffert, Bob

    2016-01-01

    Serotonin reuptake inhibitors (SRIs) are often prescribed during pregnancy. Previous studies that found an increased risk of congenital anomalies, particularly congenital heart anomalies (CHA), with SRI use during pregnancy have created concern among pregnant women and healthcare professionals about the safety of these drugs. However, subsequent studies have reported conflicting results on the association between CHA and SRI use during pregnancy. These discrepancies in the risk estimates can potentially be explained by genetic differences among exposed individuals. In this review, we explore the potential pharmacogenetic predictors involved in the pharmacokinetics and mechanism of action of SRIs, and their relation to the risk of CHA. In general, the risk is dependent on the maternal concentration of SRIs and the foetal serotonin level/effect, which can be modulated by the alteration in the expression and/or function of the metabolic enzymes, transporter proteins and serotonin receptors involved in the serotonin signalling of the foetal heart development. Pharmacogenetics might be the key to understanding why some children exposed to SRIs develop a congenital heart anomaly and others do not. PMID:27529241

  1. Megalin-mediated reuptake of retinol in the kidneys of mice is essential for vitamin A homeostasis.

    Science.gov (United States)

    Raila, Jens; Willnow, Thomas E; Schweigert, Florian J

    2005-11-01

    The reuptake of retinol (ROH) and retinol-binding protein (RBP) in the kidneys is mediated by the endocytic receptor megalin, suggesting an important role for this receptor in vitamin A (VA) metabolism. We examined the extent to which megalin deficiency may affect urinary ROH excretion, levels of ROH and RBP in plasma, as well as storage of VA in liver and kidney. For this purpose, mice with a kidney-specific megalin gene defect (megalin(lox/lox); apoE(Cre)) and control mice (megalin(lox/lox)) were fed either a basal diet containing 4500 retinol equivalents (RE)/kg diet or a diet without VA during experimental periods of 42 and 84 d. Urinary ROH excretion was observed only in megalin(lox/lox); apoE(Cre) mice (P levels in the liver (P levels of VA were not affected by the receptor gene defect. The findings demonstrate that urinary ROH excretion caused by megalin deficiency requires accelerated mobilization of hepatic VA stores to maintain normal plasma ROH levels, which suggests that megalin plays an essential role in systemic VA homeostasis.

  2. Effect of selective serotonin reuptake inhibitors and immunomodulator on cytokines levels: an alternative therapy for patients with major depressive disorder.

    Science.gov (United States)

    Hernandez, María Eugenia; Mendieta, Danelia; Pérez-Tapia, Mayra; Bojalil, Rafael; Estrada-Garcia, Iris; Estrada-Parra, Sergio; Pavón, Lenin

    2013-01-01

    Major depressive disorder (MDD) is a psychiatric illness that presents as a deficit of serotonergic neurotransmission in the central nervous system. MDD patients also experience alterations in cortisol and cytokines levels. Treatment with selective serotonin reuptake inhibitors (SSRIs) is the first-line antidepressant regimen for MDD. The aim of this study was to determine the effect of a combination of SSRIs and an immunomodulator-human dialyzable leukocyte extract (hDLE)-on cortisol and cytokines levels. Patients received SSRIs or SSRIs plus hDLE. The proinflammatory cytokines IL-1 β , IL-2, and IFN- γ ; anti-inflammatory cytokines IL-13 and IL-10; and 24-h urine cortisol were measured at weeks (W) 0, 5, 20, 36, and 52 of treatment. The reduction in cortisol levels in the SSRI-treated group was 30% until W52, in contrast, the combined treatment induced a 54% decrease at W36. The decline in cortisol in patients who were treated with SSRI plus hDLE correlated with reduction of anti-inflammatory cytokines and increases levels of proinflammatory cytokines at the study conclusion. These results suggest that the immune-stimulating activity of hDLE, in combination with SSRIs, restored the pro- and anti-inflammatory cytokine balance and cortisol levels in depressed patients versus those who were given SSRIs alone.

  3. A meta-analysis on the efficacy and safety of St John's wort extract in depression therapy in comparison with selective serotonin reuptake inhibitors in adults

    OpenAIRE

    Cui YH; Zheng Y.

    2016-01-01

    Yong-hua Cui,1 Yi Zheng1,2 1Department of Pediatrics, Beijing An’ding Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Beijing Institutes of Brain Disorders, Beijing, People’s Republic of China Objective: The aim of the study was to investigate the efficacy and safety of St John’s wort extract and selective serotonin reuptake inhibitors (SSRIs) in the treatment of depression.Methods: Databases were searched for studies compa...

  4. [The comparative study on the efficacy of the combination of serotonin reuptake inhibitor antidepressants and antipsychotics in the treatment of recurrent depressive disorders].

    Science.gov (United States)

    D'iakonov, A L; Lobanova, I V

    2012-01-01

    A combination of serotonin reuptake inhibitor antidepressants (prozac and stimulaton) with atypical antipsychotics (zyprexa and solian) reduced depression in patients with recurrent depressive disorders during 10 days. The effect was evenly distributed between 10, 20 and 40 days of treatment. Other symptoms had a peculiar dynamics depending on the therapy. By the end of the study, similar effects were achieved for all groups. The addition of antipsychotics to antidepressant treatment insignificantly increased the number of adverse events.

  5. Comparison of monoamine reuptake inhibitors for the immobility time and serotonin levels in the hippocampus and plasma of sub-chronically forced swim stressed rats.

    Science.gov (United States)

    Abbas, Ghulam; Naqvi, Sabira; Dar, Ahsana

    2012-04-01

    The current study was aimed at comparing the behavioral and biochemical (5-hydroxytryptamine and 5-hydroxyindoleacetic acid levels) effects of monoamine reuptake inhibitors (fluoxetine, venlafaxine and imipramine) in sub-chronically forced swim stressed rats. At the given doses of 10, 20 and 30 mg/kg, among aforesaid antidepressants, the imipramine treatment alone caused significant decline in the immobility time of rats (IC(50) 20 mg/kg). In the hippocampus of rats, the imipramine treatment caused significant elevation of 5-hydroxytryptamine (5-HT) whereas, the fluoxetine and venlafaxine elicited significant increase in 5-hydroxyindoleacetic acid (5-HIAA) levels. Likewise, in the plasma of rats, the imipramine treatment significantly increased the 5-HIAA levels whereas, the fluoxetine and venlafaxine treatment significantly elevate the 5-HT levels. It can therefore be inferred that the imipramine did not act like other monoamine reuptake inhibitors in biochemical study, which could possibly underlie its ability to be detected in forced swim test (behavioral study). Moreover, the re-uptake inhibition of 5-HT is not accountable for the antidepressant action exhibited in forced swim test.

  6. A Comparative Study of the Efficiency of Using Non-Selective Nonsteroidal Anti-Inflammatory Drugs in Patients with Endoprosthetic Total Knee and Hip Arthroplasty

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    V. V. Logvinenko

    2012-01-01

    Full Text Available Objective: to compare the postoperative efficacy and safety of non-selective nonsteroidal anti-inflammatory drugs in patients undergoing endoprosthetic total knee and hip arthroplasty (ETKAP and ETHAP. Subjects and methods. The study included 60 patients who were referred for ETKAP or ETHAP and randomly assigned to 3 groups. Groups 1, 2, and 3 patients were anesthetized with ketorolac, metamizol, and paracetamol, respectively. Real-time evaluation of the efficiency of postoperative analgesia was carried out within 3 days after surgery; the patients were questioned about bowel function, the onset of the first active movement in the ward, and occurring unpleasant sensations. Results. Reduced or no appetite was more common in the paracetamol and metamizol groups than in the ketorolac; the paracetamol group was found to have dizziness in 20% of cases, which was not observed in the two other groups. The patients who started to have routine hospital diet in the first 24 postoperative hours were significantly fewer among the paracetamol-treated patients. The shortest time to the first active movement was observed in the ketorolac group, which corresponded to the end of the first 24 hours and significantly distinguished it from the other groups. This appeared to be due to the best analgesic effect that, after epidural block, was significantly more effective (according to VAS scores in the ketorolac group, if not enhanced in any group, which agrees with information available on the drug as a worthy alternative to opioids due to its valid analgesic effect. Conclusion. __Intravenous ketorolac is a worthy alternative to narcotic analgesics in ensuring the comfortable course of the immediate postoperative period in patients operated on the knee and hip joints. Key words: ketorolac (ketorol, postoperative analgesia, endoprosthetic knee and hip arthroplasty.

  7. Effect of selective and non-selective serotonin receptor activation on L-DOPA-induced therapeutic efficacy and dyskinesia in parkinsonian rats.

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    Tronci, E; Fidalgo, C; Stancampiano, R; Carta, M

    2015-10-01

    Selective activation of 5-HT1 receptors has been shown to produce near to full suppression of L-DOPA-induced dyskinesia (LID) in animal models of Parkinson's disease; however, a reduction of the therapeutic effect of L-DOPA has been reported in several studies. Conversely, we recently found that increasing the serotonergic tone with chronic administration of the serotonin precursor 5-hydroxy-tryptophan (5-HTP) can reduce LID in 6-OHDA-lesioned rats, without affecting L-DOPA efficacy. To directly compare the effects of selective versus non-selective serotonin receptor activation, here we first tested different acute doses of the 5-HT1A/1B receptor agonist eltoprazine and 5-HTP on LID in order to identify doses of the individual compounds showing similar anti-dyskinetic efficacy in L-DOPA-primed dyskinetic rats. About 50% reduction of LID was observed with 0.1 mg/kg and 24 mg/kg of eltoprazine and 5-HTP, respectively; we then compared the effect of the two drugs, individually and in combination, on L-DOPA-induced stepping test in L-DOPA-naïve parkinsonian animals and LID over three weeks of L-DOPA treatment. Results showed that eltoprazine induced significant worsening of L-DOPA-mediated performance in the stepping test, while 5-HTP did not. Interestingly, combination of 5-HTP with eltoprazine prevented the reduction in the forelimb use induced by eltoprazine. Moreover, 5-HTP and eltoprazine given individually showed similar efficacy also upon chronic treatment, and had additive effect in dampening the appearance of LID when given in combination. Finally, chronic administration of eltoprazine and/or 5-HTP did not affect striatal serotonin innervation, compared to l-DOPA alone, as measured by serotonin transporter expression.

