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Sample records for 5-ht4 serotonin receptor

  1. Effect of the 5-HT4 receptor and serotonin transporter on visceral hypersensitivity in rats

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    Chi Yan

    2012-10-01

    Full Text Available Visceral hypersensitivity plays an important role in motor and sensory abnormalities associated with irritable bowel syndrome, but the underlying mechanisms are not fully understood. The present study was designed to evaluate the expression of the 5-HT4 receptor and the serotonin transporter (SERT as well as their roles in chronic visceral hypersensitivity using a rat model. Neonatal male Sprague-Dawley rats received intracolonic injections of 0.5% acetic acid (0.3-0.5 mL at different times between postnatal days 8 and 21 to establish an animal model of visceral hypersensitivity. On day 43, the threshold intensity for a visually identifiable contraction of the abdominal wall and body arching were recorded during rectal distention. Histological evaluation and the myeloperoxidase activity assay were performed to determine the severity of inflammation. The 5-HT4 receptor and SERT expression of the ascending colon were monitored using immunohistochemistry and Western blot analyses; the plasma 5-HT levels were measured using an ELISA method. As expected, transient colonic irritation at the neonatal stage led to visceral hypersensitivity, but no mucosal inflammation was later detected during adulthood. Using this model, we found reduced SERT expression (0.298 ± 0.038 vs 0.634 ± 0.200, P < 0.05 and increased 5-HT4 receptor expression (0.308 ± 0.017 vs 0.298 ± 0.021, P < 0.05. Treatment with fluoxetine (10 mg·kg-1·day-1, days 36-42, tegaserod (1 mg·kg-1·day-1, day 43, or the combination of both, reduced visceral hypersensitivity and plasma 5-HT levels. Fluoxetine treatment increased 5-HT4 receptor expression (0.322 ± 0.020 vs 0.308 ± 0.017, P < 0.01 but not SERT expression (0.219 ± 0.039 vs 0.298 ± 0.038, P = 0.654. These results indicate that both the 5-HT4 receptor and SERT play a role in the pathogenesis of visceral hypersensitivity, and its mechanism may be involved in the local 5-HT level.

  2. Effect of the 5-HT4 receptor and serotonin transporter on visceral hypersensitivity in rats

    Directory of Open Access Journals (Sweden)

    Chi Yan

    2012-10-01

    Full Text Available Visceral hypersensitivity plays an important role in motor and sensory abnormalities associated with irritable bowel syndrome, but the underlying mechanisms are not fully understood. The present study was designed to evaluate the expression of the 5-HT4 receptor and the serotonin transporter (SERT as well as their roles in chronic visceral hypersensitivity using a rat model. Neonatal male Sprague-Dawley rats received intracolonic injections of 0.5% acetic acid (0.3-0.5 mL at different times between postnatal days 8 and 21 to establish an animal model of visceral hypersensitivity. On day 43, the threshold intensity for a visually identifiable contraction of the abdominal wall and body arching were recorded during rectal distention. Histological evaluation and the myeloperoxidase activity assay were performed to determine the severity of inflammation. The 5-HT4 receptor and SERT expression of the ascending colon were monitored using immunohistochemistry and Western blot analyses; the plasma 5-HT levels were measured using an ELISA method. As expected, transient colonic irritation at the neonatal stage led to visceral hypersensitivity, but no mucosal inflammation was later detected during adulthood. Using this model, we found reduced SERT expression (0.298 ± 0.038 vs 0.634 ± 0.200, P < 0.05 and increased 5-HT4 receptor expression (0.308 ± 0.017 vs 0.298 ± 0.021, P < 0.05. Treatment with fluoxetine (10 mg·kg-1·day-1, days 36-42, tegaserod (1 mg·kg-1·day-1, day 43, or the combination of both, reduced visceral hypersensitivity and plasma 5-HT levels. Fluoxetine treatment increased 5-HT4 receptor expression (0.322 ± 0.020 vs 0.308 ± 0.017, P < 0.01 but not SERT expression (0.219 ± 0.039 vs 0.298 ± 0.038, P = 0.654. These results indicate that both the 5-HT4 receptor and SERT play a role in the pathogenesis of visceral hypersensitivity, and its mechanism may be involved in the local 5-HT level.

  3. Roles of the serotonin 5-HT4 receptor in dendrite formation of the rat hippocampal neurons in vitro.

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    Kozono, Naoki; Ohtani, Akiko; Shiga, Takashi

    2017-01-15

    Serotonin (5-HT) is involved in various aspects of hippocampal development, although the specific roles of 5-HT receptors are poorly understood. We investigated the roles of 5-HT receptors in the dendrite formation of hippocampal neurons. We focused on the 5-HT4 receptor, which is coupled with Gs protein, and compared the effects with those of the Gi-coupled 5-HT1A receptor. Neurons from rat hippocampi at embryonic day 18 were dissociated and treated for 4 days with the 5-HT4 receptor agonist BIMU8 or the 5-HT1A receptor agonist 8-OH DPAT. The formation of primary dendrites and dendrite branching were promoted by BIMU8, whereas the dendrite branching was inhibited by 8-OH DPAT. BIMU8-induced promotion of dendrite formation was neutralized by concomitant treatment with the 5-HT4 receptor antagonist, confirming the specific actions of the 5-HT4 receptor. We then examined the signaling mechanisms underlying the actions of the 5-HT4 receptor by using a protein kinase A (PKA) inhibitor. The BIMU8-induced promotion of dendrite formation was reversed partially by the PKA inhibitor, suggesting involvement of PKA signaling downstream of the 5-HT4 receptor. Finally, we examined the contribution of brain-derived neurotrophic factor (BDNF) to the promotion of dendrite formation by BIMU8. Quantitative RT-PCR analysis showed that BIMU8 increased the BDNF mRNA expression and that treatment of cultured neurons with the TrkB antagonist reversed the BIMU8-induced increase in dendrite formation. In summary, the present study suggests a novel role for the 5-HT4 receptor in facilitation of dendrite formation in which intracellular signaling of PKA and the BDNF-TrkB system may be involved.

  4. Effect of piboserod, a 5-HT4 serotonin receptor antagonist, on left ventricular function in patients with symptomatic heart failure

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    Olsen, Inge C; Kjekshus, John K; Torp-Pedersen, Christian

    2009-01-01

    AIMS: Myocardial 5-HT(4) serotonin (5-HT) receptors are increased and activated in heart failure (HF). Blockade of 5-HT(4) receptors reduced left ventricular (LV) remodelling in HF rats. We evaluated the effect of piboserod, a potent, selective, 5-HT(4) serotonin receptor antagonist, on LV function...... weeks up titration. The primary endpoint was LVEF measured by cardiac magnetic resonance imaging (MRI). Secondary endpoints were LV volumes, N-terminal pro-brain natriuretic peptide, norepinephrine, quality of life, and 6 min walk test. Piboserod significantly increased LVEF by 1.7% vs. placebo (CI 0.......3, 3.2, P = 0.020), primarily through reduced end-systolic volume from 165 to 158 mL (P = 0.060). There was a trend for greater increase in LVEF (2.7%, CI -1.1, 6.6, P = 0.15) in a small subset of patients not on chronic beta-blocker therapy. There was no significant effect on neurohormones, quality...

  5. Serotonin(4) (5-HT(4)) receptor agonists are putative antidepressants with a rapid onset of action

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    Lucas, Guillaume; Rymar, Vladimir V; Du, Jenny

    2007-01-01

    and neurogenesis in the hippocampus. In contrast, a 3 day treatment with the SSRI citalopram remains devoid of any effect on these parameters. Finally, a 3 day regimen with the 5-HT(4) agonist RS 67333 was sufficient to reduce both the hyperlocomotion induced by olfactory bulbectomy and the diminution of sucrose...

  6. The Effect of Serotonin-Targeting Antidepressants on Neurogenesis and Neuronal Maturation of the Hippocampus Mediated via 5-HT1A and 5-HT4 Receptors

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    Eri Segi-Nishida

    2017-05-01

    Full Text Available Antidepressant drugs such as selective serotonin reuptake inhibitors (SSRIs specifically increase serotonin (5-HT levels in the synaptic cleft and are widely used to treat mood and anxiety disorders. There are 14 established subtypes of 5-HT receptors in rodents, each of which has regionally different expression patterns. Many preclinical studies have suggested that the hippocampus, which contains abundant 5-HT1A and 5-HT4 receptor subtypes in the dentate gyrus (DG, is critically involved in the mechanisms of action of antidepressants. This review article will analyze studies demonstrating regulation of hippocampal functions and hippocampus-dependent behaviors by SSRIs and similar serotonergic agents. Multiple studies indicate that 5-HT1A and 5-HT4 receptor signaling in the DG contributes to SSRI-mediated promotion of neurogenesis and increased neurotrophic factors expression. Chronic SSRI treatment causes functions and phenotypes of mature granule cells (GCs to revert to immature-like phenotypes defined as a “dematured” state in the DG, and to increase monoamine reactivity at the dentate-to-CA3 synapses, via 5-HT4 receptor signaling. Behavioral studies demonstrate that the 5-HT1A receptors on mature GCs are critical for expression of antidepressant effects in the forced swim test and in novelty suppressed feeding; such studies also note that 5-HT4 receptors mediate neurogenesis-dependent antidepressant activity in, for example, novelty-suppressed feeding. Despite their limitations, the collective results of these studies describe a potential new mechanism of action, in which 5-HT1A and 5-HT4 receptor signaling, either independently or cooperatively, modulates the function of the hippocampal DG at multiple levels, any of which could play a critical role in the antidepressant actions of 5-HT-enhancing drugs.

  7. Mosapride, a selective serotonin 5-HT4 receptor agonist, and alogliptin, a selective dipeptidyl peptidase-4 inhibitor, exert synergic effects on plasma active GLP-1 levels and glucose tolerance in mice.

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    Nonogaki, Katsunori; Kaji, Takao

    2015-12-01

    Pharmacologic stimulation of serotonin 5-HT4 receptors increased plasma active glucagon-like-peptide-1 (GLP-1) levels independent of feeding, and that pharmacologic stimulation of 5-HT4 receptors and pharmacologic inhibition of dipeptidyl peptidase-4 exerted synergic effects on plasma active GLP-1 levels and glucose tolerance in mice.

  8. The 5-HT(4) receptor levels in hippocampus correlates inversely with memory test performance in humans

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    Haahr, Mette Ewers; Fisher, Patrick; Holst, Klaus Kähler

    2013-01-01

    The cerebral serotonin (5-HT) system is involved in cognitive functions such as memory and learning and animal studies have repeatedly shown that stimulation of the 5-HT type 4 receptor (5-HT(4) R) facilitates memory and learning and further that the 5-HT(4) R modulates cellular memory processes ...

  9. Identification and functional characterisation of 5-HT4 receptor in sea cucumber Apostichopus japonicus (Selenka)

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    Wang, Tianming; Yang, Zhen; Zhou, Naiming; Sun, Lina; Lv, Zhenming; Wu, Changwen

    2017-01-01

    Serotonin (5-HT) is an important neurotransmitter and neuromodulator that controls a variety of sensory and motor functions through 5-HT receptors (5-HTRs). The 5-HT4R subfamily is linked to Gs proteins, which activate adenylyl cyclases (ACs), and is involved in many responses in peripheral organs. In this study, the 5-HT4R from Apostichopus japonicus (Aj5-HT4R) was identified and characterised. The cloned full-length Aj5-HT4R cDNA is 1,544 bp long and contains an open reading frame 1,011 bp in length encoding 336 amino acid proteins. Bioinformatics analysis of the Aj5-HT4R protein indicated this receptor was a member of class A G protein coupled receptor (GPCR) family. Further experiments using Aj5-HT4R-transfected HEK293 cells demonstrated that treatment with 5-HT triggered a significant increase in intracellular cAMP level in a dose-dependent manner and induced a rapid internalisation of Aj5-HT4R fused with enhanced green fluorescent protein (Aj5-HT4R-EGFP) from the cell surface into the cytoplasm. In addition, the transcriptional profiles of Aj5-HT4R in aestivating A. japonicas and phosphofructokinase (AjPFK) in 5-HT administrated A. japonicus have been analysed by real-time PCR assays. Results have led to a basic understanding of Aj5-HT4R in A. japonicus, and provide a foundation for further exploration of the cell signaling and regulatory functions of this receptor. PMID:28059140

  10. Kinetic modeling of 11C-SB207145 binding to 5-HT4 receptors in the human brain in vivo

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    Marner, Lisbeth; Gillings, Nic; Comley, Robert A;

    2009-01-01

    The serotonin 4 receptor (5-HT(4) receptor) is known to be involved in learning and memory. We evaluated for the first time the quantification of a novel 5-HT(4) receptor radioligand, (11)C-SB207145, for in vivo brain imaging with PET in humans. METHODS: For evaluation of reproducibility, 6 subje...

  11. High trait aggression in men is associated with low 5-HT levels, as indexed by 5-HT4 receptor binding

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    da Cunha-Bang, Sofi; Mc Mahon, Brenda; Fisher, Patrick MacDonald;

    2016-01-01

    Impulsive aggression has commonly been associated with a dysfunction of the serotonin (5-HT) system: many, but not all, studies point to an inverse relationship between 5-HT and aggression. As cerebral 5-HT4 receptor (5-HT4R) binding has recently been recognized as a proxy for stable brain levels...... of 5-HT, we here test the hypothesis in healthy men and women that brain 5-HT levels, as indexed by cerebral 5-HT4R, are inversely correlated with trait aggression and impulsivity. Sixty-one individuals (47 men) underwent positron emission tomography scanning with the radioligand [(11)C]SB207145...... for quantification of brain 5-HT4R binding. The Buss-Perry Aggression Questionnaire (BPAQ) and the Barratt Impulsiveness Scale were used for assessment of trait aggression and trait impulsivity. Among male subjects, there was a positive correlation between global 5-HT4R and BPAQ total score (P = 0.037) as well...

  12. High trait aggression in men is associated with low 5-HT levels, as indexed by 5-HT4 receptor binding.

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    da Cunha-Bang, Sofi; Mc Mahon, Brenda; Fisher, Patrick MacDonald; Jensen, Peter Steen; Svarer, Claus; Knudsen, Gitte Moos

    2016-04-01

    Impulsive aggression has commonly been associated with a dysfunction of the serotonin (5-HT) system: many, but not all, studies point to an inverse relationship between 5-HT and aggression. As cerebral 5-HT4 receptor (5-HT4R) binding has recently been recognized as a proxy for stable brain levels of 5-HT, we here test the hypothesis in healthy men and women that brain 5-HT levels, as indexed by cerebral 5-HT4R, are inversely correlated with trait aggression and impulsivity. Sixty-one individuals (47 men) underwent positron emission tomography scanning with the radioligand [(11)C]SB207145 for quantification of brain 5-HT4R binding. The Buss-Perry Aggression Questionnaire (BPAQ) and the Barratt Impulsiveness Scale were used for assessment of trait aggression and trait impulsivity. Among male subjects, there was a positive correlation between global 5-HT4R and BPAQ total score (P = 0.037) as well as BPAQ physical aggression (P = 0.025). No main effect of global 5-HT4R on trait aggression or impulsivity was found in the mixed gender sample, but there was evidence for sex interaction effects in the relationship between global 5-HT4R and BPAQ physical aggression. In conclusion we found that low cerebral 5-HT levels, as indexed by 5-HT4R binding were associated with high trait aggression in males, but not in females.

  13. Familial Risk for Major Depression is Associated with Lower Striatal 5-HT4 Receptor Binding

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    Madsen, Karine; Torstensen, Eva; Holst, Klaus Kähler

    2015-01-01

    BACKGROUND: The 5-HT4 receptor provides a novel potential target for antidepressant treatment. No studies exist to elucidate the 5-HT4 receptor's in vivo distribution in the depressed state or in populations that may display trait markers for major depression disorder (MDD). The aim of this study......-degree relatives with a history of MDD binding correlated negatively with 5-HT4 receptor binding in both the striatum (p = 0.001) and limbic regions (p = 0.012). CONCLUSIONS: Our data suggest that the 5-HT4 receptor is involved in the neurobiological mechanism underlying familial risk for depression...

  14. 5-HT4-receptors modulate induction of long-term depression but not potentiation at hippocampal output synapses in acute rat brain slices.

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    Matthias Wawra

    Full Text Available The subiculum is the principal target of CA1 pyramidal cells and mediates hippocampal output to various cortical and subcortical regions of the brain. The majority of subicular pyramidal cells are burst-spiking neurons. Previous studies indicated that high frequency stimulation in subicular burst-spiking cells causes presynaptic NMDA-receptor dependent long-term potentiation (LTP whereas low frequency stimulation induces postsynaptic NMDA-receptor-dependent long-term depression (LTD. In the present study, we investigate the effect of 5-hydroxytryptamine type 4 (5-HT4 receptor activation and blockade on both forms of synaptic plasticity in burst-spiking cells. We demonstrate that neither activation nor block of 5-HT4 receptors modulate the induction or expression of LTP. In contrast, activation of 5-HT4 receptors facilitates expression of LTD, and block of the 5-HT4 receptor prevents induction of short-term depression and LTD. As 5-HT4 receptors are positively coupled to adenylate cyclase 1 (AC1, 5-HT4 receptors might modulate PKA activity through AC1. Since LTD is blocked in the presence of 5-HT4 receptor antagonists, our data are consistent with 5-HT4 receptor activation by ambient serotonin or intrinsically active 5-HT4 receptors. Our findings provide new insight into aminergic modulation of hippocampal output.

  15. A single mutation in the 5-HT4 receptor (5-HT4-R D100(3.32)A) generates a Gs-coupled receptor activated exclusively by synthetic ligands (RASSL).

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    Claeysen, Sylvie; Joubert, Lara; Sebben, Michèle; Bockaert, Joël; Dumuis, Aline

    2003-01-10

    To better understand G-protein-coupled receptor (GPCRs) signaling, cellular and animal physiology, as well as gene therapy, a new tool has recently been proposed. It consists of GPCR mutants that are insensitive to endogenous ligands but sensitive to synthetic ligands. These GPCRs are called receptor activated solely by synthetic ligands (RASSL). Only two examples of such engineered receptors have been described so far: one G(i)-coupled (opioid receptors) and one G(s)-coupled (beta(2)-adrenergic receptors). Here, we describe the first RASSL related to serotonin receptors (D100(3.32)A G(s)-coupled 5-HT(4) receptor or 5-HT(4)-RASSL). 5-HT(4)-RASSL is generated by a single mutation, is totally insensitive to serotonin (5-HT), and still responds to synthetic ligands. These ligands have affinities in the range of nanomolar concentrations for the mutant receptor and exhibit full efficacy. More interestingly, two synthetic ligands behave as antagonists on the wild type but as agonists on the 5-HT(4)-RASSL.

  16. Modifications of 5-HT4 receptor expression in rat brain during memory consolidation.

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    Manuel-Apolinar, L; Rocha, L; Pascoe, D; Castillo, E; Castillo, C; Meneses, A

    2005-04-25

    Pharmacological evidence indicates a specific role of 5-HT(4) receptors on memory function. These receptors are members of G-protein-coupled 7-transmembrane domain receptor superfamily, are positively coupled to adenylyl cyclase, and are heterogeneously located in some structures important for memory, such as the hippocampus and cortical regions. To further clarify 5-HT(4) receptors' role in memory, the expression of these receptors in passive (P3) untrained and autoshaping (A3) trained (3 sessions) adult (3 months) and old (P9 or A9; 9 months) male rats was determined by autoradiography. Adult trained (A3) rats showed a better memory respect to old trained (A9). Using [(3)H] GR113808 as ligand (0.2 nM specific activity 81 Ci/mmol) for 5-HT(4) receptor expression, 29 brain areas were analyzed, 16 areas of A3 and 17 of A9 animals displayed significant changes. The medial mammillary nucleus of A3 group showed diminished 5-HT(4) receptor expression, and in other 15 brain areas of A3 or 10 of A9 animals, 5-HT(4) receptors were increased. Thus, for A3 rats, 5-HT(4) receptors were augmented in olfactory lobule, caudate putamen, fundus striatum, CA2, retrosplenial, frontal, temporal, occipital, and cingulate cortex. Also, 5-HT(4) receptors were increased in olfactory tubercule, hippocampal CA1, parietal, piriform, and cingulate cortex of A9. However, hippocampal CA2 and CA3 areas, and frontal, parietal, and temporal cortex of A9 rats, expressed less 5-HT(4) receptors. These findings suggest that serotonergic activity, via 5-HT(4) receptors in hippocampal, striatum, and cortical areas, mediates memory function and provides further evidence for a complex and regionally specific regulation over 5-HT receptor expression during memory formation.

  17. Autoantibodies against serotoninergic 5-HT(4) receptor in patients with heart failure.

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    Breidert, M; Wördehoff, S; Hansen, A; Eftekhari, P

    2012-01-01

    Serotoninergic 5-HT(4) receptors have been detected in several tissues including the heart. An autoimmune mechanism may underline the pathogenesis of heart failure. The aim of this work was to look for autoantibodies to the 5-HT(4) receptor in patients with heart failure. We looked for the presence of autoantibodies against 5-HT(4) receptor as well as angiotensin II type (AT1), β(1)-adrenoceptor, and muscarinic M2 receptors in the sera of 176 patients with heart failure (female: n=96, male: n=80) and in 108 controls (female: n=69; male: n=39). The prevalence of 5-HT(4) receptor autoantibodies was 18.8% (n=33) in the group of patients with heart failure and 4.6% (n=5) in the control group (preceptor M2 4.2 (n=5). Female patients with diabetes and heart failure had a positive trend (p=0.07) to the presence of 5-HT(4) receptor autoantibodies. In the group of female heart failure patients we found a significant correlation with the presence of coronary heart disease (p=0.05). The clinical relevance of 5-HT(4) receptor autoantibodies has to be further studied. The prevalence of 5-HT(4) receptor autoantibodies was highly significant in patients with chronic heart failure. It was also a significant correlation between these autoantibodies and the female subgroup with coronary heart disease. It is conceivable that the increased prevalence of autoantibodies against the 5-HT(4) receptor in patients with heart failure is more than just an epiphenomenon.

  18. Effects of 5-HT4 receptor agonists and antagonists in learning.

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    Meneses, A; Hong, E

    1997-03-01

    In the present work, the effects of pre- or post-training (ip) injection of BIMU1 and BIMU8 (5-HT4 agonists) were figured out in the autoshaping learning task. Furthermore, the post-training effects of these agonists after treatment with SDZ 205-557 and GR 125487D (5-HT4 antagonists) or p-Chloroamphetamine (PCA) were also explored. Animals were individually trained in a lever-press response on the autoshaping task and 24 hours later were tested. The results showed that pre-training injection of BIMU1 (5 20 mg/Kg) or BIMU8 (20 mg/Kg) increased the CR; in contrast, the post-training administration of BIMU1 (10-20 mg/Kg) or BIMU8 (5 and 20 mg/Kg) decreased it. Further experiments revealed that the post-training injections of SDZ 205-557 (1.0-10.0 mg/Kg) or GR 125487D (0.39-1.56 mg/Kg) by themselves did not alter the CR. When BIMU1 or BIMU8 was administered to rats pretreated with SDZ 205-557 (10 mg/Kg) or GR 125487D (0.78 mg/Kg), the decrement induced by 5-HT4 the agonists was reversed; in contrast, the administration of PCA failed to modify the CR or the agonist-induced responses. The findings showed that the pre-training stimulation of 5-HT4 receptors enhanced the acquisition of CR, while, post-training activation of 5-HT4 receptors, impaired the consolidation of learning. The latter effect was not altered by PCA pretreatment. The data show that 5-HT4 receptors are involved in the acquisition and consolidation of learning. It seems that postsynaptic 5-HT4 receptors are involved in the latter effect.

  19. Does Cisapride, as a 5HT4 Receptor Agonist, Aggravate the Severity of TNBS-Induced Colitis in Rat?

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    Azadeh Motavallian

    2012-01-01

    Full Text Available There is a pressing need for research that will lead to the reveal of targets designed to analyse the possible pathways for the treatment of IBD. Because of the probable involvement of serotonin in inflammatory conditions of intestine and the important role of 5HT4 receptors in GI function, the investigation of the role of 5HT4 receptors in the pathogenesis of IBD will be interesting. The aim of this study was to investigate the effects of cisapride, a 5HT4 receptor agonist, in trinitrobenzenesulfonic-acid-(TNBS induced rat colitis. Two hours subsequent to induction of colitis using TNBS in rats, cisapride (2 mg/kg, intraperitoneally (i.p; 4 mg/kg, orally (p.o and dexamethasone (1 mg/kg, i.p; 2 mg/kg, p.o were administrated for 6 days. Animals were thereafter euthanized; macroscopic, histological, and biochemical assessments and ELISA test were carried out on distal colon samples. Our data showed that dexamethasone treatment (i.p, p.o significantly decreased macroscopic and microscopic damage and also biochemical markers, but there were no significant differences in aforementioned parameters between cisapride (i.p or p.o and TNBS-treated rats. It can be deduced that because the severity of colitis produced by TNBS is massive (through various pathways, cisapride could not bring about more colitis damages through 5HT4 receptors. Based on the present study further researches are required for investigating the exact roles of 5HT4 receptors in the pathogenesis of ulcerative colitis.

  20. 3D Pharmacophore, hierarchical methods, and 5-HT4 receptor binding data.

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    Varin, Thibault; Saettel, Nicolas; Villain, Jonathan; Lesnard, Aurelien; Dauphin, François; Bureau, Ronan; Rault, Sylvain

    2008-10-01

    5-Hydroxytryptamine subtype-4 (5-HT(4)) receptors have stimulated considerable interest amongst scientists and clinicians owing to their importance in neurophysiology and potential as therapeutic targets. A comparative analysis of hierarchical methods applied to data from one thousand 5-HT(4) receptor-ligand binding interactions was carried out. The chemical structures were described as chemical and pharmacophore fingerprints. The definitions of indices, related to the quality of the hierarchies in being able to distinguish between active and inactive compounds, revealed two interesting hierarchies with the Unity (1 active cluster) and pharmacophore fingerprints (4 active clusters). The results of this study also showed the importance of correct choice of metrics as well as the effectiveness of a new alternative of the Ward clustering algorithm named Energy (Minimum E-Distance method). In parallel, the relationship between these classifications and a previously defined 3D 5-HT(4) antagonist pharmacophore was established.

  1. Effects of the 5-HT(4) receptor agonist RS67333 and paroxetine on hippocampal extracellular 5-HT levels

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    Licht, Cecilie Löe; Knudsen, Gitte Moos; Sharp, Trevor

    2010-01-01

    The 5-HT(4) receptor modulates activity of serotonergic neurons and is a new potential target for antidepressant treatment. This microdialysis study evaluated the effect of the 5-HT(4) receptor agonist, RS67333, on extracellular serotonin (5-hydroxytryptamine, 5-HT) and 5-HIAA levels in rat ventral...... on extracellular 5-HT or 5-HIAA levels, while acute paroxetine (0.5mg/kg i.v.) increased 5-HT levels by 299+/-16% and decreased 5-HIAA levels by 25+/-4%. Administration of RS67333 80 min after paroxetine caused an additional transient increase in 5-HT levels (to 398+/-52% of baseline). Subchronic RS67333...... administration (1.5mg/kg i.p.) increased basal 5-HT levels by 73+/-15% and decreased 5-HIAA levels by 27+/-13%. In conclusion, the 5-HT(4) receptor agonist RS67333 augmented the acute effect of paroxetine on extracellular 5-HT levels in the ventral hippocampus, and after 3 days increased basal hippocampal 5-HT...