  8. Design of non-selective refocusing pulses with phase-free rotation axis by gradient ascent pulse engineering algorithm in parallel transmission at 7T.

    Science.gov (United States)

    Massire, Aurélien; Cloos, Martijn A; Vignaud, Alexandre; Le Bihan, Denis; Amadon, Alexis; Boulant, Nicolas

    2013-05-01

    At ultra-high magnetic field (≥ 7T), B1 and ΔB0 non-uniformities cause undesired inhomogeneities in image signal and contrast. Tailored radiofrequency pulses exploiting parallel transmission have been shown to mitigate these phenomena. However, the design of large flip angle excitations, a prerequisite for many clinical applications, remains challenging due the non-linearity of the Bloch equation. In this work, we explore the potential of gradient ascent pulse engineering to design non-selective spin-echo refocusing pulses that simultaneously mitigate severe B1 and ΔB0 non-uniformities. The originality of the method lays in the optimization of the rotation matrices themselves as opposed to magnetization states. Consequently, the commonly used linear class of large tip angle approximation can be eliminated from the optimization procedure. This approach, combined with optimal control, provides additional degrees of freedom by relaxing the phase constraint on the rotation axis, and allows the derivative of the performance criterion to be found analytically. The method was experimentally validated on an 8-channel transmit array at 7T, using a water phantom with B1 and ΔB0 inhomogeneities similar to those encountered in the human brain. For the first time in MRI, the rotation matrix itself on every voxel was measured by using Quantum Process Tomography. The results are complemented with a series of spin-echo measurements comparing the proposed method against commonly used alternatives. Both experiments confirm very good performance, while simultaneously maintaining a low energy deposition and pulse duration compared to well-known adiabatic solutions. Copyright © 2013 Elsevier Inc. All rights reserved.

  9. Oxidative transformation of micropollutants during municipal wastewater treatment: comparison of kinetic aspects of selective (chlorine, chlorine dioxide, ferrate VI, and ozone) and non-selective oxidants (hydroxyl radical).

    Science.gov (United States)

    Lee, Yunho; von Gunten, Urs

    2010-01-01

    Chemical oxidation processes have been widely applied to water treatment and may serve as a tool to minimize the release of micropollutants (e.g. pharmaceuticals and endocrine disruptors) from municipal wastewater effluents into the aquatic environment. The potential of several oxidants for the transformation of selected micropollutants such as atenolol, carbamazepine, 17 alpha-ethinylestradiol (EE2), ibuprofen, and sulfamethoxazole was assessed and compared. The oxidants include chlorine, chlorine dioxide, ferrate(VI), and ozone as selective oxidants versus hydroxyl radicals as non-selective oxidant. Second-order rate constants (k) for the reaction of each oxidant show that the selective oxidants react only with some electron-rich organic moieties (ERMs), such as phenols, anilines, olefins, and deprotonated-amines. In contrast, hydroxyl radicals show a nearly diffusion-controlled reactivity with almost all organic moieties (k>or=10(9)M(-1) s(-1)). Due to a competition for oxidants between a target micropollutant and wastewater matrix (i.e. effluent organic matter, EfOM), a higher reaction rate with a target micropollutant does not necessarily translate into more efficient transformation. For example, transformation efficiencies of EE2, a phenolic micropollutant, in a selected wastewater effluent at pH 8 varied only within a factor of 7 among the selective oxidants, even though the corresponding k for the reaction of each selective oxidant with EE2 varied over four orders of magnitude. In addition, for the selective oxidants, the competition disappears rapidly after the ERMs present in EfOM are consumed. In contrast, for hydroxyl radicals, the competition remains practically the same during the entire oxidation. Therefore, for a given oxidant dose, the selective oxidants were more efficient than hydroxyl radicals for transforming ERMs-containing micropollutants, while hydroxyl radicals are capable of transforming micropollutants even without ERMs. Besides Ef

  10. A trs20 mutation that mimics an SEDT-causing mutation blocks selective and non-selective autophagy: a model for TRAPP III organization.

    Science.gov (United States)

    Brunet, Stephanie; Shahrzad, Nassim; Saint-Dic, Djenann; Dutczak, Hartley; Sacher, Michael

    2013-10-01

    TRAPP is a multisubunit complex that functions in membrane traffic. Mutations in the mammalian TRAPP protein C2 are linked to the skeletal disorder spondyloepiphyseal dysplasia tarda (SEDT) that is thought to arise from an inability to secrete procollagen from the endoplasmic reticulum. Here, we show that C2 binds to the SNARE protein Syntaxin 5 and this interaction is weakened by an SEDT-causing missense mutation (D47Y). Interestingly, the equivalent mutation (D46Y) in the yeast C2 homolog Trs20p does not block anterograde traffic but did affect endocytosis. The trs20D46Y mutation interfered with the interaction between Trs20p and Trs85p (TRAPP III-specific subunit), Trs120p and Trs130p (TRAPP II-specific subunits). Size exclusion chromatography suggested that this yeast mutation destabilized the TRAPP III complex that is involved in autophagy. We further show that this mutation blocks both the selective cytosol-to-vacuole (cvt) pathway as well as non-selective autophagy. We demonstrate that the apparent molecular size of the TRAPP III complex is dependent upon membranes, and that the presence of TRAPP III is dependent upon Atg9p. Finally, we demonstrate that lipidated Bet3p is enriched in TRAPP III and that lipidation increases the efficiency of autophagy. Our study suggests that Trs20p acts as an adaptor for Trs85p and Trs120p and reveals complexities in TRAPP III assembly and function. The implications of C2D47Y in SEDT are discussed. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  11. Reduction of progressive burn injury by using a new nonselective endothelin-A and endothelin-B receptor antagonist, TAK-044: an experimental study in rats.

    Science.gov (United States)

    Battal, M N; Hata, Y; Matsuka, K; Ito, O; Matsuda, H; Yoshida, Y; Kawazoe, T

    1997-05-01

    Endothelins are well-known vasoconstrictor peptides produced by vascular endothelial cells that have been reported to have a fundamental role in regulation of the systemic blood circulation. Plasma levels of endothelins are increased by burn injury, which also causes thrombosis and occlusion of vessels in the dermis as well as a vascular response in the adjacent uninjured dermis. Diminished blood flow leads to progressive ischemia and necrosis of the dermis beneath and around the burn (zone of stasis). If blood flow could be restored in this zone, secondary tissue damage would be minimized. In this study we examined the effects of a new nonselective endothelin receptor antagonist, TAK-044 (Takeda Chemical Industries, Ltd., Osaka, Japan), on burn trauma in rats. Fifty male Sprague-Dawley rats weighing an average of 450 gm were burned with a brass probe that produced a row of three burns 10 x 30 mm in size and two intervening unburned areas 5 x 30 mm in size. Rats were divided into five groups of 10 animals. Four groups received 0.01, 0.1, 1 or 10 mg/kg of TAK-044 via the dorsal vein of the penis immediately after burn trauma, while the control group received the same volume of saline. Skin blood flow was measured with a laser-Doppler flowmeter, and the development of edema and the area of necrotic tissue also were determined. Inhibition of endothelin activity by TAK-044 after burn injury improved microvascular perfusion in the zone of stasis and prevented the progression of tissue damage in this zone. This supports the role of endothelins in the progression of burn injury in the zone of stasis. TAK-044 was most effective in preventing progressive burn damage at a dose of 1 mg/kg. The extent of necrosis and edema was reduced significantly, and blood flow in the zone of stasis was increased in the treated rats.

  12. The selective and non-selective cyclooxygenase inhibitors valdecoxib and piroxicam induce the same postoperative analgesia and control of trismus and swelling after lower third molar removal

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    V. Benetello

    2007-08-01

    Full Text Available We compared the clinical efficacy of orally administered valdecoxib and piroxicam for the prevention of pain, trismus and swelling after removal of horizontally and totally intrabony impacted lower third molars. Twenty-five patients were scheduled to undergo removal of symmetrically positioned lower third molars in two separate appointments. Valdecoxib (40 mg or piroxicam (20 mg was administered in a double-blind, randomized and crossed manner for 4 days after the surgical procedures. Objective and subjective parameters were recorded for comparison of postoperative courses. Both agents were effective for postoperative pain relief (N = 19. There was a similar mouth opening at suture removal compared with the preoperative values (86.14 ± 4.36 and 93.12 ± 3.70% of the initial measure for valdecoxib and piroxicam, respectively; ANOVA. There was no significant difference regarding the total amount of rescue medication taken by the patients treated with valdecoxib or piroxicam (173.08 ± 91.21 and 461.54 ± 199.85 mg, respectively; Wilcoxon test. There were no significant differences concerning the swelling observed on the second postoperative day compared to baseline measures (6.15 ± 1.84 and 8.46 ± 2.04 mm for valdecoxib and piroxicam, respectively; ANOVA or on the seventh postoperative day (1.69 ± 1.61 and 2.23 ± 2.09 mm for valdecoxib and piroxicam, respectively; ANOVA. The cyclooxygenase-2 selective inhibitor valdecoxib is as effective as the non-selective cyclooxygenase inhibitor piroxicam for pain, trismus and swelling control after removal of horizontally and totally intrabony impacted lower third molars.