  2. Comparison of 5-HT4 and 5-HT7 receptor expression and function in the circular muscle of the human colon.

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    Irving, Helen R; Tan, Yean Y; Tochon-Danguy, Nathalie; Liu, Haihuang; Chetty, Navinisha; Desmond, Paul V; Pouton, Colin W; Coupar, Ian M

    2007-03-06

    Serotonin receptors are potential targets for treating functional bowel disorders. This study investigated the functional roles and expression of the 5-HT4 and the 5-HT7 receptor, which coexist in human colon circular smooth muscle. 5-HT3 receptor expression was also investigated. Part of the relaxant response to 5-HT was due to activation of 5-HT4 receptors as the apparent pKB value of the selective 5-HT4 antagonist, GR 113808, was 9.36. 5-HT4 mRNA levels were low in five tissues and undetectable in four others, but all responded to 5-HT with an EC50 value of 102.54+/-19.32 nM. The contribution of 5-HT7 receptors to the response was not readily demonstrated using the selective 5-HT7 antagonist, SB-269970, as its apparent pKB value of 7.19 (5-HT4 block with 1 microM GR 113808) was lower than the value obtained using the 5-HT7 guinea pig ileum assay (8.62). Nevertheless, the 5-HT7 receptor was expressed more consistently than the 5-HT4, but at similar levels. The 5-HT(3Ashort) and 5-HT(3B) subunits were co-expressed at similar levels, but the 5-HT(3Along) subunit was detected in only five of the nine samples tested. The findings show that 5-HT4-induced relaxation occurs at low to undetectable levels of tissue mRNA, as measured by qPCR. Although 5-HT7 receptor mRNA is detected at low, but consistent levels, the functional activity of this receptor is not readily identified given the currently available drugs.

  3. Changes in 5-HT4 receptor and 5-HT transporter binding in olfactory bulbectomized and glucocorticoid receptor heterozygous mice

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    Licht, Cecilie L; Kirkegaard, Lisbeth; Zueger, Maha;

    2010-01-01

    . The olfactory bulbectomized mice displayed increased activity in the open field test, a characteristic depression-like feature of this model. After bulbectomy, 5-HT(4) receptor binding was increased in the ventral hippocampus (12%) but unchanged in the dorsal hippocampus, frontal and caudal caudate putamen....... Among post hoc analyzed regions, there was a 14% decrease in 5-HT(4) receptor binding in the olfactory tubercles. The 5-HTT binding was unchanged in the hippocampus and caudate putamen of bulbectomized mice but post hoc analysis showed small decreases in lateral septum and lateral globus pallidus....... In comparison, GR(+/-) mice had increased 5-HT(4) receptor (11%) binding in the caudal caudate putamen and decreased 5-HTT binding in the frontal caudate putamen but no changes in dorsal and ventral hippocampus. Post hoc analysis showed increased 5-HT(4) receptor binding in the olfactory tubercles of GR...

  4. Induction of neonatal lupus in pups of mice immunized with synthetic peptides derived from amino acid sequences of the serotoninergic 5-HT4 receptor.

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    Eftekhari, P; Roegel, J C; Lezoualc'h, F; Fischmeister, R; Imbs, J L; Hoebeke, J

    2001-02-01

    We have previously suggested that the recognition of a cross-reactive epitope on the 5-HT4 receptor and the 52-kDa SSA/Ro protein by serotonin-antagonizing autoantibodies could explain the electrophysiological symptoms of congenital heart block in neonatal lupus. To confirm this hypothesis, we immunized female mice with four synthetic peptides corresponding to the recognized epitopes. All mice developed anti-peptide antibodies, which cross-reacted with the Ro52 and 5-HT4 receptor peptides and recognized both cognate proteins. Peptide-immune mice were mated. The pups from mice immunized with the Ro52 peptides had no symptoms of neonatal lupus apart from bradycardia. However, pups from mice immunized with the 5-HT4 receptor peptides and bradycardia, atrioventricular block of type I or II, longer QT intervals, skin rashes and neuromotor problems. The 5-HT4 receptor was detectable in the different fetal tissues affected (heart, skin and brain) by immunohistochemistry. Hearts from diseased pups were less developed and showed disorganized myocardial hyperplasia, compared to the normal littermates. These results demonstrate that the serotoninergic 5-HT4 receptor is the antigenic target of physiopathological autoantibodies in neonatal lupus.

  5. Evaluation of the novel 5-HT4 receptor PET ligand [11C]SB207145 in the Gottingen minipig

    DEFF Research Database (Denmark)

    Kornum, B.R.; Lind, N.M.; Gillings, N.;

    2009-01-01

    model provides stable and precise estimates of the binding potential in all regions. The binding potentials calculated for striatum, midbrain, and cortex from the PET data were highly correlated with 5-HT(4) receptor concentrations determined in brain homogenates from the same regions, except...... for hippocampus where PET-measurements significantly underestimate the 5-HT(4) receptor binding, probably because of partial volume effects. This study validates the use of [(11)C]SB207145 as a promising PET radioligand for in vivo brain imaging of the 5-HT(4) receptor in humans Udgivelsesdato: 2009/1...

  6. Modulation of hippocampal excitability by 5-HT4 receptor agonists persists in a transgenic model of Alzheimer's disease.

    Science.gov (United States)

    Spencer, J P; Brown, J T; Richardson, J C; Medhurst, A D; Sehmi, S S; Calver, A R; Randall, A D

    2004-01-01

    5-HT(4) receptors are widely distributed in both peripheral and central nervous systems where they couple, via a G-protein, to the activation of adenylate cyclase. In the brain, the highest 5-HT(4) receptor densities are found in the limbic system, including the hippocampus and frontal cortex. It has been suggested that activation of these receptors may be of therapeutic benefit in diseases that produce cognitive deficits such as Alzheimer's disease (AD). Previous electrophysiological studies have shown that the 5-HT(4) agonist, Zacopride, can increase population spike amplitude recorded in region CA1 of rat hippocampal slices in a cyclic AMP (cAMP)/cAMP-dependent protein kinase A-dependent manner. We report here that the 5-HT(4) agonist, Prucalopride, and the 5-HT(4) partial agonist, SL65.0155, produce a similar effect in rat hippocampal slices and that the specific 5-HT(4) antagonist, GR113808, blocks these effects. To investigate the potential use of 5-HT(4) agonists in the treatment of AD, Prucalopride was applied to hippocampal slices from a transgenic mouse line that overexpresses the Abeta peptide. Despite the deficit in synaptic transmission present in these mice, the percentage increase of the CA1 population spike induced by Prucalopride was the same as that observed in wild-type mice. These data support 5-HT(4) receptors as a target for cognitive enhancement and suggest that a partial agonist would be sufficient to produce benefits, while reducing potential peripheral side effects. In addition, we show that 5-HT(4) receptors remain functional in the presence of excess Abeta peptide and may therefore be a useful target in AD.

  7. Changes in 5-HT4 receptor and 5-HT transporter binding in olfactory bulbectomized and glucocorticoid receptor heterozygous mice

    DEFF Research Database (Denmark)

    Licht, Cecilie Löe; Kirkegaard, Lisbeth; Zueger, Maha;

    2010-01-01

    The 5-HT(4) receptor is a new potential target for antidepressant treatment and may be implicated in the pathogenesis of depression. This study investigated differences in 5-HT(4) receptor and 5-HT transporter (5-HTT) binding by quantitative autoradiography of [(3)H]SB207145 and (S)-[N-methyl-(3)H......]citalopram in two murine models of depression-related states, olfactory bulbectomy and glucocorticoid receptor heterozygous (GR(+/-)) mice. The olfactory bulbectomy model is characterized by 5-HT system changes, while the GR(+/-) mice have a deficit in hypothalamic-pituitary-adrenal (HPA) system control....... The olfactory bulbectomized mice displayed increased activity in the open field test, a characteristic depression-like feature of this model. After bulbectomy, 5-HT(4) receptor binding was increased in the ventral hippocampus (12%) but unchanged in the dorsal hippocampus, frontal and caudal caudate putamen...

  8. Pharmacological profile of DA-6886, a novel 5-HT4 receptor agonist to accelerate colonic motor activity in mice.

    Science.gov (United States)

    Lee, Min Jung; Cho, Kang Hun; Park, Hyun Min; Sung, Hyun Jung; Choi, Sunghak; Im, Weonbin

    2014-07-15

    DA-6886, the gastrointestinal prokinetic benzamide derivative is a novel 5-HT4 receptor agonist being developed for the treatment of constipation-predominant irritable bowel syndrome (IBS-C). The purpose of this study was to characterize in vitro and in vivo pharmacological profile of DA-6886. We used various receptor binding assay, cAMP accumulation assay, organ bath experiment and colonic transit assay in normal and chemically constipated mice. DA-6886 exhibited high affinity and selectivity to human 5-HT4 receptor splice variants, with mean pKi of 7.1, 7.5, 7.9 for the human 5-HT4a, 5-HT4b and 5-HT4d, respectively. By contrast, DA-6886 did not show significant affinity for several receptors including dopamine D2 receptor, other 5-HT receptors except for 5-HT2B receptor (pKi value of 6.2). The affinity for 5-HT4 receptor was translated into functional agonist activity in Cos-7 cells expressing 5-HT4 receptor splice variants. Furthermore, DA-6886 induced relaxation of the rat oesophagus preparation (pEC50 value of 7.4) in a 5-HT4 receptor antagonist-sensitive manner. The evaluation of DA-6886 in CHO cells expressing hERG channels revealed that it inhibited hERG channel current with an pIC50 value of 4.3, indicating that the compound was 1000-fold more selective for the 5-HT4 receptor over hERG channels. In the normal ICR mice, oral administration of DA-6886 (0.4 and 2mg/kg) resulted in marked stimulation of colonic transit. Furthermore, in the loperamide-induced constipation mouse model, 2mg/kg of DA-6886 significantly improved the delay of colonic transit, similar to 10mg/kg of tegaserod. Taken together, DA-6886 is a highly potent and selective 5-HT4 receptor agonist to accelerate colonic transit in mice, which might be therapeutic agent having a favorable safety profile in the treatment of gastrointestinal motor disorders such as IBS-C and chronic constipation.

  9. Early administration of RS 67333, a specific 5-HT4 receptor agonist, prevents amyloidogenesis and behavioral deficits in the 5XFAD mouse model of Alzheimer’s disease

    Directory of Open Access Journals (Sweden)

    Patrizia eGiannoni

    2013-12-01

    Full Text Available Amyloid β (Aβ accumulation is considered the main culprit in the pathogenesis of Alzheimer's disease (AD. Recent studies suggest that decreasing Aβ production at very early stages of AD could be a promising strategy to slow down disease progression. Serotonin 5-HT4 receptor activation stimulates α-cleavage of the amyloid precursor protein (APP, leading to the release of the soluble and neurotrophic sAPPα fragment and thus precluding Aβ formation. Using the 5XFAD mouse model of AD that shows accelerated Aβ deposition, we investigated the effect of chronic treatments (treatment onset at different ages and different duration with the 5-HT4 receptor agonist RS 67333 during the asymptomatic phase of the disease. Chronic administration of RS 67333 decreased concomitantly the number of amyloid plaques and the level of Aβ species. Reduction of Aβ levels was accompanied by a striking decrease in hippocampal astrogliosis and microgliosis. RS 67333 also transiently increased sAPPα concentration in the cerebrospinal fluid and brain. Moreover, a specific 5-HT4 receptor antagonist (RS 39604 prevented the RS 67333-mediated reduction of the amyloid pathology. Finally, the novel object recognition test deficits of 5XFAD mice were reversed by chronic treatment with RS 67333. Collectively, these results strongly highlight this 5-HT4 receptor agonist as a promising disease modifying-agent for AD.

  10. Central 5-HT4 receptor binding as biomarker of serotonergic tonus in humans

    DEFF Research Database (Denmark)

    Haahr, M E; Fisher, P M; Jensen, C G

    2014-01-01

    levels, is associated with a decline in brain 5-HT4R binding. A total of 35 healthy men were studied in a placebo-controlled, randomized, double-blind study. Participants were assigned to receive 3 weeks of oral dosing with placebo or fluoxetine, 40 mg per day. Brain 5-HT4R binding was quantified...... at baseline and at follow-up with [(11)C]SB207145 positron emission tomography (PET). Three weeks of intervention with fluoxetine was associated with a 5.2% reduction in brain 5-HT4R binding (P=0.017), whereas placebo intervention did not change 5-HT4R binding (P=0.52). Our findings are consistent...

  11. Isolation of the serotoninergic 5-HT4(e) receptor from human heart and comparative analysis of its pharmacological profile in C6-glial and CHO cell lines

    Science.gov (United States)

    Mialet, Jeanne; Berque-Bestel, Isabelle; Eftekhari, Pierre; Gastineau, Monique; Giner, Mireille; Dahmoune, Yamina; Donzeau-Gouge, Patrick; Hoebeke, Johan; Langlois, Michel; Sicsic, Sames; Fischmeister, Rodolphe; Lezoualc'h, Frank

    2000-01-01

    RT–PCR technique was used to clone the human 5-HT4(e) receptor (h5-HT4(e)) from heart atrium. We showed that this h5-HT4(e) receptor splice variant is restricted to brain and heart atrium. Recombinant h5-HT4(e) receptor was stably expressed in CHO and C6-glial cell lines at 347 and 88 fmol mg−1 protein, respectively. Expression of h5-HT4(e) receptors at the cell membrane was confirmed by immunoblotting. The receptor binding profile, determined by competition with [3H]-GR113808 of a number of 5-HT4 ligands, was consistent with that previously reported for other 5-HT4 receptor isoforms. Surprisingly, we found that the rank order of potencies (EC50) of 5-HT4 agonists obtained from adenylyl cyclase functional assays was inversely correlated to their rank order of affinities (Ki) obtained from binding assays. Furthermore, EC50 values for 5-HT, renzapride and cisapride were 2 fold lower in C6-glial cells than in CHO cells. ML10302 and renzapride behaved like partial agonists on the h5-HT4(e) receptor. These results are in agreement with the reported low efficacy of the these two compounds on L-type Ca2+ currents and myocyte contractility in human atrium. A constitutive activity of the h5-HT4(e) receptor was observed in CHO cells in the absence of any 5-HT4 ligand and two 5-HT4 antagonists, GR113808 and ML10375, behaved as inverse agonists. These data show that the h5-HT4(e) receptor has a pharmacological profile which is close to the native h5-HT4 receptor in human atrium with a functional potency which is dependent on the cellular context in which the receptor is expressed. PMID:10683202

  12. Genetic variation in 5-hydroxytryptamine transporter expression causes adaptive changes in 5-HT4 receptor levels

    DEFF Research Database (Denmark)

    Jennings, Katie Ann; Licht, Cecilie Löe; Bruce, Aynsley

    2012-01-01

    +/+ mice in all brain regions. Compared to wild-type (WT) littermate controls, 5-HTT OE mice had increased 5-HT4 binding density across all brain regions, except amygdala (118-164% of WT) and this difference between genotypes was reduced by the 5-HTT inhibitor, fluoxetine (20 mg/kg twice daily, 3 d...

  13. The brain 5-HT4 receptor binding is down-regulated in the Flinders Sensitive Line depression model and in response to paroxetine administration

    DEFF Research Database (Denmark)

    Licht, Cecilie Löe; Marcussen, Anders Bue; Wegener, Gregers

    2009-01-01

    The 5-hydroxytryptamine (5-HT(4)) receptor may be implicated in depression and is a new potential target for antidepressant treatment. We have investigated the brain 5-HT(4) receptor [(3)H]SB207145 binding in the Flinders Sensitive Line rat depression model by quantitative receptor autoradiography......, and related this to 5-HT transporter (S)-[N-methyl-(3)H]citalopram binding. We also determined the regulation of 5-HT(4) receptor binding by 1, 14, and 21 days of paroxetine administration and subchronic 5-HT depletion, and compared this with changes in 5-HT(2A) receptor [(3)H]MDL100907 binding....... In the Flinders Sensitive Line, the 5-HT(4) receptor and 5-HT transporter binding were decreased in the dorsal and ventral hippocampus, and the changes in binding were directly correlated within the dorsal hippocampus. Chronic but not acute paroxetine administration caused a 16-47% down-regulation of 5-HT(4...

  14. Evaluation of the novel 5-HT4 receptor PET ligand [11C]SB207145 in the Göttingen minipig

    DEFF Research Database (Denmark)

    Kornum, Birgitte R; Lind, Nanna M; Gillings, Nic;

    2009-01-01

    This study investigates 5-hydroxytryptamine 4 (5-HT(4)) receptor binding in the minipig brain with positron emission tomography (PET), tissue homogenate-binding assays, and autoradiography in vitro. The cerebral uptake and binding of the novel 5-HT(4) receptor radioligand [(11)C]SB207145 in vivo...... autoradiographic 5-HT(4) receptor distribution resembles the human 5-HT(4) receptor distribution with the highest binding in the striatum and no detectable binding in the cerebellum. We found that in the minipig brain [(11)C]SB207145 follows one-tissue compartment kinetics, and the simplified reference tissue...... model provides stable and precise estimates of the binding potential in all regions. The binding potentials calculated for striatum, midbrain, and cortex from the PET data were highly correlated with 5-HT(4) receptor concentrations determined in brain homogenates from the same regions, except...

  15. Dual histamine H3R/serotonin 5-HT4R ligands with antiamnesic properties: pharmacophore-based virtual screening and polypharmacology.

    Science.gov (United States)

    Lepailleur, Alban; Freret, Thomas; Lemaître, Stéphane; Boulouard, Michel; Dauphin, François; Hinschberger, Antoine; Dulin, Fabienne; Lesnard, Aurélien; Bureau, Ronan; Rault, Sylvain

    2014-06-23

    In recent years, preclinical and clinical studies have generated considerable interest in the development of histamine H3 receptor (H3R) antagonists as novel treatment for degenerative disorders associated with impaired cholinergic function. To identify novel scaffolds for H3R antagonism, a common feature-based pharmacophore model was developed and used to screen the 17,194 compounds of the CERMN (Centre d'Etudes et de Recherche sur le Médicament de Normandie) chemical library. Out of 268 virtual hits which have been gathered in 34 clusters, we were particularly interested in tricyclic derivatives also exhibiting a potent 5HT4R affinity. Benzo[h][1,6]naphthyridine derivatives showed the highest H3R affinity, and compound 17 (H3R Ki = 41.6 nM; 5-HT4R Ki = 208 nM) completely reversed the amnesiant effect of scopolamine at 3 mg/kg in a spatial working memory experiment. For the first time we demonstrated the feasibility to combine H3R and 5-HT4R activities in a single molecule, raising the exciting possibility that dual H3R antagonist/5HT4R agonist have potential for the treatment of neurodegenerative diseases such as Alzheimer's disease.

  16. Age and sex effects on 5-HT(4) receptors in the human brain: a [(11)C]SB207145 PET study

    DEFF Research Database (Denmark)

    Madsen, Karine; Haahr, Mette T; Marner, Lisbeth;

    2011-01-01

    Experimental studies indicate that the 5-HT(4) receptor activation influence cognitive function, affective symptoms, and the development of Alzheimer's disease (AD). The prevalence of AD increases with aging, and women have a higher predisposition to both AD and affective disorders than men....... This study aimed to investigate sex and age effects on 5-HT(4) receptor-binding potentials in striatum, the limbic system, and neocortex. Positron-emission tomographic scans were conducted using the radioligand [(11)C]SB207145 in a cohort of 30 healthy subjects (mean age 44 years; range 20 to 86 years; 14...... men and 16 women). The output parameter, BP(ND), was modeled using the simplified reference tissue model, and partial volume correction was performed with the Muller-Gartner method. A decline with age of 1% per decade was found only in striatum. Women had a 13% lower 5-HT(4) receptor binding...

  17. Age and sex effects on 5-HT(4) receptors in the human brain: a [(11)C]SB207145 PET study

    DEFF Research Database (Denmark)

    Madsen, Karine; Haahr, Mette T; Marner, Lisbeth;

    2011-01-01

    . This study aimed to investigate sex and age effects on 5-HT(4) receptor-binding potentials in striatum, the limbic system, and neocortex. Positron-emission tomographic scans were conducted using the radioligand [(11)C]SB207145 in a cohort of 30 healthy subjects (mean age 44 years; range 20 to 86 years; 14...

  18. Clinical pharmacodynamics of SDZ HTF 919, a new 5-HT4 receptor agonist, in a model of slow colonic transit.

    Science.gov (United States)

    Appel, S; Kumle, A; Meier, R

    1997-11-01

    To explore the pharmacodynamic effects of the new promotile agent SDZ HTF 919, a selective partial 5-HT4 receptor agonist, in healthy subjects. A pharmacodynamic model was applied to prolong colonic transit by dietary means. Subsequently, the effects of twice-daily multiple doses of SDZ HTF 919 (1, 5, 25, and 100 mg) were investigated in a randomized, double-blind, placebo-controlled parallel-group study with 12 subjects per dose level. The sequential design with three study periods of 7 days each included intake of a self-selected diet, a liquid formula diet with soluble fiber supplementation, and a fiber-supplemented diet together with either SDZ HTF 919 or placebo administration. Stool characteristics (frequency and consistency) and total colonic transit times (with use of radiopaque markers) were recorded in each study period. SDZ HTF 919 was well tolerated at all dose levels. The frequency of loose stool and headache increased with higher doses. After a fiber-supplemented diet intake, the median stool frequency decreased from 8 1/2-9 to 5-7 defecations per study period. SDZ HTF 919 in doses of 25 and 100 mg twice a day increased the stool frequency (p HTF 919 dose. A fiber-supplemented diet prolonged total colonic transit time in all groups by 45 hours on average. Twice-a-day administration of SDZ HTF 919 for 6 days in addition to a fiber-supplemented diet significantly shortened the total colonic transit time only at the 5 mg dose. The lack of effect at lower and higher SDZ HTF 919 doses suggests a biphasic dose-response relationship for total colonic transit time. The suitability of total colonic transit time measurements in healthy subjects as a surrogate marker should be confirmed by patient studies.

  19. Hyperfunction of muscarinic receptor maintains long-term memory in 5-HT4 receptor knock-out mice.

    Directory of Open Access Journals (Sweden)

    Luis Segu

    Full Text Available Patients suffering from dementia of Alzheimer's type express less serotonin 4 receptors (5-HTR(4, but whether an absence of these receptors modifies learning and memory is unexplored. In the spatial version of the Morris water maze, we show that 5-HTR(4 knock-out (KO and wild-type (WT mice performed similarly for spatial learning, short- and long-term retention. Since 5-HTR(4 control mnesic abilities, we tested whether cholinergic system had circumvented the absence of 5-HTR(4. Inactivating muscarinic receptor with scopolamine, at an ineffective dose (0.8 mg/kg to alter memory in WT mice, decreased long-term but not short-term memory of 5-HTR(4 KO mice. Other changes included decreases in the activity of choline acetyltransferase (ChAT, the required enzyme for acetylcholine synthesis, in the septum and the dorsal hippocampus in 5-HTR(4 KO under baseline conditions. Training- and scopolamine-induced increase and decrease, respectively in ChAT activity in the septum in WT mice were not detected in the 5-HTR(4 KO animals. Findings suggest that adaptive changes in cholinergic systems may circumvent the absence of 5-HTR(4 to maintain long-term memory under baseline conditions. In contrast, despite adaptive mechanisms, the absence of 5-HTR(4 aggravates scopolamine-induced memory impairments. The mechanisms whereby 5-HTR(4 mediate a tonic influence on ChAT activity and muscarinic receptors remain to be determined.

  20. Behavioral effects of D3 receptor inhibition and 5-HT4 receptor activation on animals undergoing chronic cannabinoid exposure during adolescence.

    Science.gov (United States)

    Abboussi, Oualid; Said, Nadia; Fifel, Karim; Lakehayli, Sara; Tazi, Abdelouahhab; El Ganouni, Soumaya

    2016-04-01

    Chronic exposure to cannabinoids during adolescence results in long-lasting behavioral deficits that match some symptomatologic aspects of schizophrenia. The aim of this study was to investigate the reversibility of the emotional and the cognitive effects of chronic exposure to cannabinoids during adolescence, via subsequent modulation of the serotoninergic 5-HT4 and dopaminergic D3 receptors. RS67333 as a 5-HT4 agonist and U-99194A as a D3 antagonist were administered separately at 1 mg/kg and 20 mg/kg, and in combination at 0.5 mg/kg and 10 mg/kg to adult animals undergoing chronic treatment with the synthetic cannabinoid receptor agonist WIN55,212-2 (1 mg/kg) during adolescence. Animals were tested for anxiety-like behavior and episodic-like memory in the open field and novel object recognition tests respectively 30 minutes after the last drug administration. Chronic WIN55,212-2 treated animals exhibited a lasting disruption of episodic memory and increased anxiety levels. The effect on episodic-like memory were partially restored by acute administration of RS67333 and U-99194A and completely by administration of both drugs in combination at lower doses. However, only RS67333 (20 mg/kg) improved the anxiogenic-like effect of WIN55,212-2. These findings give further support that chronic exposure to cannabinoids during adolescence may be used as an animal model for schizophrenia, and highlight D3 and 5-HT4 receptors as potential targets for an enhanced treatment of the cognitive aspect of this disease.

  1. The absence of 5-HT4 receptors modulates depression- and anxiety-like responses and influences the response of fluoxetine in olfactory bulbectomised mice: Adaptive changes in hippocampal neuroplasticity markers and 5-HT1A autoreceptor.

    Science.gov (United States)

    Amigó, J; Díaz, A; Pilar-Cuéllar, F; Vidal, R; Martín, A; Compan, V; Pazos, A; Castro, E

    2016-12-01

    Preclinical studies support a critical role of 5-HT4 receptors (5-HT4Rs) in depression and anxiety, but their influence in depression- and anxiety-like behaviours and the effects of antidepressants remain partly unknown. We evaluated 5-HT4R knockout (KO) mice in different anxiety and depression paradigms and mRNA expression of some neuroplasticity markers (BDNF, trkB and Arc) and the functionality of 5-HT1AR. Moreover, the implication of 5-HT4Rs in the behavioural and molecular effects of chronically administered fluoxetine was assessed in naïve and olfactory bulbectomized mice (OBX) of both genotypes. 5-HT4R KO mice displayed few specific behavioural impairments including reduced central activity in the open-field (anxiety), and decreased sucrose consumption and nesting behaviour (anhedonia). In these mice, we measured increased levels of BDNF and Arc mRNA and reduced levels of trkB mRNA in the hippocampus, and a desensitization of 5-HT1A autoreceptors. Chronic administration of fluoxetine elicited similar behavioural effects in WT and 5-HT4R KO mice on anxiety-and depression-related tests. Following OBX, locomotor hyperactivity and anxiety were similar in both genotypes. Interestingly, chronic fluoxetine failed to reverse this OBX-induced syndrome in 5-HT4R KO mice, a response associated with differential effects in hippocampal neuroplasticity biomarkers. Fluoxetine reduced hippocampal Arc and BDNF mRNA expressions in WT but not 5-HT4R KO mice subjected to OBX. These results demonstrate that the absence of 5-HT4Rs triggers adaptive changes that could maintain emotional states, and that the behavioural and molecular effects of fluoxetine under pathological depression appear to be critically dependent on 5-HT4Rs. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. The effects of the specific 5HT(4) receptor agonist, prucalopride, on colonic motility in healthy volunteers

    NARCIS (Netherlands)

    De Schryver, AMP; Andriesse, GI; Samsom, M; Smout, AJPM; Gooszen, HG; Akkermans, LMA

    2002-01-01

    Background: Prucalopride is a selective and specific 5-hydroxytryptamine(4) receptor agonist that is known to increase stool frequency and to accelerate colonic transit. Aim: To investigate the effect of prucalopride on high-amplitude propagated contractions and segmental pressure waves in healthy v

  3. Integrated modelling of the clinical pharmacokinetics of SDZ HTF 919, a novel selective 5-HT4 receptor agonist, following oral and intravenous administration.