  13. A COMPARATIVE STUDY OF CHAIN DYNAMICS OF DI-AND TRI-BLOCK COPOLYMERS IN SEMIDILUTE SOLUTION IN A NON-SELECTIVE SOLVENT

    Institute of Scientific and Technical Information of China (English)

    Wei Li; Liang-zhi Hong; To Ngai; Hai-ying Huang; Tian-bai He; Chi Wu

    2004-01-01

    The chain dynamics of a pair of diblock poly(styrene-b-butadiene) (PS210-b-PB960) and triblock poly(styrene-b-butadiene-b-styrene) (PS200-b-PB1815-b-PS200) copolymers in both dilute and semidilute toluene solutions has been comparatively studied by dynamic laser light scattering. As expected, the mutual diffusion of individual chain changes into a fast cooperative diffusion of the chain segments ("blobs") between two neighboring entanglement points for both the copolymers as the solution changes from dilute to semidilute. Further increases of the concentration lead to a second slow relaxation mode. For the triblock chains, there exists an additional middle relaxation between the fast and the slow modes.with 0.33 <α< 0.44, much smaller than 0.75 predicted or 0.72 observed for linear homopolymer chains in good solvent. It implies that the solvent quality of toluene for PB might not be as good as that for PS. Due to such a difference in solubility, it is reasonable to speculate that the PB and PS blocks are transiently segregated in semidilute solution. The relaxation of these transient PB and PS richer domains leads to the observed slow relaxation. Such a speculation is supported by the appearance of an additional slow relaxation mode in the study of polyisoprene-b-polystyrene-b-polyisoprene in semidilute solution in cyclohexane, a non-selective solvent, in which we alternated the solubility difference by a variation of the solution temperature.

  14. The effect of antenatal depression and selective serotonin reuptake inhibitor treatment on nerve growth factor signaling in human placenta.

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    Helena Kaihola

    Full Text Available Depressive symptoms during pregnancy are common and may have impact on the developing child. Selective serotonin reuptake inhibitors (SSRIs are the most prescribed antidepressant treatment, but unfortunately, these treatments can also negatively affect the behavioral development and health of a child during pregnancy. In addition, serotonin (5-HT exerts neurotrophic actions with thus far not fully known effects in the offspring. The neurotrophic growth factor (NGF is involved in neuronal cell survival and differentiation, and altered placenta levels have been found to increase the risk for pregnancy complications, similar to those found in women treated with SSRIs. We therefore investigated whether the NGF signaling pathway was altered in the placenta from women treated with SSRIs (n = 12 and compared them with placenta from depressed (n = 12 and healthy mothers (n = 12. Results from immunohistochemical stainings revealed that placental NGF protein levels of SSRI-treated women were increased in both trophoblasts and endothelial cells compared with depressed and control women. In addition, downstream of the NGF receptor TrkA, increased levels of the signaling proteins ROCK2 and phosphorylated Raf-1 were found in stromal cells and a tendency towards increased levels of ROCK2 in trophoblasts and endothelial cells in SSRI-treated women when compared to healthy controls. SSRI-treated women also displayed increased levels of phosphorylated ROCK2 in all placental cell types studied in comparison with depressed and control women. Interestingly, in placental endothelial cells from depressed women, NGF levels were significantly lower compared to control women, but ROCK2 levels were increased compared with control and SSRI-treated women. Taken together, these results show that the NGF signaling and downstream pathways in the placenta are affected by SSRI treatment and/or antenatal depression. This might lead to an altered placental function, although the

  15. Environmental risk assessment of three selective serotonin reuptake inhibitors in the aquatic environment: a case study including a cocktail scenario.

    Science.gov (United States)

    Styrishave, Bjarne; Halling-Sørensen, Bent; Ingerslev, Flemming

    2011-01-01

    We present an environmental risk assessment of three selective serotonin reuptake inhibitors (SSRIs; citalopram, sertraline, and fluoxetine) in the aquatic environment based on two case scenarios. Abiotic and biotic degradation experiments and sorption estimates were used to predict environmental concentrations of three SSRIs from the wastewater of two psychiatric hospitals, the primary sector, and wastewater entering and leaving wastewater treatment plants (WWTPs). Assuming a sewage treatment retention time of 8 h, abiotic degradation was low, for all three SSRIs inhibitors, ranging between 0 and 2% for hydrolysis and 0 and 6% for photolysis. The biodegradation was also slow, ranging from 0 to 3% within an 8-h period. In untreated sewage, citalopram (CIT) and sertraline (SER) concentrations may be high enough to exert effects on the aquatic biota (CIT: 0.19-10.3 µg/L; SER: 0.14-17.1 µg/L). Removal of the pharmaceuticals is due primarily to sorption in the WWTP. Sertraline was estimated to have the highest concentrations in the sewage effluents, 4.4 and 19.9 ng/L for the two cases, respectively. In treated wastewater, individual SSRI concentrations are probably too low to exert effects on biota. By using concentration addition, a cocktail exposure scenario was estimated. The predicted concentration in the biota calculated from the cocktail effect was 0.05 and 0.16 nmol/g for the two cases, respectively, and SER was found to give the highest contribution to this cocktail effect. The results indicate that the concentrations in the wastewater effluents are one to two orders of magnitude lower than the concentrations likely to cause an effect in the aquatic biota.

  16. Which adverse effects influence the dropout rate in selective serotonin reuptake inhibitor (SSRI treatment? Results for 50,824 patients

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    Kostev, Karel

    2014-10-01

    Full Text Available [english] Background: Nowadays, selective serotonin reuptake inhibitors (SSRIs are the most frequently prescribed antidepressants due to their superior clinical efficacy, effectiveness, tolerability, and safety as compared to tricyclic antidepressants or monoamino oxidase inhibitors. However, despite these advantages SSRIs are still associated with a number of adverse drug reactions, especially in the early stages of treatment, which may lead to premature discontinuation of therapy in some cases. The aim of the present study was to assess the most common adverse drug reactions of SSRIs as well as their impact on dropout rate in a large study population.Patients and methods: Data for 50,824 patients treated for major depressive disorder with SSRIs for the first time was accessed via the Disease Analyzer database (IMS Health, Germany, providing information on SSRI adverse drug reactions and their influence on premature treatment discontinuation calculated by regression analysis. The presence of certain co-morbidities was also registered. Results: The mean age was 54.5 ± 19 years, two-thirds of the study population being female. The adverse effects mentioned most frequently were: “discomfort” of the digestive system (10%, sleep disorders (8.6%, and heart rhythm disorders (4%; however, these were of tolerable severity as they did not significantly influence the dropout rate. Contrary to that, somnolence and younger age (≤50 years in particular increased the chance of premature treatment discontinuation, while patients suffering from cardiovascular risk factors or osteoporosis tended to adhere to the therapy.Conclusions: Overall, there is high tolerability for early SSRI treatment, whereas the occurrence of somnolence leads to discontinuation.

  17. An association between initiation of selective serotonin reuptake inhibitors and suicide - a nationwide register-based case-crossover study.

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    Charlotte Björkenstam

    Full Text Available BACKGROUND: Treatment with selective serotonin reuptake inhibitors (SSRI is one of the most common treatments for depression. It is however not clear whether or not there is an increased short-term suicide risk during initiation with SSRI. METHODS: A register-based nationwide case-crossover study including 5,866 suicides, 1,698 women and 4,168 men, from the Death Register 2007-2010 in Sweden. SSRI initiation was defined as a dispensed prescription of SSRI within 28 days prior to the date of suicide with no previous dispensed prescription of SSRI within 4 months prior that prescription. The control period took place one year earlier. Odds ratio (OR was estimated using conditional logistic regression. RESULT: During the 28 day period prior to suicide 48 women and 138 men were exposed to SSRI initiation (while not being exposed in the control period and 22 women and 43 men were exposed in the control period (while not being exposed in the case period. The OR for suicide after initiation with SSRI was 2.7 (95% CI: 1.6-44 for women, and 4.3 (95% CI: 3.0-6.1 for men. The highest OR was found 8-11 days after initiation with SSRI 9.7 (95% CI: 3.0-31.7 for women and men combined. CONCLUSION: The main limitation in this study is confounding by indication, but the descriptive question is however not confounded by indication. Together with plausible biological mechanisms and previous clinical and epidemiological observations our findings, linking initiation of SSRI to increased short-term suicide risk, deserve further attention specifically in the clinical setting.

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

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    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.

  19. Determination of selective serotonin reuptake inhibitors in plasma and urine by micellar liquid chromatography coupled to fluorescence detection.