    Science.gov (United States)

    Appel-Dingemanse, S; Lemarechal, M O; Kumle, A; Hubert, M; Legangneux, E

    1999-05-01

    The purpose of the present study was to assess the pharmacokinetics of the novel selective 5-HT4 receptor agonist SDZ HTF 919 (HTF) including food effect, absolute bioavailability, interoccasion and intersubject variabilities. In the randomized, open-label, three treatment, four period crossover study, HTF was administered to 12 young healthy male subjects as a 12 mg tablet (twice under fasted and once under fed conditions) and a 3 mg intravenous (i.v.) infusion over 40 min (fasted). Pharmacokinetic parameters were obtained by noncompartmental methods. A more comprehensive pharmacokinetic characterization was achieved by integrated modelling of oral (p.o.) and i.v. data. To describe the absorption phase a Weibull function and a classical first order input function were compared. Noncompartmental pharmacokinetic analysis revealed a rapid absorption (tmax 1.3 h, fasted), an absolute bioavailability of 11+/-3%, a biphasic disposition phase with a terminal half-life of 11+/-5 h, a clearance of 77+/-15 l h-1, and a volume of distribution at steady state of 368+/-223 l. The coefficients of interoccasion and interindividual variability in Cmax and AUC ranged between 17 and 28%. Food intake caused a delay (tmax 2.0 h) and decrease in absorption with consequently lower systemic exposure ( approximately 5% absolute bioavailability). Integrated p.o./i.v. pharmacokinetic modelling with a Weibull input function allowed accurate description of individual profiles. Modelling of the data from the p.o. dosing improved the description of the terminal phase by inclusion of the i. v. data and additionally provided quantitative characterization of the absorption phase. The pharmacokinetics of HTF could be well described by an integrated modelling approach for both p.o. and i.v. data. The derived model will provide guidance in the design of future studies.

  4. Stimulation of 5-HT1A, 5-HT1B, 5-HT2A/2C, 5-HT3 and 5-HT4 receptors or 5-HT uptake inhibition: short- and long-term memory.

    Science.gov (United States)

    Meneses, Alfredo

    2007-11-22

    In order to determine whether short- (STM) and long-term memory (LTM) function in serial or parallel manner, serotonin (5-hydroxtryptamine, 5-HT) receptor agonists were tested in autoshaping task. Results show that control-vehicle animals were modestly but significantly mastering the autoshaping task as illustrated by memory scores between STM and LTM. Thus, post-training administration of 8-OHDPAT (agonist for 5-HT(1A/7) receptors) only at 0.250 and 0.500 mg/kg impaired both STM and LTM. CGS12066 (agonist for 5-HT(1B)) produced biphasic affects, at 5.0 mg/kg impaired STM but at 1.0 and 10.0 mg/kg, respectively, improved or impaired LTM. DOI (agonist for 5-HT(2A/2C) receptors) dose-dependently impaired STM and, at 10.0 mg/kg only impaired LTM. Both, STM and LTM were impaired by either mCPP (mainly agonist for 5-HT(2C) receptors) or mesulergine (mainly antagonist for 5-HT(2C) receptors) lower dose. The 5-HT(3) agonist mCPBG at 1.0 impaired STM and its higher dose impaired both STM and LTM. RS67333 (partial agonist for 5-HT(4) receptors), at 5.0 and 10.0 mg/kg facilitated both STM and LTM. The higher dose of fluoxetine (a 5-HT uptake inhibitor) improved both STM and LTM. Using as head-pokes during CS as an indirect measure of food-intake showed that of 30 memory changes, 21 of these were unrelated to the former. While some STM or LTM impairments can be attributed to decrements in food-intake, but not memory changes (either increase or decreases) produced by 8-OHDPAT, CGS12066, RS67333 or fluoxetine. Except for animals treated with DOI, mCPBG or fluoxetine, other groups treated with 5-HT agonists 6 h following autoshaping training showed similar LTM and unmodified CS-head-pokes scores.

  5. Mass dose effects and in vivo affinity in brain PET receptor studies--a study of cerebral 5-HT4 receptor binding with [11C]SB207145

    DEFF Research Database (Denmark)

    Madsen, Karine; Marner, Lisbeth; Haahr, Mette;

    2011-01-01

    Attention to tracer dose principles is crucial in positron emission tomography (PET), and deviations can induce serious errors. In this study, we devise a method for determining receptor occupancy of the mass dose of the radioligand itself and the in vivo affinity.......Attention to tracer dose principles is crucial in positron emission tomography (PET), and deviations can induce serious errors. In this study, we devise a method for determining receptor occupancy of the mass dose of the radioligand itself and the in vivo affinity....

  6. Obesity is associated with high serotonin 4 receptor availability in the brain reward circuitry

    DEFF Research Database (Denmark)

    Haahr, M. E.; Rasmussen, Peter Mondrup; Madsen, K.

    2012-01-01

    The neurobiology underlying obesity is not fully understood. The neurotransmitter serotonin (5-HT) is established as a satiety-generating signal, but its rewarding role in feeding is less well elucidated. From animal experiments there is now evidence that the 5-HT4 receptor (5-HT4R) is involved...... in food intake, and that pharmacological or genetic manipulation of the receptor in reward-related brain areas alters food intake.Here, we used positron emission tomography in humans to examine the association between cerebral 5-HT4Rs and common obesity.We found in humans a strong positive association...... between body mass index and the 5-HT4R density bilaterally in the two reward ‘hot spots’ nucleus accumbens and ventral pallidum, and additionally in the left hippocampal region and orbitofrontal cortex.These findings suggest that the 5-HT4R is critically involved in reward circuits that regulate people...

  7. Brain serotonin 4 receptor binding is associated with the cortisol awakening response

    DEFF Research Database (Denmark)

    Jakobsen, Gustav R; Fisher, Patrick M; Dyssegaard, Agnete

    2016-01-01

    Serotonin signalling is considered critical for an appropriate and dynamic adaptation to stress. Previously, we have shown that prefrontal serotonin transporter (SERT) binding is positively associated with the cortisol awakening response (CAR) (Frokjaer et al., 2013), which is an index...... and serotonin signaling in vivo in humans. We suggest that higher synaptic serotonin concentration, here indexed by lower 5-HT4r binding, supports HPA-axis dynamics, which in healthy volunteers is reflected by a robust CAR....... of hypothalamic-pituitary-adrenal (HPA)-axis output dynamics. Here, we investigated in healthy individuals if cerebral serotonin 4 receptor (5-HT4r) binding, reported to be a proxy for serotonin levels, is associated with CAR. Thirty healthy volunteers (25 males, age range 20-56 years) underwent 5-HT4r PET...

  8. The underlying proantiarrhythmic mechanism of 5-HT_4 receptor agonist and 5-HT_3 receptor antagonist 2-[1-(4-piperonyl)piperazinyl]benzothiazole%5-HT_4受体激动剂兼5-HT_3 受体阻断剂2-[1-(4-piperonyl)piperazinyl]-benzothiazole致心律失常机制探析

    Institute of Scientific and Technical Information of China (English)

    刘清华; 张杨; 林媛媛; 吴博威

    2010-01-01

    目的 观察5-HT_4受体激动剂兼5-HT_3受体阻断剂2-[1-(4-piperonyl)piperazinyl]benzothiazole对大鼠离体心脏心律的影响,并探析其电生理学机制.方法 采用成年健康SD大鼠建立离体心脏Langendorff主动脉逆行灌流系统,观察0.1~10 μmol · L~(-1) 2-[1-(4-piperonyl)piperazinyl]benzothiazole对离体心脏节律的影响,全程记录心电图的变化.应用全细胞膜片钳技术观察2-[1-(4-piperonyl)piperazinyl]benzothiazole对胶原酶分解的大鼠心室肌细胞膜内向整流钾电流(I_(K1))、瞬时外向钾电流(I_(to))、静息膜电位(RMP)及动作电位(AP)的影响.结果 在大鼠离体心脏,0.1~10 μmol·L~(-1) 2-[1-(4-piperonyl)piperazinyl]benzothiazole可诱发明显的心律失常.给药15 min内,药物(10 μmol·L~(-1))诱发期前收缩(PVB)236±37个,室速(VT)和室颤(VF)发生率分别达到87.5%和62.5%(n=8,P<0.01).膜片钳记录结果显示,0.1~10 μmol·L~(-1) 2-[1-(4-piperonyl)piperazinyl]benzothiazole可浓度依赖性抑制大鼠心室肌IK1(EC50=0.74 μmol·L~(-1))和I_(to)(EC_(50)=2.16 μmol·L~(-1)),降低膜电位,并明显延长动作电位时程(n=6,P<0.01).结论 作为5-HT_4受体激动剂和5-HT_3受体阻断剂2-[1-(4-pipero-nyl)piperazinyl]benzothiazole致大鼠心律失常风险的电生理学机制为抑制I_(K1)和I_(to),降低膜电位,延长动作电位时程.

  9. Brain serotonin 4 receptor binding is inversely associated with verbal memory recall.

    Science.gov (United States)

    Stenbæk, Dea S; Fisher, Patrick M; Ozenne, Brice; Andersen, Emil; Hjordt, Liv V; McMahon, Brenda; Hasselbalch, Steen G; Frokjaer, Vibe G; Knudsen, Gitte M

    2017-04-01

    We have previously identified an inverse relationship between cerebral serotonin 4 receptor (5-HT 4R) binding and nonaffective episodic memory in healthy individuals. Here, we investigate in a novel sample if the association is related to affective components of memory, by examining the association between cerebral 5-HT 4R binding and affective verbal memory recall. Twenty-four healthy volunteers were scanned with the 5-HT 4R radioligand [(11)C]SB207145 and positron emission tomography, and were tested with the Verbal Affective Memory Test-24. The association between 5-HT 4R binding and affective verbal memory was evaluated using a linear latent variable structural equation model. We observed a significant inverse association across all regions between 5-HT 4R binding and affective verbal memory performances for positive (p = 5.5 × 10(-4)) and neutral (p = .004) word recall, and an inverse but nonsignificant association for negative (p = .07) word recall. Differences in the associations with 5-HT 4R binding between word categories (i.e., positive, negative, and neutral) did not reach statistical significance. Our findings replicate our previous observation of a negative association between 5-HT 4R binding and memory performance in an independent cohort and provide novel evidence linking 5-HT 4R binding, as a biomarker for synaptic 5-HT levels, to the mnestic processing of positive and neutral word stimuli in healthy humans.

  10. Brain serotonin 4 receptor binding is inversely associated with verbal memory recall

    DEFF Research Database (Denmark)

    Stenbæk, Dea S; Fisher, Patrick M; Ozenne, Brice

    2017-01-01

    BACKGROUND: We have previously identified an inverse relationship between cerebral serotonin 4 receptor (5-HT 4R) binding and nonaffective episodic memory in healthy individuals. Here, we investigate in a novel sample if the association is related to affective components of memory, by examining t...

  11. Serotonin receptor modulators in the treatment of irritable bowel syndrome

    Directory of Open Access Journals (Sweden)

    Mohammad Fayyaz

    2008-03-01

    Full Text Available Mohammad Fayyaz, Jeffrey M LacknerDivision of Gastroenterology, Department of Medicine, University at Buffalo School of Medicine, SUNY, Buffalo, NY, USAAbstract: The aim of this article is to review the pathophysiology and clinical role of serotonin receptor modulators used in the treatment of irritable bowel syndrome. Serotonin is an important monoamine neurotransmitter that plays a key role in the initiation of peristaltic and secretory reflexes, and in modulation of visceral sensations. Several serotonin receptor subtypes have been characterized, of which 5HT3, 5HT4, and 5HT1b are the most important for GI function. 5HT4 agonists (eg, tegaserod potentiate peristalsis initiated by 5HT1 receptor stimulation. 5HT4 agonists are therefore useful in constipation predominant form of IBS and in chronic constipation. 5HT3 antagonists (Alosetron and Cilansetron prevent the activation of 5HT3 receptors on extrinsic afferent neurons and can decrease the visceral pain associated with IBS. These agents also retard small intestinal and colonic transit, and are therefore useful in diarrhea-predominant IBS. Tegaserod has been demonstrated in several randomized, placebo controlled trials to relieve global IBS symptoms as well as individual symptoms of abdominal discomfort, number of bowel movements and stool consistency. Several randomized, controlled trials have shown that alosetron relieves pain, improves bowel function, and provides global symptom improvement in women with diarrhea-predominant irritable bowel syndrome. However, ischemic colitis and severe complications of constipation have been major concerns leading to voluntary withdrawal of Alosetron from the market followed by remarketing with a comprehensive risk management program.Keywords: serotonin, irritable bowel syndrome, tegaserod

  12. An approach for serotonin depletion in pigs: effects on serotonin receptor binding

    DEFF Research Database (Denmark)

    Ettrup, Anders; Kornum, Birgitte R; Weikop, Pia

    2011-01-01

    concentrations of 5-HT in seven distinct brain structures from one hemisphere: frontal and occipital cortex, striatum, hippocampus, cerebellum, rostral, and caudal brain stem, were determined. The other hemisphere was processed for receptor autoradiography. Treatments with 50 mg/kg and 100 mg/kg pCPA caused...... is increasingly used as an experimental animal model especially in neuroscience research. Here, we present an approach for serotonin depletion in the pig brain. Central serotonin depletion in Danish Landrace pigs was achieved following 4 days treatment with para-chlorophenylalanine (pCPA). On day 5, tissue...... average decreases in 5-HT concentrations of 61% ± 14% and 66% ± 16%, respectively, and a substantial loss of 5-HT immunostaining was seen throughout the brain. The serotonin depletion significantly increased 5-HT4 receptor binding in nucleus accumbens, but did not alter 5-HT(1A) and 5-HT(2A) receptor...

  13. Expression of serotonin receptors in human lower esophageal sphincter

    OpenAIRE

    Li, He-Fei; Liu, Jun-Feng; Zhang, Ke; Feng, Yong

    2014-01-01

    Serotonin (5-HT) is a neurotransmitter and vasoactive amine that is involved in the regulation of a large number of physiological functions. The wide variety of 5-HT-mediated functions is due to the existence of different classes of serotonergic receptors in the mammalian gastrointestinal tract and nervous system. The aim of this study was to explore the expression of multiple types of 5-HT receptor (5-HT1AR, 5-HT2AR, 5-HT3AR, 5-HT4R, 5-HT5AR, 5-HT6R and 5-HT7R) in sling and clasp fibers from...