    Science.gov (United States)

    Agrawal, Nitasha; Esteve-Romero, Josep; Bose, Devasish; Dubey, Neeti Prakesh; Peris-Vicente, Juan; Carda-Broch, Samuel

    2014-08-15

    Citalopram, paroxetine and fluoxetine are selective serotonin reuptake inhibitor (SSRIs) currently used in the treatment of psychiatric disorders. We present an analytical method using micellar liquid chromatography to quantify these three drugs in pharmaceutical formulations, plasma and urine. The resolution was performed using a mobile phase of 0.075 M SDS - 6% (v/v) butanol buffered at pH 7 running through a C18 column under isocratic mode at 1 mL/min at 25°C. The analytes were eluted in less than 20 min. The fluorescence detection was programmed at the maximum excitation (236, 295 and 230 nm) and emission (310, 350 and 305 nm) wavelengths for citalopram, paroxetine and fluoxetine, respectively. The experimental procedure was expedited to 1/5 dilution of the sample in the micellar mobile phase and filtration, thus avoiding clean-up and extraction steps. An aliquot of 20 μL was injected after 80 min of preparation, to obtain maximum sensitivity. The method was validated according to the guidelines of the Food and Drug Administration (FDA) in terms of calibration range (20-500 ng/mL; r(2)>0.999), sensitivity, accuracy (91.3-103.2%), precision (<9.3%), and robustness (<6.1%). The suitability of the method was successfully evaluated by analyzing plasma and urine samples from patients treated with SSRIs and checking the content of the active principle in tablets. Thus, the method can be applied to pharmacokinetics studies and in forensic cases, as well as in quality control of commercial pharmaceutical formulations.

  20. The Comparison of Acceptance and Commitment Therapy with Selective Serotonin Reuptake Inhibitors in the Treatment of Obsessive-Compulsive Disorder

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    Yaghoob Vakili

    2014-08-01

    Full Text Available Background: The aim of this study was to compare the effectiveness of acceptance and commitment therapy (ACT, selective serotonin reuptake inhibitors (SSRIs, and the combination of ACT and SSRIs in the treatment of adults with obsessive-compulsive disorder (OCD. Materials and Methods: In This experimental study 32 outpatients meeting DSM-IV-TR criteria for OCD were randomly assigned to one of three treatment conditions: ACT, SSRIs, and combined treatment. The Yale-Brown Obsessive-Compulsive Scale (Y-BOCS, Beck Depression Inventory-II-Second edition (BDI-II, and Beck Anxiety Inventory (BAI were administered at pre- and post-treatment. Twenty-seven patients completed the study. Data were analyzed by one-way analysis of variance (ANOVAs and one - way analysis of covariance (ANCOVAs, clinically significant change, and complete remission status. Results: Analyses with ANCOVA revealed that the patients treated with ACT and combined treatment experienced a significantly greater improvement in obsessive- compulsive symptoms at post-treatment as compared to those treated with SSRIs alone. However, there were no significant differences between ACT and combined treatment on OC symptoms. In addition, no significant differences were found between all the 3 treatment groups regarding reduction in the BDI-II and BAI scores at post-treatment. Clinically significant change and complete remission status results also showed that, unlike the SSRI, the ACT and combined treatment lead to more improvement in OC symptoms. Conclusion: ACT and combined treatment are more effective than SSRIs alone in treating OC symptoms. However, it seems that adding SSRIs to ACT does not increase the effectiveness of ACT in the treatment of adults with OCD in the short-term.

  1. The effects of compound stimulus extinction and inhibition of noradrenaline reuptake on the renewal of alcohol seeking

    Science.gov (United States)

    Furlong, T M; Pan, M J; Corbit, L H

    2015-01-01

    Alcohol-related stimuli can trigger relapse of alcohol-seeking behaviors even after extended periods of abstinence. Extinction of such stimuli can reduce their impact on relapse; however, the expression of extinction can be disrupted when testing occurs outside the context where extinction learning took place, an effect termed renewal. Behavioral and pharmacological methods have recently been shown to augment extinction learning; yet, it is not known whether the improved expression of extinction following these treatments remains context-dependent. Here we examined whether two methods, compound–stimulus extinction and treatment with the noradrenaline reuptake inhibitor atomoxetine, would reduce the vulnerability of extinction to a change in context. Following alcohol self-administration, responding was extinguished in a distinct context. After initial extinction, further extinction was given to a target stimulus presented in compound with another alcohol-predictive stimulus intended to augment prediction error (Experiment 1) or after a systemic injection of atomoxetine (1.0 mg kg−1; Experiment 2). A stimulus extinguished as part of a compound elicited less responding than a stimulus receiving equal extinction alone regardless of whether animals were tested in the training or extinction context; however, reliable renewal was not observed in this paradigm. Importantly, atomoxetine enhanced extinction relative to controls even in the presence of a reliable renewal effect. Thus, extinction of alcohol-seeking behavior can be improved by extinguishing multiple alcohol-predictive stimuli or enhancing noradrenaline neurotransmission during extinction training. Importantly, both methods improve extinction even when the context is changed between extinction training and test, and thus could be utilized to enhance the outcome of extinction-based treatments for alcohol-use disorders. PMID:26327688

  2. Effect of selective serotonin reuptake inhibitors use on endocrine therapy adherence and breast cancer mortality: a population-based study.

    Science.gov (United States)

    Valachis, Antonis; Garmo, Hans; Weinman, John; Fredriksson, Irma; Ahlgren, Johan; Sund, Malin; Holmberg, Lars

    2016-09-01

    The purpose of the study was to investigate whether the concomitant use of selective serotonin reuptake inhibitors (SSRI) with tamoxifen influences the risk of death due to breast cancer, and we also investigated the association between SSRI use and adherence to oral endocrine therapy (ET). We analyzed data from BCBaSe Sweden, which is a database created by the data linkage of Registries from three different regions of Sweden. To investigate the association between ET adherence and SSRI use, we included all women who were diagnosed with non-distant metastatic ER-positive invasive breast cancer from July 2007 to July 2011 and had at least one dispensed prescription of oral tamoxifen or aromatase inhibitor. To investigate the role of concurrent administration of SSRI and tamoxifen on breast cancer prognosis, we performed a nested case-control study. In the adherence cohort, 9104 women were included in the analyses. Women who received SSRI, either before or after breast cancer diagnosis, were at higher risk for low adherence to ET. However, when the overlapping period between SSRI use and ET was >50 %, no excess risk for low adherence was observed. Non-adherence (breast cancer survival (OR 4.07; 95 % CI 3.27-5.06). In the case-control study, 445 cases and 11125 controls were included. The concomitant administration of SSRI and tamoxifen did not influence breast cancer survival, neither in short-term (OR 1.41; 95 % CI 0.74-2.68) nor in long-term SSRI users (OR 0.85; 95 % CI 0.35-2.08). Concomitant SSRI and tamoxifen use does not seem to increase risk for death due to breast cancer. Given the positive association between continuing antidepressive pharmacotherapy for a longer period of time and adherence to ET, it is essential to capture and treat depression in breast cancer patients to secure adherence to ET.

  3. Effects of serotonin reuptake inhibitors on aggressive behavior in psychiatrically hospitalized adolescents: results of an open trial.

    Science.gov (United States)

    Constantino, J N; Liberman, M; Kincaid, M

    1997-01-01

    Low concentrations of the neurotransmitter serotonin and its 5-hydroxyindoleacetic acid metabolite in the central nervous system have been associated with increased aggressive behavior in animals and humans. Controlled clinical trials of serotonin agonists in depressed adults have suggested that aggressive behavior is less likely during treatment with these medications than with placebo, but there have been no previous studies of selective serotonin reuptake inhibitors (SSRIs) and aggression in children. We prospectively followed the course of aggressive behavior in 19 psychiatrically hospitalized adolescents (not selected for aggressiveness) who received open clinical trials of fluoxetine, paroxetine, or sertraline. The patients received standard doses (equivalent to fluoxetine 10-40 mg daily) for a minimum of 5 weeks. The starting dose was 15 +/- 5 mg, and dosages were raised at a mean rate of 5 mg every 4 days up to a mean dose of 25 +/- 10 mg daily. Results from trials of the three SSRIs were clustered because the sample sizes were not sufficient for separate analyses. Overall, there were no statistically meaningful improvements in the level of aggressive behavior, as measured on a modified version of the Overt Aggression Scale, over the course of these patients' SSRI trials. Symptoms of physical aggression toward others or self were manifest in 12 of the 19 patients while on SSRIs. Of the 19 patients, 13 were assessed both on and off SSRIs: verbal aggression (p = 0.04), physical aggression toward objects (p = 0.05), and physical aggression toward self (p < 0.02) occurred significantly more frequently on SSRIs than off; no increase was observed in physical aggression toward others. Patients with the highest baseline aggressivity scores did not show greater improvement during SSRI treatment. Further research is warranted, particularly to explore whether SSRIs may have therapeutic effects on aggression at higher (or lower) doses than were administered in this

  4. Acute and chronic effects of selective serotonin reuptake inhibitor treatment on fear conditioning: implications for underlying fear circuits.

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    Burghardt, N S; Bauer, E P

    2013-09-01

    Selective serotonin reuptake inhibitors (SSRIs) are widely used for the treatment of a spectrum of anxiety disorders, yet paradoxically they may increase symptoms of anxiety when treatment is first initiated. Despite extensive research over the past 30 years focused on SSRI treatment, the precise mechanisms by which SSRIs exert these opposing acute and chronic effects on anxiety remain unknown. By testing the behavioral effects of SSRI treatment on Pavlovian fear conditioning, a well characterized model of emotional learning, we have the opportunity to identify how SSRIs affect the functioning of specific brain regions, including the amygdala, bed nucleus of the stria terminalis (BNST) and hippocampus. In this review, we first define different stages of learning involved in cued and context fear conditioning and describe the neural circuits underlying these processes. We examine the results of numerous rodent studies investigating how acute SSRI treatment modulates fear learning and relate these effects to the known functions of serotonin in specific brain regions. With these findings, we propose a model by which acute SSRI administration, by altering neural activity in the extended amygdala and hippocampus, enhances both acquisition and expression of cued fear conditioning, but impairs the expression of contextual fear conditioning. Finally, we review the literature examining the effects of chronic SSRI treatment on fear conditioning in rodents and describe how downregulation of N-methyl-d-aspartate (NMDA) receptors in the amygdala and hippocampus may mediate the impairments in fear learning and memory that are reported. While long-term SSRI treatment effectively reduces symptoms of anxiety, their disruptive effects on fear learning should be kept in mind when combining chronic SSRI treatment and learning-based therapies, such as cognitive behavioral therapy.

  5. Pulmonary vascular effects of serotonin and selective serotonin reuptake inhibitors in the late-gestation ovine fetus.

    Science.gov (United States)

    Delaney, Cassidy; Gien, Jason; Grover, Theresa R; Roe, Gates; Abman, Steven H

    2011-12-01

    Maternal use of selective serotonin (5-HT) reuptake inhibitors (SSRIs) is associated with an increased risk for persistent pulmonary hypertension of the newborn (PPHN), but little is known about 5-HT signaling in the developing lung. We hypothesize that 5-HT plays a key role in maintaining high pulmonary vascular resistance (PVR) in the fetus and that fetal exposure to SSRIs increases 5-HT activity and causes pulmonary hypertension. We studied the hemodynamic effects of 5-HT, 5-HT receptor antagonists, and SSRIs in chronically prepared fetal sheep. Brief infusions of 5-HT (3-20 μg) increased PVR in a dose-related fashion. Ketanserin, a 5-HT 2A receptor antagonist, caused pulmonary vasodilation and inhibited 5-HT-induced pulmonary vasoconstriction. In contrast, intrapulmonary infusions of GR127945 and SB206553, 5-HT 1B and 5-HT 2B receptor antagonists, respectively, had no effect on basal PVR or 5-HT-induced vasoconstriction. Pretreatment with fasudil, a Rho kinase inhibitor, blunted the effects of 5-HT infusion. Brief infusions of the SSRIs, sertraline and fluoxetine, caused potent and sustained elevations of PVR, which was sustained for over 60 min after the infusion. SSRI-induced pulmonary vasoconstriction was reversed by infusion of ketanserin and did not affect the acute vasodilator effects of acetylcholine. We conclude that 5-HT causes pulmonary vasoconstriction, contributes to maintenance of high PVR in the normal fetus through stimulation of 5-HT 2A receptors and Rho kinase activation, and mediates the hypertensive effects of SSRIs. We speculate that prolonged exposure to SSRIs can induce PPHN through direct effects on the fetal pulmonary circulation.

  6. Pharmacokinetics and tolerability of DA-8031, a novel selective serotonin reuptake inhibitor for premature ejaculation in healthy male subjects

    Science.gov (United States)

    Shin, Dongseong; Lee, SeungHwan; Yi, Sojeong; Yoon, Seo Hyun; Cho, Joo-Youn; Bahng, Mi Young; Jang, In-Jin; Yu, Kyung-Sang

    2017-01-01

    Objective DA-8031 is a selective serotonin reuptake inhibitor under development for the treatment of premature ejaculation. This is the first-in-human study aimed at evaluating the pharmacokinetics and tolerability of DA-8031 and its metabolites (M1, M2, M4, and M5) in the plasma and urine after administration of a single oral dose in healthy male subjects. Methods A dose block-randomized, double-blind, placebo-controlled, single ascending dose study was conducted. Subjects received either placebo or a single dose of DA-8031 at 5, 10, 20, 40, 60, 80, or 120 mg. DA-8031 and its four metabolites were analyzed in the plasma and urine for pharmacokinetic evaluation. The effect of genetic polymorphisms of cytochrome-P450 (CYP) enzymes on the pharmacokinetics of DA-8031 was evaluated. Results After a single dose, plasma DA-8031 reached the maximum concentration at a median of 2–3 h and was eliminated with terminal elimination half-life of 17.9–28.7 h. The mean renal clearance was 3.7–5.6 L/h. Dose-proportional pharmacokinetics was observed over the dose range of 20–80 mg. Among the metabolites, M4 had the greatest plasma concentration, followed by M5 and M1. Subjects with CYP2D6 intermediate metabolizer had significantly greater dose-normalized Cmax and AUC0–t of DA-8031 as well as smaller metabolic ratios than those subjects with CYP2D6 extensive metabolizer. The most common adverse events were nausea, dizziness, and headache, and no serious adverse events were reported. Conclusion In conclusion, the systemic exposure of DA-8031 was increased proportionally to the dose within 20–80 mg. Genetic polymorphisms of CYP2D6 had an effect on the systemic exposure of DA-8031. DA-8031 was well tolerated after single doses of 80 mg or less. PMID:28331291

  7. Elevated blood plasma levels of epinephrine, norepinephrine, tyrosine hydroxylase, TGFβ1, and TNFα associated with high-altitude pulmonary edema in an Indian population

    Science.gov (United States)

    Pandey, Priyanka; Ali, Zahara; Mohammad, Ghulam; Pasha, M A Qadar

    2016-01-01

    Biomarkers are essential to unravel the locked pathophysiology of any disease. This study investigated the role of biomarkers and their interactions with each other and with the clinical parameters to study the physiology of high-altitude pulmonary edema (HAPE) in HAPE-patients (HAPE-p) against adapted highlanders (HLs) and healthy sojourners, HAPE-controls (HAPE-c). For this, seven circulatory biomarkers, namely, epinephrine, norepinephrine, tyrosine hydroxylase, transforming growth factor beta 1, tumor necrosis factor alpha (TNFα), platelet-derived growth factor beta beta, and C-reactive protein (CRP), were measured in blood plasma of the three study groups. All the subjects were recruited at ~3,500 m, and clinical features such as arterial oxygen saturation (SaO2), body mass index, and mean arterial pressure were measured. Increased levels of epinephrine, norepinephrine, tyrosine hydroxylase, transforming growth factor-beta 1, and TNFα were observed in HAPE-p against the healthy groups, HAPE-c, and HLs (P0.01). Correlation analysis revealed a negative correlation between epinephrine and norepinephrine (P=4.6E−06) in HAPE-p and positive correlation in HAPE-c (P=0.004) and HLs (P=9.78E−07). A positive correlation was observed between TNFα and CRP (P=0.004) in HAPE-p and a negative correlation in HAPE-c (P=4.6E−06). SaO2 correlated negatively with platelet-derived growth factor beta beta (HAPE-p; P=0.05), norepinephrine (P=0.01), and TNFα (P=0.005) and positively with CRP (HAPE-c; P=0.02) and norepinephrine (HLs; P=0.04). Body mass index correlated negatively with epinephrine (HAPE-p; P=0.001) and positively with norepinephrine and tyrosine hydroxylase in HAPE-c (P0.70, P<0.05). The results clearly suggest that increased plasma levels of these circulatory biomarkers associated with HAPE. PMID:27540296

  8. Angiotensin AT1 and AT2 receptor antagonists modulate nicotine-evoked [³H]dopamine and [³H]norepinephrine release.

    Science.gov (United States)

    Narayanaswami, Vidya; Somkuwar, Sucharita S; Horton, David B; Cassis, Lisa A; Dwoskin, Linda P

    2013-09-01

    Tobacco smoking is the leading preventable cause of death in the United States. A major negative health consequence of chronic smoking is hypertension. Untoward addictive and cardiovascular sequelae associated with chronic smoking are mediated by nicotine-induced activation of nicotinic receptors (nAChRs) within striatal dopaminergic and hypothalamic noradrenergic systems. Hypertension involves both brain and peripheral angiotensin systems. Activation of angiotensin type-1 receptors (AT1) release dopamine and norepinephrine. The current study determined the role of AT1 and angiotensin type-2 (AT2) receptors in mediating nicotine-evoked dopamine and norepinephrine release from striatal and hypothalamic slices, respectively. The potential involvement of nAChRs in mediating effects of AT1 antagonist losartan and AT2 antagonist, 1-[[4-(dimethylamino)-3-methylphenyl]methyl]-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid (PD123319) was evaluated by determining their affinities for α4β2* and α7* nAChRs using [³H]nicotine and [³H]methyllycaconitine binding assays, respectively. Results show that losartan concentration-dependently inhibited nicotine-evoked [³H]dopamine and [³H]norepinephrine release (IC₅₀: 3.9 ± 1.2 and 2.2 ± 0.7 μM; Imax: 82 ± 3 and 89 ± 6%, respectively). In contrast, PD123319 did not alter nicotine-evoked norepinephrine release, and potentiated nicotine-evoked dopamine release. These results indicate that AT1 receptors modulate nicotine-evoked striatal dopamine and hypothalamic norepinephrine release. Furthermore, AT1 receptor activation appears to be counteracted by AT2 receptor activation in striatum. Losartan and PD123319 did not inhibit [³H]nicotine or [³H]methyllycaconitine binding, indicating that these AT1 and AT2 antagonists do not interact with the agonist recognition sites on α4β2* and α7* nAChRs to mediate these effects of nicotine. Thus, angiotensin receptors contribute to the effects of

  9. Neurotoxic compound N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP4) depletes endogenous norepinephrine and enhances release of (/sup 3/H)norepinephrine from rat cortical slices

    Energy Technology Data Exchange (ETDEWEB)

    Landa, M.E.; Rubio, M.C.; Jaim-Etcheverry, G.