  14. Expression of serotonin receptors in the colonic tissue of chronic diarrhea rats

    Directory of Open Access Journals (Sweden)

    Tong Zhu

    2016-01-01

    Full Text Available Background/Aims: This study aimed to investigate the difference among the expression of serotonin receptors (5-HT3, 5-HT4, and 5-HT7 receptors in colonic tissue of chronic diarrhea rats. Materials and Methods: A rat model of chronic diarrhea was established by lactose diet. The expression of 5-HT3, 5-HT4, and 5-HT7 receptors in the colonic tissue was detected using immunohistochemistry, real-time PCR and Western blotting techniques. Results: There is no significant difference on the protein expression of 5-HT3receptor between the normal group and the chronic diarrhea model group. The mRNA expression of 5-HT3 receptor in the chronic diarrhea model group was significantly lower than that in the normal group (n = 10; P< 0.01. The protein and mRNA expression of 5-HT4 receptor in the chronic diarrhea model group were significantly higher than those in the normal group (n = 10; P< 0.05, P< 0.01. On the contrary, the protein and mRNA expressions of 5-HT7 receptor in the chronic diarrhea model group were significantly decreased compared with the normal group (n = 10; P< 0.01, P< 0.01. Conclusions: The results suggested the receptors of 5-HT4and 5-HT7 may be involved in inducing diarrhea by lactose diet.

  15. Serotonin receptors in hippocampus.

    Science.gov (United States)

    Berumen, Laura Cristina; Rodríguez, Angelina; Miledi, Ricardo; García-Alcocer, Guadalupe

    2012-01-01

    Serotonin is an ancient molecular signal and a recognized neurotransmitter brainwide distributed with particular presence in hippocampus. Almost all serotonin receptor subtypes are expressed in hippocampus, which implicates an intricate modulating system, considering that they can be localized as autosynaptic, presynaptic, and postsynaptic receptors, even colocalized within the same cell and being target of homo- and heterodimerization. Neurons and glia, including immune cells, integrate a functional network that uses several serotonin receptors to regulate their roles in this particular part of the limbic system.

  16. Serotonin Receptors in Hippocampus

    Directory of Open Access Journals (Sweden)

    Laura Cristina Berumen

    2012-01-01

    Full Text Available Serotonin is an ancient molecular signal and a recognized neurotransmitter brainwide distributed with particular presence in hippocampus. Almost all serotonin receptor subtypes are expressed in hippocampus, which implicates an intricate modulating system, considering that they can be localized as autosynaptic, presynaptic, and postsynaptic receptors, even colocalized within the same cell and being target of homo- and heterodimerization. Neurons and glia, including immune cells, integrate a functional network that uses several serotonin receptors to regulate their roles in this particular part of the limbic system.

  17. Serotonin Receptors in Hippocampus

    Science.gov (United States)

    Berumen, Laura Cristina; Rodríguez, Angelina; Miledi, Ricardo; García-Alcocer, Guadalupe

    2012-01-01

    Serotonin is an ancient molecular signal and a recognized neurotransmitter brainwide distributed with particular presence in hippocampus. Almost all serotonin receptor subtypes are expressed in hippocampus, which implicates an intricate modulating system, considering that they can be localized as autosynaptic, presynaptic, and postsynaptic receptors, even colocalized within the same cell and being target of homo- and heterodimerization. Neurons and glia, including immune cells, integrate a functional network that uses several serotonin receptors to regulate their roles in this particular part of the limbic system. PMID:22629209

  18. Serotonin Receptors in Hippocampus

    OpenAIRE

    Laura Cristina Berumen; Angelina Rodríguez; Ricardo Miledi; Guadalupe García-Alcocer

    2012-01-01

    Serotonin is an ancient molecular signal and a recognized neurotransmitter brainwide distributed with particular presence in hippocampus. Almost all serotonin receptor subtypes are expressed in hippocampus, which implicates an intricate modulating system, considering that they can be localized as autosynaptic, presynaptic, and postsynaptic receptors, even colocalized within the same cell and being target of homo- and heterodimerization. Neurons and glia, including immune cells, integrate a fu...

  19. Serotonin 1A and Serotonin 4 Receptors: Essential Mediators of the Neurogenic and Behavioral Actions of Antidepressants.

    Science.gov (United States)

    Samuels, Benjamin Adam; Mendez-David, Indira; Faye, Charlène; David, Sylvain André; Pierz, Kerri A; Gardier, Alain M; Hen, René; David, Denis J

    2016-02-01

    Selective serotonin reuptake inhibitors are the mostly widely used treatment for major depressive disorders and also are prescribed for several anxiety disorders. However, similar to most antidepressants, selective serotonin reuptake inhibitors suffer from two major problems: They only show beneficial effects after 2 to 4 weeks and only about 33% of patients show remission to first-line treatment. Thus, there is a considerable need for development of more effective antidepressants. There is a growing body of evidence supporting critical roles of 5-HT1A and 5-HT4 receptor subtypes in mediating successful depression treatments. In addition, appropriate activation of these receptors may be associated with a faster onset of the therapeutic response. This review will examine the known roles of 5-HT1A and 5-HT4 receptors in mediating both the pathophysiology of depression and anxiety and the treatment of these mood disorders. At the end of the review, the role of these receptors in the regulation of adult hippocampal neurogenesis will also be discussed. Ultimately, we propose that novel antidepressant drugs that selectively target these serotonin receptors could be developed to yield improvements over current treatments for major depressive disorders. © The Author(s) 2014.

  20. Expression of Serotonin Receptors in the Colonic Tissue of Chronic Diarrhea Rats

    Science.gov (United States)

    Zhu, Tong; Qiu, Juanjuan; Wan, Jiajia; Wang, Fengyun; Tang, Xudong; Guo, Huishu

    2016-01-01

    Background/Aims: This study aimed to investigate the difference among the expression of serotonin receptors (5-HT3, 5-HT4, and 5-HT7 receptors) in colonic tissue of chronic diarrhea rats. Materials and Methods: A rat model of chronic diarrhea was established by lactose diet. The expression of 5-HT3, 5-HT4, and 5-HT7 receptors in the colonic tissue was detected using immunohistochemistry, real-time PCR and Western blotting techniques. Results: There is no significant difference on the protein expression of 5-HT3 receptor between the normal group and the chronic diarrhea model group. The mRNA expression of 5-HT3 receptor in the chronic diarrhea model group was significantly lower than that in the normal group (n = 10; P 5-HT7 receptor in the chronic diarrhea model group were significantly decreased compared with the normal group (n = 10; P < 0.01, P < 0.01). Conclusions: The results suggested the receptors of 5-HT4 and 5-HT7 may be involved in inducing diarrhea by lactose diet. PMID:27184643

  1. 5-HT3 and 5-HT4 antagonists inhibit peristaltic contractions in guinea-pig distal colon by mechanisms independent of endogenous 5-HT

    Directory of Open Access Journals (Sweden)

    Tiong Cheng Sia

    2013-08-01

    Full Text Available Recent studies have shown that endogenous serotonin is not required for colonic peristalsis in vitro, nor gastrointestinal (GI transit in vivo. However, antagonists of 5-Hydroxytryptamine (5-HT receptors can inhibit peristalsis and GI-transit in mammals, including humans. This raises the question of how these antagonists inhibit GI-motility and transit, if depletion of endogenous 5-HT does not cause any significant inhibitory changes to either GI-motility or transit ? We investigated the mechanism by which 5-HT3 and 5-HT4 antagonists inhibit distension-evoked peristaltic contractions in guinea-pig distal colon. In control animals, repetitive peristaltic contractions of the circular muscle were evoked in response to fixed fecal pellet distension. Distension-evoked peristaltic contractions were unaffected in animals with mucosa and submucosal plexus removed, that were also treated with reserpine (to deplete neuronal 5-HT. In control animals, peristaltic contractions were blocked temporarily by ondansetron (1-10µM and SDZ-205-557 (1-10µM in many animals. Interestingly, after this temporary blockade, and whilst in the continued presence of these antagonists, peristaltic contractions recovered, with characteristics no different from controls. Surprisingly, similar effects were seen in mucosa-free preparations, which had no detectable 5-HT, as detected by mass spectrometry. In summary, distension-evoked peristaltic reflex contractions of the circular muscle layer of the guinea-pig colon can be inhibited temporarily, or permanently, in the same preparation by selective 5-HT3 and 5-HT4 antagonists, depending on the concentration of the antagonists applied. These effects also occur in preparations that lack any detectable 5-HT. We suggest caution should be exercised when interpreting the effects of 5-HT3 and 5-HT4 antagonists; and the role of endogenous 5-HT, in the generation of distension-evoked colonic peristalsis.

  2. Phosphoinositide system-linked serotonin receptor subtypes and their pharmacological properties and clinical correlates.

    OpenAIRE

    Pandey, S. C.; Davis, J M; PANDEY, G. N.

    1995-01-01

    Serotonergic neurotransmission represents a complex mechanism involving pre- and post-synaptic events and distinct 5-HT receptor subtypes. Serotonin (5-HT) receptors have been classified into several categories, and they are termed as 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5-HT7 type receptors. 5-HT1 receptors have been further subdivided into 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E and 5-HT1F. 5-HT2 receptors have been divided into 5-HT2A, 5-HT2B and 5-HT2C receptors. All 5-HT2 receptor subtype...

  3. Serotonin receptors as cardiovascular targets

    NARCIS (Netherlands)

    C.M. Villalón (Carlos); P.A.M. de Vries (Peter); P.R. Saxena (Pramod Ranjan)

    1997-01-01

    textabstractSerotonin exerts complex effects in the cardiovascular system, including hypotension or hypertension, vasodilatation or vasoconstriction, and/or bradycardia or tachycardia; the eventual response depends primarily on the nature of the 5-HT receptors involved. In the light of current 5-HT

  4. Increased cholinergic contractions of jejunal smooth muscle caused by a high cholesterol diet are prevented by the 5-HT4 agonist – tegaserod

    Directory of Open Access Journals (Sweden)

    Shaffer Eldon

    2006-02-01

    Full Text Available Abstract Background Excess cholesterol in bile and in blood is a major risk factor for the respective development of gallbladder disease and atherosclerosis. This lipid in excess negatively impacts the functioning of other smooth muscles, including the intestine. Serotonin is an important mediator of the contractile responses of the small intestine. Drugs targeting the serotonin receptor are used as prokinetic agents to manage intestinal motor disorders, in particular irritable bowel syndrome. Thus, tegaserod, acting on 5-HT4 receptor, ideally should obviate detrimental effects of excessive cholesterol on gastrointestinal smooth muscle. In this study we examined the effect of tegaserod on cholesterol-induced changes in the contractile responses of intestinal smooth muscle. Methods The effects of a high cholesterol (1% diet on the in vitro contractile responses of jejunal longitudinal smooth muscle from Richardson ground squirrels to the cholinergic agonist carbachol were examined in the presence or absence of tetrodrodotoxin (TTX. Two groups of animals, fed either low (0.03% or high cholesterol rat chow diet, were further divided into two subgroups and treated for 28 days with either vehicle or tegaserod. Results The high cholesterol diet increased, by nearly 2-fold, contractions of the jejunal longitudinal smooth muscle elicited by carbachol. These cholinergic contractions were mediated by muscarinic receptors since they were blocked by scopolamine, a muscarinic receptor antagonist, but not by the nicotinic receptor antagonist, hexamethonium. Tegaserod treatment, which did not affect cholinergic contractions of tissues from low cholesterol fed animals, abrogated the increase caused by the high cholesterol diet. With low cholesterol diet TTX enhanced carbachol-evoked contractions, whereas this action potential blocker did not affect the augmented cholinergic contractions seen with tissues from animals on the high cholesterol diet. Tegaserod

  5. Two Distinct Central Serotonin Receptors with Different Physiological Functions

    Science.gov (United States)

    Peroutka, Stephen J.; Lebovitz, Richard M.; Snyder, Solomon H.

    1981-05-01

    Two distinct serotonin (5-hydroxytryptamine) receptors designated serotonin 1 and serotonin 2 bind tritium-labeled serotonin and tritium-labeled spiroperidol, respectively. Drug potencies at serotonin 2 sites, but not at serotonin 1 sites, predict their effects on the ``serotonin behavioral syndrome,'' indicating that serotonin 2 sites mediate these behaviors. The limited correlation of drug effects with regulation by guanine nucleotides suggests that serotonin 1 sites might be linked to adenylate cyclase. Drug specificities of serotonin-elicited synaptic inhibition and excitation may reflect serotonin 1 and serotonin 2 receptor interactions, respectively.

  6. Do serotonin(1-7) receptors modulate short and long-term memory?

    Science.gov (United States)

    Meneses, A

    2007-05-01

    Evidence from invertebrates to human studies indicates that serotonin (5-hydroxytryptamine; 5-HT) system modulates short- (STM) and long-term memory (LTM). This work is primarily focused on analyzing the contribution of 5-HT, cholinergic and glutamatergic receptors as well as protein synthesis to STM and LTM of an autoshaping learning task. It was observed that the inhibition of hippocampal protein synthesis or new mRNA did not produce a significant effect on autoshaping STM performance but it did impair LTM. Both non-contingent protein inhibition and 5-HT depletion showed no effects. It was basically the non-selective 5-HT receptor antagonist cyproheptadine, which facilitated STM. However, the blockade of glutamatergic and cholinergic transmission impaired STM. In contrast, the selective 5-HT(1B) receptor antagonist SB-224289 facilitated both STM and LTM. Selective receptor antagonists for the 5-HT(1A) (WAY100635), 5-HT(1D) (GR127935), 5-HT(2A) (MDL100907), 5-HT(2C/2B) (SB-200646), 5-HT(3) (ondansetron) or 5-HT(4) (GR125487), 5-HT(6) (Ro 04-6790, SB-399885 and SB-35713) or 5-HT(7) (SB-269970) did not impact STM. Nevertheless, WAY100635, MDL100907, SB-200646, GR125487, Ro 04-6790, SB-399885 or SB-357134 facilitated LTM. Notably, some of these changes shown to be independent of food-intake. Concomitantly, these data indicate that '5-HT tone via 5-HT(1B) receptors' might function in a serial manner from STM to LTM, whereas working in parallel using 5-HT(1A), 5-HT(2A), 5-HT(2B/2C), 5-HT(4), or 5-HT(6) receptors.