    1984-10-01

    The alkylating compound N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP4) injected to rodents blocks norepinephrine (NE) uptake and reduces endogenous NE levels in the central nervous system and in the periphery. To investigate the processes leading to these alterations, rat cortical slices were incubated in the presence of DSP4. Cortical NE was depleted by 40% after incubation of slices in 10(-5) M DSP4 for 60 min and this was blocked by desipramine. The spontaneous outflow of radioactivity from cortical slices labeled previously with (/sup 3/H)NE was enhanced markedly both during exposure to DSP4 and during the subsequent washings, suggesting that NE depletion could be due to this stimulation of NE release. The radioactivity released by DSP4 was accounted for mainly by NE and its deaminated metabolite 3,4-dihydroxyphenylglycol. The enhanced release, independent of external Ca++, apparently originated from the vesicular pool as it was absent after reserpine pretreatment. Activities of the enzymes related to NE synthesis were not altered by DSP4 in vitro and only monoamine oxidase activity was inhibited at high concentrations. Thus, the depletion of endogenous NE produced by DSP4 is probably due to a persistent enhancement of its release from the vesicular pool. Fixation of DSP4 to the NE transport system is necessary but not sufficient to produce the acute NE depletion and the characteristic long-term actions of the compound.

  10. Effect of neuropeptide Y on norepinephrine-induced constriction in the rabbit facial artery after carotid artery occlusion

    Directory of Open Access Journals (Sweden)

    Roganović Jelena

    2014-01-01

    Full Text Available Background/Aim. Atherosclerotic-occlusive changes could be observed in orofacial branches of the external carotid artery. Atherosclerosis-induced ischemia caused alteration in production and release of endothelial factors. The aim of this study was to investigate the influence of carotid artery occlusion (10, 30 and 60 min on vascular effects of norepinephrine (NOR and neuropeptide Y (NPY in the isolated glandular branch of the rabbit facial artery, the main feeding artery for the submandibular gland. Method. Changes in isometric tension were recorded in organ bath studies with arterial rings, before and after carotid artery occlusion. Results. Concentrationdependent vasocontractile effect of NOR was significantly augmented after 30 and 60 min of carotid occlusion, but only in the rings with intact endothelium. Given alone, NPY showed no effect in isolated glandular branch of the rabbit facial artery, but enhanced NOR vasoconstriction in all the investigated rings. NOR vasocontractile effect enhancement in the presence of NPY was attenuated after 30 and 60 min of carotid occlusion. Also, enhancement of NOR vasoconstriction by NPY was significantly higher in endothelium-intact rings compared to endotheliumdenuded rings obtained after 30 and 60 min of carotid occlusion. Conclusion. The present investigation provides results of increased vasocontractile effect of NOR and decreased enhancing effect of NPY on NOR vasoconstriction in the rabbit facial artery after carotid occlusion that is related to altered endothelium function.

  11. Chlordiazepoxide-induced released responding in extinction and punishment-conflict procedures is not altered by neonatal forebrain norepinephrine depletion.

    Science.gov (United States)

    Bialik, R J; Pappas, B A; Pusztay, W

    1982-02-01

    The effects of chlordiazepoxide (CDZ) in extinction and punishment-conflict tasks were examined in rats after neonatal systemic administration of 6-hydroxydopamine (6-OHDA) to deplete forebrain norepinephrine (NE). At about 70 days of age the rats were water deprived and trained for three days to drink in a novel apparatus. On the fourth day (test day) drinking was either extinguished by elimination of water from the drinking tube or punished by lick-contingent shock. Just prior to this test session half of the vehicle and half of the 6-OHDA treated rats were given an injection of CDZ (8 mg/kg IP). Both the injection of CDZ and forebrain NE depletion prolonged responding during extinction and reduced the suppressant effects of punishment in male rats, and these effects were of similar magnitude. Furthermore, CDZ was as effective in neonatal 6-OHDA treated male rats as in vehicle treated rats indicating that decreased transmission is ascending NE fibers caused by CDZ is not solely responsible for its behavioral effects in extinction and conflict tasks. Rather, these effects may involve cooperative mediation by both noradrenergic and serotonergic forebrain terminals. Unexpectedly, CDZ's anti-extinction effect was absent in female rats and its anti-conflict effect observed only in NE depleted females.

  12. Variation in key genes of serotonin and norepinephrine function predicts gamma-band activity during goal-directed attention.

    Science.gov (United States)

    Enge, Sören; Fleischhauer, Monika; Lesch, Klaus-Peter; Reif, Andreas; Strobel, Alexander

    2014-05-01

    Recent evidence shows that genetic variations in key regulators of serotonergic (5-HT) signaling explain variance in executive tasks, which suggests modulatory actions of 5-HT on goal-directed selective attention as one possible underlying mechanism. To investigate this link, 130 volunteers were genotyped for the 5-HT transporter gene-linked polymorphic region (5-HTTLPR) and for a variation (TPH2-703 G/T) of the TPH2 gene coding for the rate-limiting enzyme of 5-HT synthesis in the brain. Additionally, a functional polymorphism of the norepinephrine transporter gene (NET -3081 A/T) was considered, which was recently found to predict attention and working memory processes in interaction with serotonergic genes. The flanker-based Attention Network Test was used to assess goal-directed attention and the efficiency of attentional networks. Event-related gamma-band activity served to indicate selective attention at the intermediate phenotype level. The main findings were that 5-HTTLPR s allele and TPH2 G-allele homozygotes showed increased induced gamma-band activity during target processing when combined with the NET A/A genotype compared with other genotype combinations, and that gamma activity mediates the genotype-specific effects on task performance. The results further support a modulatory role of 5-HT and NE function in the top-down attentional selection of motivationally relevant over competing or irrelevant sensory input.

  13. Effect of wine polyphenol resveratrol on the contractions elicited electrically or by norepinephrine in the rat portal vein.

    Science.gov (United States)

    Protić, Dragana; Beleslin-Čokić, Bojana; Novaković, Radmila; Kanjuh, Vladimir; Heinle, Helmut; Sćepanović, Radisav; Gojković-Bukarica, Ljiljana

    2013-11-01

    We investigated the effects of resveratrol on rat portal vein (RPV) contractility without endothelium. Contractions were produced by electrical field stimulation of perivascular nerves (EFS), norepinephrine (NE), adenosine 5'-triphosphate (ATP), high K(+) solution and by calcium chloride (CaCl2 ) in Ca(2+) -free and high K(+) , Ca(2+) -free solution. The EFS-evoked contractions were more sensitive to resveratrol and to NS1619-selective openers of big calcium-sensitive (BKCa ) channels, than NE-evoked contractions. Effects of resveratrol on the ATP-evoked contractions were weak. Blockers of BKCa channels partly inhibited the effect of resveratrol only in EFS-contracted preparations. Western blotting showed that RPV expressed KCa 1.1 protein. Inhibitors of ATP- and voltage-sensitive K(+) channels did not modify the effects of resveratrol. None of the antagonists of K(+) channels affected the resveratrol inhibition of NE-evoked contractions and effect of high concentrations of resveratrol on the EFS-evoked contractions. Resveratrol more potently inhibited CaCl2 than potassium chloride contractions of RPV. Thus, BKCa channels partly mediate the inhibitory effect of resveratrol on the neurogenic contractions of RPV. The smooth muscle Ca(2+) channels and/or Ca(2+) mobilizing through cells might be involved in the effects of resveratrol on the contractility of RPV. Our results are important for better understanding the impact of resveratrol on the portal circulation.

  14. The in vitro maintenance of clock genes expression within the rat pineal gland under standard and norepinephrine-synchronized stimulation.

    Science.gov (United States)

    Andrade-Silva, Jéssica; Cipolla-Neto, José; Peliciari-Garcia, Rodrigo A

    2014-01-01

    Although the norepinephrine (NE) synchronization protocol was proved to be an important procedure for further modulating in vitro pineal melatonin synthesis, the maintenance of clock genes under the same conditions remained to be investigated. The aim of this study was to investigate the maintenance of the clock genes expression in pineal gland cultures under standard and NE-synchronized stimulation. The glands were separated into three experimental groups: Control, Standard (acute NE-stimulation), and NE-synchronized. The expression of Bmal1, Per2, Cry2, Rev-erbα, the clock controlled gene Dbp and Arylalkylamine-N-acetyltransferase were investigated, as well as melatonin content. No oscillations were observed in the expression of the investigated genes from the control group. Under Standard NE stimulation, the clock genes did not exhibit a rhythmic pattern of expression. However, in the NE-synchronized condition, a rhythmic expression pattern was observed in all cases. An enhancement in pineal gland responsiveness to NE stimulation, reflected in an advanced synthesis of melatonin was also observed. Our results reinforce our previous hypothesis that NE synchronization of pineal gland culture mimics the natural rhythmic release of NE in the gland, increasing melatonin synthesis and keeping the pineal circadian clock synchronized, ensuring the fine adjustments that are relied in the clockwork machinery.

  15. Effect of epinephrine, norepinephrine and(or) GnRH on serum LH in prepuberal beef heifers.

    Science.gov (United States)

    Hardin, D R; Randel, R D

    1983-09-01

    Forty prepuberal Simmental X Brahman-Hereford heifers were utilized to determine the effects of epinephrine (E), norepinephrine (NE), gonadotropin releasing hormone (GnRH) or combinations of GnRH + E and GnRH + NE on serum luteinizing hormone (LH) concentrations. Animals were assigned randomly to one of five treatments with four replicates/treatment. Treatments consisted of I) 100 micrograms GnRH at time 0 (n = 8); II) 50 mg NE at time -15 and 0 (n = 8); III) 50 mg E at time -15 and 0 (n = 8); IV) 100 micrograms GnRH at time 0, plus 50 mg NE at time -15 and 0 (n = 8) and V) 100 micrograms GnRH at time 0, plus 50 mg E at time -15 and 0 (n = 8). All treatment compounds were administered im in 2 ml physiological saline and blood samples were collected via tail vessel puncture at -30, -15, 0, 15, 30, 45, 60, 90, 120, 180, 240, 300 and 360 min from GnRH injection. Treatment with NE or E alone had no effect (P greater than .10) on serum LH during the sampling period. The initial LH release to GnRH was altered (P less than .05) by concomitant treatment with NE (treatment IV) or E (treatment V). Magnitude of the LH release was reduced (P less than .01) by treatment V. Area under the LH surge was reduced (P less than .05) by treatment IV (NE) and V (E).

  16. Electrochemical stimulation of plasma LH and hypothalamic norepinephrine concentrations at short- and long-term intervals after hypothalamic knife cuts.

    Science.gov (United States)

    Phelps, C P; Saporta, S

    1985-11-18

    Norepinephrine (NE) concentrations in several diencephalic locations were studied in female rats in conjunction with luteinizing hormone (LH) release after medial preoptic area (MPOA) stimulation at short (7 days) and longer time intervals after surgical interruption of anterior or anterolateral neural connections of mediobasal hypothalamus (MBH). Concentrations of diencephalic NE were altered in two general ways after brain surgery: (1) transient early postoperative increases in some regions which appeared unrelated to the type of surgery performed; and (2) other specific decreases in NE concentration which were related to the types of surgery performed and whether a particular ascending noradrenergic pathway was interrupted. At 180 days after surgery, these two types of change in NE concentrations were no longer present. Maximum increases in plasma LH concentrations observed after electrochemical stimulation of the MPOA at either 7 or 180 days after MBH deafferentation also varied according to: (1) the postoperative interval studied; and (2) the location of pathway interruption. Interruption of anterior MBH pathways showed only a transient (7 day interval) reduction in LH release after MPOA stimulation, whereas when both lateral and anterior pathways were severed, there was a more nearly permanent (180 day interval) disruption of LH release after stimulation. The results of these studies support the contention that anterolateral MBH neural connections may constitute a dynamic neural substrate contributing to a gradual improvement in neuroendocrine function observed after early surgical disconnections.

  17. Small doses of arginine vasopressin in combination with norepinephrine "buy" time for definitive treatment for uncontrolled hemorrhagic shock in rats.

    Science.gov (United States)

    Liu, Liangming; Tian, Kunlun; Xue, Mingying; Zhu, Yu; Lan, Dan; Peng, Xiaoyong; Wu, Yue; Li, Tao

    2013-11-01

    Implementation of fluid resuscitation and blood transfusion are greatly limited in prehospital or evacuation settings after severe trauma or war wounds. With uncontrolled hemorrhagic shock rats, we investigated if arginine vasopressin (AVP) in combination with norepinephrine (NE) is independent (or slightly dependent) of fluid resuscitation and can "buy" time for the subsequently definitive treatment of traumatic hemorrhagic shock in the present study. The results showed that AVP (0.4 U/kg) alone or with NE (3 μg/kg) with one-eighth and one-fourth volumes of total blood volume of lactated Ringer's infusion significantly increased and maintained the mean arterial pressure. Among all groups, 0.4 U/kg of AVP + NE (3 μg/kg) with one-eighth volume of lactated Ringer's infusion had the best effect: it significantly increased and maintained hemodynamics and prolonged the survival time. This early treatment strategy significantly improved the effects of subsequently definitive treatments (after bleeding controlled): it increased the subsequent survival, improved the hemodynamic parameters, improved the cardiac function, and increased the tissue blood flow and oxygen delivery. These results suggested that early application of small doses of AVP (0.4 U/kg) + NE before bleeding control can "buy" time for the definitive treatment of uncontrolled hemorrhagic shock, which may be an effective measure for the early treatment of traumatic hemorrhagic shock.

  18. Conventional hemodynamic resuscitation may fail to optimize tissue perfusion: An observational study on the effects of dobutamine, enoximone, and norepinephrine in patients with acute myocardial infarction complicated by cardiogenic shock

    NARCIS (Netherlands)

    C.A. den Uil (Corstiaan); W.K. Lagrand (Wim); M. van der Ent (Martin); K. Nieman (Koen); A. Struijs (Ard); L.S.D. Jewbali (Lucia); A.A. Constantinescu (Alina); P.E. Spronk (Peter); M.L. Simoons (Maarten)

    2014-01-01

    textabstractAim: To investigate the effects of inotropic agents on parameters of tissue perfusion in patients with cardiogenic shock. Methods and Results: Thirty patients with cardiogenic shock were included. Patients received dobutamine, enoximone, or norepinephrine. We performed hemodynamic measur

  19. Effects of monoamine releasers with varying selectivity for releasing dopamine/norepinephrine versus serotonin on choice between cocaine and food in rhesus monkeys.

    Science.gov (United States)

    Banks, Matthew L; Blough, Bruce E; Negus, S Stevens

    2011-12-01

    Monoamine releasers constitute one class of candidate medications for the treatment of cocaine abuse, and concurrent cocaine-versus-food choice procedures are potentially valuable as experimental tools to evaluate the efficacy and safety of candidate medications. This study assessed the choice between cocaine and food by rhesus monkeys during treatment with five monoamine releasers that varied in selectivity to promote the release of dopamine and norepinephrine versus serotonin (5HT) [m-fluoroamphetamine, (+)-phenmetrazine, (+)-methamphetamine, napthylisopropylamine and (±)-fenfluramine]. Rhesus monkeys (n=8) responded under a concurrent-choice schedule of food delivery (1-g pellets, fixed ratio 100 schedule) and cocaine injections (0-0.1 mg/kg/injection, fixed ratio 10 schedule). Cocaine choice dose-effect curves were determined daily during continuous 7-day treatment with saline or with each test compound dose. During saline treatment, cocaine maintained a dose-dependent increase in cocaine choice, and the highest cocaine doses (0.032-0.1 mg/kg/injection) maintained almost exclusive cocaine choice. Efficacy of monoamine releasers to decrease cocaine choice corresponded to their pharmacological selectivity to release dopamine and norepinephrine versus 5HT. None of the releasers reduced cocaine choice or promoted reallocation of responding to food choice to the same extent as when saline was substituted for cocaine. These results extend the range of conditions across which dopamine and norepinephrine-selective releasers have been shown to reduce cocaine self-administration.

  20. Bioartificial Therapy of Sepsis: Changes of Norepinephrine-Dosage in Patients and Influence on Dynamic and Cell Based Liver Tests during Extracorporeal Treatments

    Directory of Open Access Journals (Sweden)

    Martin Sauer

    2016-01-01

    Full Text Available Purpose. Granulocyte transfusions have been used to treat immune cell dysfunction in sepsis. A granulocyte bioreactor for the extracorporeal treatment of sepsis was tested in a prospective clinical study focusing on the dosage of norepinephrine in patients and influence on dynamic and cell based liver tests during extracorporeal therapies. Methods and Patients. Ten patients with severe sepsis were treated twice within 72 h with the system containing granulocytes from healthy donors. Survival, physiologic parameters, extended hemodynamic measurement, and the indocyanine green plasma disappearance rate (PDR were monitored. Plasma of patients before and after extracorporeal treatments were tested with a cell based biosensor for analysis of hepatotoxicity. Results. The observed mortality rate was 50% during stay in hospital. During the treatments, the norepinephrine-dosage could be significantly reduced while mean arterial pressure was stable. In the cell based analysis of hepatotoxicity, the viability and function of sensor-cells increased significantly during extracorporeal treatment in all patients and the PDR-values increased significantly between day 1 and day 7 only in survivors. Conclusion. The extracorporeal treatment with donor granulocytes showed promising effects on dosage of norepinephrine in patients, liver cell function, and viability in a cell based biosensor. Further studies with this approach are encouraged.

  1. Increased norepinephrine by medium-chain triglyceride attributable to lipolysis in white and brown adipose tissue of C57BL/6J mice.

    Science.gov (United States)

    Liu, Ying-hua; Zhang, Yong; Xu, Qing; Yu, Xiao-ming; Zhang, Xin-sheng; Wang, Jin; Xue, Chao; Yang, Xue-yan; Zhang, Rong-xin; Xue, Chang-yong

    2012-01-01

    A further investigation of the lipolysis induced by medium-chain triglyceride (MCT) was conducted on C57BL/6J mice fed with a diet containing 2% MCT or 2% long-chain triglyceride (LCT). Blood norepinephrine, body fat and blood lipid variables, and the protein or mRNA expression of the genes relevant to lipolysis were measured and analyzed in the white and brown adipose tissue (WAT, BAT). Decreased body fat and improved blood lipid profiles attributable to MCT were confirmed. A higher level of blood norepinephrine was observed with the MCT diet. The adipose triglyceride lipase (ATGL) activity and its mRNA expression, the expression of protein and mRNA of the beta 3 adrenergic receptor (β3-AR) in both WAT and BAT, and the hormone-sensitive lipase (HSL) activity and its mRNA expression in BAT were significantly increased in the mice with MCT feeding. The lipolysis induced by MCT might be partially mediated by increasing norepinephrine, thereafter signaling the up-regulation of β3-AR, ATGL, and HSL in WAT and BAT.