  7. Interplay between serotonin and cannabinoid function in the amygdala in fear conditioning.

    Science.gov (United States)

    Nasehi, Mohammad; Davoudi, Kamelia; Ebrahimi-Ghiri, Mohaddeseh; Zarrindast, Mohammad-Reza

    2016-04-01

    The possible interactions between the cannabinoid and serotonin systems in the regions of the brain involved in emotional learning and memory formation have been studied by some researchers. In view of the key role of the amygdala in the acquisition and expression of fear memory, we investigated the involvement of basolateral amygdala (BLA) serotonin 5-HT4 receptors in arachidonylcyclopropylamide (ACPA; selective CB1 cannabinoid receptor agonist)-induced fear memory consolidation impairment. In our study, a context and tone fear conditioning apparatus was used for testing fear conditioning in adult male NMRI mice. The results showed that intraperitoneal administration of ACPA 0.5 or 0.05, 0.1 and 0.5mg/kg immediately after training decreased the percentage of freezing time in context or tone fear conditioning respectively, suggesting a context- or tone-dependent fear memory consolidation impairment. Post-training intra-BLA microinjections of RS67333, as 5-HT4 serotonin receptor agonist, at doses of 0.025 and 0.05 µg/mouse also impaired context or tone memory consolidation, while RS23597, as 5-HT4 serotonin receptor antagonist, did not produce a marked difference in both fear memories as compared with the control group. Moreover, a subthreshold dose of RS67333 did not alter ACPA response in both fear conditionings. Interestingly, a subthreshold dose of RS23597 potentiated or reversed ACPA response at the dose of 0.01 or 0.05 respectively. It is concluded that BLA serotonin 5-HT4 receptors are involved in tone-dependent fear memory consolidation impairment induced by CB1 activation using ACPA, suggesting a modulatory role for serotonin 5-HT4 receptor.

  8. Serotonin modulates insect hemocyte phagocytosis via two different serotonin receptors.

    Science.gov (United States)

    Qi, Yi-Xiang; Huang, Jia; Li, Meng-Qi; Wu, Ya-Su; Xia, Ren-Ying; Ye, Gong-Yin

    2016-03-14

    Serotonin (5-HT) modulates both neural and immune responses in vertebrates, but its role in insect immunity remains uncertain. We report that hemocytes in the caterpillar, Pieris rapae are able to synthesize 5-HT following activation by lipopolysaccharide. The inhibition of a serotonin-generating enzyme with either pharmacological blockade or RNAi knock-down impaired hemocyte phagocytosis. Biochemical and functional experiments showed that naive hemocytes primarily express 5-HT1B and 5-HT2B receptors. The blockade of 5-HT1B significantly reduced phagocytic ability; however, the blockade of 5-HT2B increased hemocyte phagocytosis. The 5-HT1B-null Drosophila melanogaster mutants showed higher mortality than controls when infected with bacteria, due to their decreased phagocytotic ability. Flies expressing 5-HT1B or 5-HT2B RNAi in hemocytes also showed similar sensitivity to infection. Combined, these data demonstrate that 5-HT mediates hemocyte phagocytosis through 5-HT1B and 5-HT2B receptors and serotonergic signaling performs critical modulatory functions in immune systems of animals separated by 500 million years of evolution.

  9. Effect of the intracerebroventricular administration of GR 113808, a selective 5-HT4 antagonist, on water intake during hyperosmolarity and hypovolemia

    Directory of Open Access Journals (Sweden)

    Castro L.

    2001-01-01

    Full Text Available We demonstrate here that acute third ventricle injections of GR 113808, a highly selective 5-HT4 antagonist, decrease water intake induced by a previous salt load while potentiating drinking elicited by hypovolemia induced by previous subcutaneous administration of polyethylene glycol in male Wistar rats (200 ± 20 g. At the dose of 160 nmol/rat, third ventricle injections of GR 113808 induced a significant reduction of water intake in salt-loaded animals after 120 min as compared to salt-loaded animals receiving third ventricle injections of saline (salt load + GR = 3.44 ± 0.41 ml, N = 12; salt load + saline = 5.74 ± 0.40 ml, N = 9. At the dose of 80 nmol/rat, GR 113808 significantly enhanced water intake in hypovolemic animals after 120 min as compared to hypovolemic animals receiving third ventricle injections of saline (hypovol + GR = 4.01 ± 0.27 ml, N = 8; hypovol + saline = 2.41 ± 0.23 ml, N = 12. We suggest that central 5-HT4 receptors may exert a positive drive on water intake due to hyperosmolarity and a negative input on drinking provoked by hypovolemia.

  10. Cerebral serotonin 4 receptors and amyloid-β in early Alzheimer's disease

    DEFF Research Database (Denmark)

    Madsen, Karine; Neumann, Wolf-Julian; Holst, Klaus Kähler

    2011-01-01

    Alzheimer disease (AD) patients in relation to cortical Aß burden. Eleven newly diagnosed untreated AD patients (mean MMSE 24, range 19–27) and twelve age- and gender-matched healthy controls underwent a two-hour dynamic [11C]SB207145 PET scan to measure the binding potential of the 5-HT4 receptor. All AD...

  11. Serotonin 2c receptors in pro-opiomelanocortin neurons regulate energy and glucose homeostasis

    Science.gov (United States)

    Energy and glucose homeostasis are regulated by central serotonin 2C receptors. These receptors are attractive pharmacological targets for the treatment of obesity; however, the identity of the serotonin 2C receptor-expressing neurons that mediate the effects of serotonin and serotonin 2C receptor a...

  12. Effects of gravity changes on gene expression of BDNF and serotonin receptors in the mouse brain.

    Science.gov (United States)

    Ishikawa, Chihiro; Li, Haiyan; Ogura, Rin; Yoshimura, Yuko; Kudo, Takashi; Shirakawa, Masaki; Shiba, Dai; Takahashi, Satoru; Morita, Hironobu; Shiga, Takashi

    2017-01-01

    Spaceflight entails various stressful environmental factors including microgravity. The effects of gravity changes have been studied extensively on skeletal, muscular, cardiovascular, immune and vestibular systems, but those on the nervous system are not well studied. The alteration of gravity in ground-based animal experiments is one of the approaches taken to address this issue. Here we investigated the effects of centrifugation-induced gravity changes on gene expression of brain-derived neurotrophic factor (BDNF) and serotonin receptors (5-HTRs) in the mouse brain. Exposure to 2g hypergravity for 14 days showed differential modulation of gene expression depending on regions of the brain. BDNF expression was decreased in the ventral hippocampus and hypothalamus, whereas increased in the cerebellum. 5-HT1BR expression was decreased in the cerebellum, whereas increased in the ventral hippocampus and caudate putamen. In contrast, hypergravity did not affect gene expression of 5-HT1AR, 5-HT2AR, 5-HT2CR, 5-HT4R and 5-HT7R. In addition to hypergravity, decelerating gravity change from 2g hypergravity to 1g normal gravity affected gene expression of BDNF, 5-HT1AR, 5-HT1BR, and 5-HT2AR in various regions of the brain. We also examined involvement of the vestibular organ in the effects of hypergravity. Surgical lesions of the inner ear's vestibular organ removed the effects induced by hypergravity on gene expression, which suggests that the effects of hypergravity are mediated through the vestibular organ. In summary, we showed that gravity changes induced differential modulation of gene expression of BDNF and 5-HTRs (5-HT1AR, 5-HT1BR and 5-HT2AR) in some brain regions. The modulation of gene expression may constitute molecular bases that underlie behavioral alteration induced by gravity changes.

  13. The serotonin 5-HT7 receptors: two decades of research.

    Science.gov (United States)

    Gellynck, Evelien; Heyninck, Karen; Andressen, Kjetil W; Haegeman, Guy; Levy, Finn Olav; Vanhoenacker, Peter; Van Craenenbroeck, Kathleen

    2013-10-01

    Like most neurotransmitters, serotonin possesses a simple structure. However, the pharmacological consequences are more complex and diverse. Serotonin is involved in numerous functions in the human body including the control of appetite, sleep, memory and learning, temperature regulation, mood, behavior, cardiovascular function, muscle contraction, endocrine regulation, and depression. Low levels of serotonin may be associated with several disorders, namely increase in aggressive and angry behaviors, clinical depression, Parkinson's disease, obsessive-compulsive disorder, eating disorders, migraine, irritable bowel syndrome, tinnitus, and bipolar disease. These effects are mediated via different serotonin (5-HT) receptors. In this review, we will focus on the last discovered member of this serotonin receptor family, the 5-HT7 receptor. This receptor belongs to the G protein-coupled receptor superfamily and was cloned two decades ago. Later, different splice variants were described but no major functional differences have been described so far. All 5-HT7 receptor variants are coupled to Gαs proteins and stimulate cAMP formation. Recently, several interacting proteins have been reported, which can influence receptor signaling and trafficking.

  14. An approach for serotonin depletion in pigs: effects on serotonin receptor binding

    DEFF Research Database (Denmark)

    Ettrup, Anders; Kornum, Birgitte R; Weikop, Pia

    2011-01-01

    concentrations of 5-HT in seven distinct brain structures from one hemisphere: frontal and occipital cortex, striatum, hippocampus, cerebellum, rostral, and caudal brain stem, were determined. The other hemisphere was processed for receptor autoradiography. Treatments with 50 mg/kg and 100 mg/kg pCPA caused...... is increasingly used as an experimental animal model especially in neuroscience research. Here, we present an approach for serotonin depletion in the pig brain. Central serotonin depletion in Danish Landrace pigs was achieved following 4 days treatment with para-chlorophenylalanine (pCPA). On day 5, tissue...... average decreases in 5-HT concentrations of 61% ± 14% and 66% ± 16%, respectively, and a substantial loss of 5-HT immunostaining was seen throughout the brain. The serotonin depletion significantly increased 5-HT₄ receptor binding in nucleus accumbens, but did not alter 5-HT(1A) and 5-HT(2A) receptor...

  15. Modulation of auditory brainstem responses by serotonin and specific serotonin receptors.

    Science.gov (United States)

    Papesh, Melissa A; Hurley, Laura M

    2016-02-01

    The neuromodulator serotonin is found throughout the auditory system from the cochlea to the cortex. Although effects of serotonin have been reported at the level of single neurons in many brainstem nuclei, how these effects correspond to more integrated measures of auditory processing has not been well-explored. In the present study, we aimed to characterize the effects of serotonin on far-field auditory brainstem responses (ABR) across a wide range of stimulus frequencies and intensities. Using a mouse model, we investigated the consequences of systemic serotonin depletion, as well as the selective stimulation and suppression of the 5-HT1 and 5-HT2 receptors, on ABR latency and amplitude. Stimuli included tone pips spanning four octaves presented over a forty dB range. Depletion of serotonin reduced the ABR latencies in Wave II and later waves, suggesting that serotonergic effects occur as early as the cochlear nucleus. Further, agonists and antagonists of specific serotonergic receptors had different profiles of effects on ABR latencies and amplitudes across waves and frequencies, suggestive of distinct effects of these agents on auditory processing. Finally, most serotonergic effects were more pronounced at lower ABR frequencies, suggesting larger or more directional modulation of low-frequency processing. This is the first study to describe the effects of serotonin on ABR responses across a wide range of stimulus frequencies and amplitudes, and it presents an important step in understanding how serotonergic modulation of auditory brainstem processing may contribute to modulation of auditory perception.

  16. Autoradiography reveals selective changes in serotonin binding in neocortex of patients with temporal lobe epilepsy.

    Science.gov (United States)

    Rocha, Luisa; Lorigados-Pedre, Lourdes; Orozco-Suárez, Sandra; Morales-Chacón, Lilia; Alonso-Vanegas, Mario; García-Maeso, Iván; Villeda-Hernández, Juana; Osorio-Rico, Laura; Estupiñán, Bárbara; Quintana, Christian

    2007-08-15

    The main goal of the present study was to evaluate binding to serotonin in the neocortex surrounding the epileptic focus of patients with mesial temporal lobe epilepsy (MTLE). Binding to 5-HT, 5-HT(1A), 5-HT(4), 5-HT(7) receptors and serotonin transporter (5-HTT) in T1-T2 gyri of 15 patients with MTLE and their correlations with clinical data, neuronal count and volume were determined. Autopsy material acquired from subjects without epilepsy (n=6) was used as control. The neocortex from MTLE patients demonstrated decreased cell count in layers III-IV (21%). No significant changes were detected on the neuronal volume. Autoradiography experiments showed the following results: reduced 5-HT and 5-HT(1A) binding in layers I-II (24% and 92%, respectively); enhanced 5-HT(4) binding in layers V-VI (32%); no significant changes in 5-HT(7) binding; reduced 5-HTT binding in all layers (I-II, 90.3%; III-IV, 90.3%, V-VI, 86.9%). Significant correlations were found between binding to 5-HT(4) and 5-HT(7) receptors and age of seizure onset, duration of epilepsy and duration of antiepileptic treatment. The present results support an impaired serotoninergic transmission in the neocortex surrounding the epileptic focus of patients with MTLE, a situation that could be involved in the initiation and propagation of seizure activity.

  17. Serotonin receptors: Subtypes, functional responses and therapeutic relevance

    NARCIS (Netherlands)

    P.R. Saxena (Pramod Ranjan)

    1995-01-01

    textabstractRecent, rapid progress in the molecular biology of serotonin (5-HT) receptors requires conceptual re-thinking with respect to receptor classification. Thus, based on operational criteria (agonist and antagonist rank order), as well as transduction mechanisms involved and the structure of

  18. Molecular modeling of the human serotonin(1A) receptor : role of membrane cholesterol in ligand binding of the receptor

    NARCIS (Netherlands)

    Paila, Yamuna Devi; Tiwari, Shrish; Sengupta, Durba; Chattopadhyay, Amitabha

    2011-01-01

    Serotonin(1A) receptors are important neurotransmitter receptors and belong to the superfamily of G-protein coupled receptors (GPCRs). Although it is an important drug target, the crystal structure of the serotonin(1A) receptor has not been solved yet. Earlier homology models of the serotonin(1A) re

  19. Sex Differences in Serotonin 1 Receptor Binding in Rat Brain

    Science.gov (United States)

    Fischette, Christine T.; Biegon, Anat; McEwen, Bruce S.