  2. Effects of selective and non-selective inhibitors of nitric oxide synthase on morphine- and endomorphin-1-induced analgesia in acute and neuropathic pain in rats.

    Science.gov (United States)

    Makuch, Wioletta; Mika, Joanna; Rojewska, Ewelina; Zychowska, Magdalena; Przewlocka, Barbara

    2013-12-01

    Nitric oxide (NO) has been reported to be involved in the mechanisms of pain generation throughout the nervous system. We examined the effects of intrathecally (i.t.) administered nitric oxide synthase (NOS) inhibitors on the antinociceptive effects of morphine and endomorphin-1 during acute pain and in chronic constriction injury (CCI)-exposed rats. We used N(G)-nitro-l-arginine methyl ester (l-NAME), a non-selective NOS inhibitor; 7-nitroindazole (7-NI) or 1-(2-trifluoromethyl-phenyl)-imidazole (TRIM), selective inhibitors of neuronal NOS (NOS1); and 1400W dihydrochloride, a selective inhibitor of inducible NOS (NOS2). Morphine (0.5-2.5 μg) and endomorphin-1 (2.5-20 μg) in acute pain and morphine (10-40 μg) and endomorphin-1 (5-20 μg) after CCI-injury were combined with NOS inhibitors. For acute pain, the ED50 for endomorphin-1 (7.1 μg) was higher than that of morphine (1.3 μg) in the tail-flick test. For neuropathic pain, the ED50 value for morphine was much higher (43.2 μg) than that of endomorphin-1 (9.2 μg) in von Frey test. NOS inhibitors slightly influenced pain thresholds in both pain models. Moreover, in neuropathic pain, the effects of morphine were more potentiated by L-NAME, TRIM, 7-NI and 1400W (12×, 8.6×, 4.1× and 5.3×, respectively) than were the effects of endomorphin-1 (2.7×, 4.3×, 3.4× and 2.1×, respectively) in the von Frey test. Minocycline which is known to enhance the efficiency of morphine in neuropathic pain, decreased the mRNA expression of NOS1 in the DRG and NOS2 and C1q in the spinal cord after CCI. Both NOS2 and IBA-1 protein levels in the spinal cord and NOS1, NOS2 and IBA1 protein levels in DRG decreased after minocycline administration. In conclusion, our results provide evidence that both neuronal and non-neuronal NOS/NO pathways contribute to the behavioural pain responses evoked by nerve injury. The NOS inhibitors regardless of the type of pain enhanced morphine antinociception and, to a lesser extent, altered the

  3. Effects of a non-selective TRPC channel blocker, SKF-96365, on melittin-induced spontaneous persistent nociception and inflammatory pain hypersensitivity

    Institute of Scientific and Technical Information of China (English)

    Jing Ding; Jia-Rui Zhang; Yan Wang; Chun-Li Li; Dan Lu; Su-Min Guan; Jun Chen

    2012-01-01

    Objective Melittin is the main peptide in bee venom and causes both persistent spontaneous nociception and pain hypersensitivity.Our recent studies indicated that both transient receptor potential (TRP) vanilloid receptor 1 (TRPV1) and canonical TRPs (TRPCs) are involved in mediating the melittin-induced activation of different subpopulations of primary nociceptive cells.Here,we further determined whether TRPC channels are involved in melittin-induced inflammatory nociceptive responses in behavioral assays.Methods The anti-nociceptive and anti-hyperalgesic effects of localized peripheral administration of three doses of the non-selective TRPC antagonist,SKF-96365 (1-{β-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenyl}-1H-imidazole hydrochloride),were evaluated in melittin tests.Pain-related behaviors were rated by counting the number of paw flinches,and measuring paw withdrawal thermal latency (s) and paw withdrawl mechanical threshold (g),over a 1-h time-course.Results Localized peripheral SKF-96365 given before melittin prevented,and given after melittin significantly suppressed,the melittin-evoked persistent spontaneous nociception.Pre-blockade and post-suppression of activation of primary nociceptive activity resulted in decreased hypersensitivity to both thermal and mechanical stimuli applied to the primary injury site of the ipsilateral hindpaw,despite dose-effect differences between thermal and mechanical hyperalgesia.However,local administration of SKF-96365 into the contralateral hindpaw had no significant effect on any pain-associated behaviors.In addition,SKF-96365 had no effect on baseline threshold for either thermal or mechanical sensitivity under normal conditions.Conclusion Besides TRPV1,SKF-96365-sensitive TRPC channels might also be involved in the pathophysiological processing of melittin-induced inflammatory pain and hypersensitivity.Therapeutically,SKF-96365 is equally effective in preventing primary thermal and mechanical hyperalgesia as well as

  4. Differential effects of selective frankincense (Ru Xiang) essential oil versus non-selective sandalwood (Tan Xiang) essential oil on cultured bladder cancer cells: a microarray and bioinformatics study

    Science.gov (United States)

    2014-01-01

    cancer cell death. While frankincense essential oil elicited selective cancer cell death via NRF-2-mediated oxidative stress, sandalwood essential oil induced non-selective cell death via DNA damage and cell cycle arrest. PMID:25006348

  5. Association of Selective Serotonin Reuptake Inhibitor Exposure During Pregnancy With Speech, Scholastic, and Motor Disorders in Offspring.

    Science.gov (United States)

    Brown, Alan S; Gyllenberg, David; Malm, Heli; McKeague, Ian W; Hinkka-Yli-Salomäki, Susanna; Artama, Miia; Gissler, Mika; Cheslack-Postava, Keely; Weissman, Myrna M; Gingrich, Jay A; Sourander, Andre

    2016-11-01

    Speech/language, scholastic, and motor disorders are common in children. It is unknown whether exposure to selective serotonin reuptake inhibitors (SSRIs) during pregnancy influences susceptibility to these disorders. To examine whether SSRI exposure during pregnancy is associated with speech/language, scholastic, and motor disorders in offspring up to early adolescence. This prospective birth cohort study examined national population-based register data in Finland from 1996 to 2010. The sampling frame includes 845 345 pregnant women and their singleton offspring with data on maternal use of antidepressants and depression-related psychiatric disorders during pregnancy. There were 3 groups of offspring: 15 596 were in the SSRI-exposed group, ie, had mothers diagnosed as having depression-related psychiatric disorders with a history of purchasing SSRIs during pregnancy; 9537 were in the unmedicated group, ie, had mothers diagnosed as having depression-related psychiatric disorders without a history of purchasing SSRIs during pregnancy; and 31 207 were in the unexposed group, ie, had mothers without a psychiatric diagnosis or a history of purchasing SSRIs. Cumulative incidence of speech/language, scholastic, or motor disorders (829, 187, and 285 instances, respectively) from birth to 14 years. All hypotheses tested were formulated before data collection. Of the 56 340 infants included in the final cohort, 28 684 (50.9%) were male and 48 782 (86.6%) were 9 years or younger. The mean (SD) ages of children at diagnosis were 4.43 (1.67), 3.55 (2.67), and 7.73 (2.38) for speech/language, scholastic, and motor disorders, respectively. Offspring of mothers who purchased SSRIs at least twice during pregnancy had a significant 37% increased risk of speech/language disorders compared with offspring in the unmedicated group. The cumulative hazard of speech/language disorders was 0.0087 in the SSRI-exposed group vs 0.0061 in the unmedicated group (hazard ratio, 1

  6. The novel triple monoamine reuptake inhibitor tesofensine induces sustained weight loss and improves glycemic control in the diet-induced obese rat: comparison to sibutramine and rimonabant

    DEFF Research Database (Denmark)

    Hansen, Henrik H; Hansen, Gitte; Tang-Christensen, Mads

    2010-01-01

    Tesofensine, a novel triple monoamine reuptake inhibitor, produces a significant weight loss in humans. The present study aimed at characterizing the weight-reducing effects of tesofensine in a rat model of diet-induced obesity. Sibutramine and rimonabant were used as reference comparators....... Compared to baseline, long-term treatment with tesofensine (28 days, 1.0 or 2.5mg/kg, p.o.) resulted in a significant, dose-dependent and sustained weight loss of 5.7 and 9.9%, respectively. Sibutramine (7.5mg/kg, p.o.) treatment caused a sustained weight loss of 7.6%, whereas the employed dose...

  7. Elevated blood plasma levels of epinephrine, norepinephrine, tyrosine hydroxylase, TGFβ1, and TNFα associated with high-altitude pulmonary edema in Indian population

    Directory of Open Access Journals (Sweden)

    Pandey P

    2016-08-01

    Full Text Available Priyanka Pandey,1,2 Zahara Ali,1,2 Ghulam Mohammad,3 MA Qadar Pasha1,2 1Functional Genomics Unit, CSIR-Institute of Genomics and Integrative Biology, Delhi, 2Department of Biotechnology, Savitribai Phule Pune University, Pune, 3Department of Medicine, SNM Hospital, Ladakh, Jammu and Kashmir, India Abstract: Biomarkers are essential to unravel the locked pathophysiology of any disease. This study investigated the role of biomarkers and their interactions with each other and with the clinical parameters to study the physiology of high-altitude pulmonary edema (HAPE in HAPE-patients (HAPE-p against adapted highlanders (HLs and healthy sojourners, HAPE-controls (HAPE-c. For this, seven circulatory biomarkers, namely, epinephrine, norepine