    1983-10-01

    Male and female rats exhibit sex differences in binding by serotonin 1 receptors in discrete areas of the brain, some of which have been implicated in the control of ovulation and of gonadotropin release. The sex-specific changes in binding, which occur in response to the same hormonal (estrogenic) stimulus, are due to changes in the number of binding sites. Castration alone also affects the number of binding sites in certain areas. The results lead to the conclusion that peripheral hormones modulate binding by serotonin 1 receptors. The status of the serotonin receptor system may affect the reproductive capacity of an organism and may be related to sex-linked emotional disturbances in humans.

  20. Dual role of endogenous serotonin in 2,4,6-trinitrobenzene sulfonic acid-induced colitis

    Directory of Open Access Journals (Sweden)

    Alberto eRapalli

    2016-03-01

    Full Text Available Background and Aims: Changes in gut serotonin content have been described in Inflammatory Bowel Disease and in different experimental models of colitis: the critical role of this monoamine in the pathogenesis of chronic gastrointestinal inflammation is gradually emerging. Aim of the present study was to evaluate the contribution of endogenous serotonin through the activation of its specific receptor subtypes to the local and systemic inflammatory responses in an experimental model of Inflammatory Bowel Disease. Methods: Colitis was induced by intrarectal 2,4,6-TriNitroBenzene Sulfonic acid in mice subacutely treated with selective antagonists of 5-HT1A (WAY100135, 5-HT2A (Ketanserin, 5-HT3 (Ondansetron, 5-HT4 (GR125487, 5-HT7 (SB269970 receptors and with 5-HT1A agonist 8-Hydroxy-2-(di-n-propylaminotetralin. Results: Blockade of 5-HT1A receptors worsened TNBS-induced local and systemic neutrophil recruitment while 5-HT1A agonist delayed and mitigated the severity of colitis, counteracting the increase in colonic 5-HT content. On the contrary, blockade of 5-HT2A receptors improved global health conditions, reduced colonic morphological alterations, down-regulated neutrophil recruitment, inflammatory cytokines levels and colonic apoptosis. Antagonism of 5-HT3, 5-HT4 and 5-HT7 receptor sites did not remarkably affect the progression and outcome of the pathology or only slightly improved it.Conclusions: The prevailing deleterious contribution given by endogenous serotonin to inflammation in TNBS-induced colitis is seemingly mediated by 5-HT2A and, to a lesser extent, by 5-HT4 receptors and coexists with the weak beneficial effect elicited by 5-HT1A stimulation. These findings suggest how only a selective interference with 5-HT pro-inflammatory actions may represent an additional potential therapeutic option for intestinal inflammatory disorders.

  1. The serotonin 5-HT3 receptor: a novel neurodevelopmental target.

    NARCIS (Netherlands)

    Engel, M.; Smidt, M.P.; van Hooft, J.A.

    2013-01-01

    Serotonin (5-hydroxytryptamine, 5-HT), next to being an important neurotransmitter, recently gained attention as a key-regulator of pre- and postnatal development in the mammalian central nervous system (CNS). Several receptors for 5-HT are expressed in the developing brain including a ligand-gated

  2. Serotonin 2A Receptors, Citalopram and Tryptophan-Depletion

    DEFF Research Database (Denmark)

    Macoveanu, Julian; Hornboll, Bettina; Elliott, Rebecca;

    2013-01-01

    in serotonergic regulation of response inhibition. In 24 healthy adults, we used (18)F-altanserin positron emission tomography to assess cerebral 5-HT(2A) receptors, which have been related to impulsivity. We then investigated the impact of two acute manipulations of brain serotonin levels on behavioral...

  3. 5-HT7 receptor is coupled to G alpha subunits of heterotrimeric G12-protein to regulate gene transcription and neuronal morphology.

    Science.gov (United States)

    Kvachnina, Elena; Liu, Guoquan; Dityatev, Alexander; Renner, Ute; Dumuis, Aline; Richter, Diethelm W; Dityateva, Galina; Schachner, Melitta; Voyno-Yasenetskaya, Tatyana A; Ponimaskin, Evgeni G

    2005-08-24

    The neurotransmitter serotonin (5-HT) plays an important role in the regulation of multiple events in the CNS. We demonstrated recently a coupling between the 5-HT4 receptor and the heterotrimeric G13-protein resulting in RhoA-dependent neurite retraction and cell rounding (Ponimaskin et al., 2002). In the present study, we identified G12 as an additional G-protein that can be activated by another member of serotonin receptors, the 5-HT7 receptor. Expression of 5-HT7 receptor induced constitutive and agonist-dependent activation of a serum response element-mediated gene transcription through G12-mediated activation of small GTPases. In NIH3T3 cells, activation of the 5-HT7 receptor induced filopodia formation via a Cdc42-mediated pathway correlating with RhoA-dependent cell rounding. In mouse hippocampal neurons, activation of the endogenous 5-HT7 receptors significantly increased neurite length, whereas stimulation of 5-HT4 receptors led to a decrease in the length and number of neurites. These data demonstrate distinct roles for 5-HT7R/G12 and 5-HT4R/G13 signaling pathways in neurite outgrowth and retraction, suggesting that serotonin plays a prominent role in regulating the neuronal cytoarchitecture in addition to its classical role as neurotransmitter.

  4. Agonist-directed signaling of serotonin 5-HT2C receptors: differences between serotonin and lysergic acid diethylamide (LSD).

    Science.gov (United States)

    Backstrom, J R; Chang, M S; Chu, H; Niswender, C M; Sanders-Bush, E

    1999-08-01

    For more than 40 years the hallucinogen lysergic acid diethylamide (LSD) has been known to modify serotonin neurotransmission. With the advent of molecular and cellular techniques, we are beginning to understand the complexity of LSD's actions at the serotonin 5-HT2 family of receptors. Here, we discuss evidence that signaling of LSD at 5-HT2C receptors differs from the endogenous agonist serotonin. In addition, RNA editing of the 5-HT2C receptor dramatically alters the ability of LSD to stimulate phosphatidylinositol signaling. These findings provide a unique opportunity to understand the mechanism(s) of partial agonism.

  5. Serotonin 1A receptors alter expression of movement representations.

    Science.gov (United States)

    Scullion, Kathleen; Boychuk, Jeffery A; Yamakawa, Glenn R; Rodych, Justin T G; Nakanishi, Stan T; Seto, Angela; Smith, Victoria M; McCarthy, Ryan W; Whelan, Patrick J; Antle, Michael C; Pittman, Quentin J; Teskey, G Campbell

    2013-03-13

    Serotonin has a myriad of central functions involving mood, appetite, sleep, and memory and while its release within the spinal cord is particularly important for generating movement, the corresponding role on cortical movement representations (motor maps) is unknown. Using adult rats we determined that pharmacological depletion of serotonin (5-HT) via intracerebroventricular administration of 5,7 dihydroxytryptamine resulted in altered movements of the forelimb in a skilled reaching task as well as higher movement thresholds and smaller maps derived using high-resolution intracortical microstimulation (ICMS). We ruled out the possibility that reduced spinal cord excitability could account for the serotonin depletion-induced changes as we observed an enhanced Hoffman reflex (H-reflex), indicating a hyperexcitable spinal cord. Motor maps derived in 5-HT1A receptor knock-out mice also showed higher movement thresholds and smaller maps compared with wild-type controls. Direct cortical application of the 5-HT1A/7 agonist 8-OH-DPAT lowered movement thresholds in vivo and increased map size in 5-HT-depleted rats. In rats, electrical stimulation of the dorsal raphe lowered movement thresholds and this effect could be blocked by direct cortical application of the 5-HT1A antagonist WAY-100135, indicating that serotonin is primarily acting through the 5-HT1A receptor. Next we developed a novel in vitro ICMS preparation that allowed us to track layer V pyramidal cell excitability. Bath application of WAY-100135 raised the ICMS current intensity to induce action potential firing whereas the agonist 8-OH-DPAT had the opposite effect. Together our results demonstrate that serotonin, acting through 5-HT1A receptors, plays an excitatory role in forelimb motor map expression.

  6. Serotonin signaling in Schistosoma mansoni: a serotonin-activated G protein-coupled receptor controls parasite movement.

    Directory of Open Access Journals (Sweden)

    Nicholas Patocka

    2014-01-01

    Full Text Available Serotonin is an important neuroactive substance in all the parasitic helminths. In Schistosoma mansoni, serotonin is strongly myoexcitatory; it potentiates contraction of the body wall muscles and stimulates motor activity. This is considered to be a critical mechanism of motor control in the parasite, but the mode of action of serotonin is poorly understood. Here we provide the first molecular evidence of a functional serotonin receptor (Sm5HTR in S. mansoni. The schistosome receptor belongs to the G protein-coupled receptor (GPCR superfamily and is distantly related to serotonergic type 7 (5HT7 receptors from other species. Functional expression studies in transfected HEK 293 cells showed that Sm5HTR is a specific serotonin receptor and it signals through an increase in intracellular cAMP, consistent with a 5HT7 signaling mechanism. Immunolocalization studies with a specific anti-Sm5HTR antibody revealed that the receptor is abundantly distributed in the worm's nervous system, including the cerebral ganglia and main nerve cords of the central nervous system and the peripheral innervation of the body wall muscles and tegument. RNA interference (RNAi was performed both in schistosomulae and adult worms to test whether the receptor is required for parasite motility. The RNAi-suppressed adults and larvae were markedly hypoactive compared to the corresponding controls and they were also resistant to exogenous serotonin treatment. These results show that Sm5HTR is at least one of the receptors responsible for the motor effects of serotonin in S. mansoni. The fact that Sm5HTR is expressed in nerve tissue further suggests that serotonin stimulates movement via this receptor by modulating neuronal output to the musculature. Together, the evidence identifies Sm5HTR as an important neuronal protein and a key component of the motor control apparatus in S. mansoni.

  7. The serotonin 5-HT3 receptor: a novel neurodevelopmental target

    Directory of Open Access Journals (Sweden)

    Mareen eEngel

    2013-05-01

    Full Text Available Serotonin (5-HT, next to being an important neurotransmitter, recently gained attention as a key regulator of pre- and postnatal development in the mammalian central nervous system (CNS. Several receptors for 5-HT are expressed in the developing brain including a ligand-gated ion channel, the 5-HT3 receptor. Over the past years, evidence has been accumulating that 5-HT3 receptors are involved in the regulation of neurodevelopment by serotonin.Here, we review the spatial and temporal expression patterns of 5-HT3 receptors in the pre- and early postnatal rodent brain and its functional implications. First, 5-HT3 receptors are expressed on GABAergic interneurons in neocortex and limbic structures derived from the caudal ganglionic eminence. Mature inhibitory GABAergic interneurons fine-tune neuronal excitability and thus are crucial for the physiological function of the brain. Second, 5-HT3 receptors are expressed on specific glutamatergic neurons, Cajal-Retzius cells in the cortex and granule cells in the cerebellum, where they regulate morphology, positioning and connectivity of the local microcircuitry. Taken together, the 5-HT3 receptor emerges as a potential key-regulator of network formation and function in the CNS, which could have a major impact on our understanding of neurodevelopmental disorders in which 5-HT plays a role.

  8. Ontogeny of serotonin and serotonin2A receptors in rat auditory cortex.

    Science.gov (United States)

    Basura, Gregory J; Abbas, Atheir I; O'Donohue, Heather; Lauder, Jean M; Roth, Bryan L; Walker, Paul D; Manis, Paul B

    2008-10-01

    Maturation of the mammalian cerebral cortex is, in part, dependent upon multiple coordinated afferent neurotransmitter systems and receptor-mediated cellular linkages during early postnatal development. Given that serotonin (5-HT) is one such system, the present study was designed to specifically evaluate 5-HT tissue content as well as 5-HT(2A) receptor protein levels within the developing auditory cortex (AC). Using high performance liquid chromatography (HPLC), 5-HT and the metabolite, 5-hydroxyindoleacetic acid (5-HIAA), was measured in isolated AC, which demonstrated a developmental dynamic, reaching young adult levels early during the second week of postnatal development. Radioligand binding of 5-HT(2A) receptors with the 5-HT(2A/2C) receptor agonist, (125)I-DOI ((+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl; in the presence of SB206553, a selective 5-HT(2C) receptor antagonist, also demonstrated a developmental trend, whereby receptor protein levels reached young adult levels at the end of the first postnatal week (P8), significantly increased at P10 and at P17, and decreased back to levels not significantly different from P8 thereafter. Immunocytochemical labeling of 5-HT(2A) receptors and confocal microscopy revealed that 5-HT(2A) receptors are largely localized on layer II/III pyramidal cell bodies and apical dendrites within AC. When considered together, the results of the present study suggest that 5-HT, likely through 5-HT(2A) receptors, may play an important role in early postnatal AC development.

  9. Crystal Structure of an LSD-Bound Human Serotonin Receptor

    Energy Technology Data Exchange (ETDEWEB)

    Wacker, Daniel; Wang, Sheng; McCorvy, John D.; Betz, Robin M.; Venkatakrishnan, A.J.; Levit, Anat; Lansu, Katherine; Schools, Zachary L.; Che, Tao; Nichols, David E.; Shoichet, Brian K.; Dror, Ron O.; Roth, Bryan L. (UNCSM); (UNC); (Stanford); (Stanford-MED); (UCSF)

    2017-01-01

    The prototypical hallucinogen LSD acts via serotonin receptors, and here we describe the crystal structure of LSD in complex with the human serotonin receptor 5-HT2B. The complex reveals conformational rearrangements to accommodate LSD, providing a structural explanation for the conformational selectivity of LSD’s key diethylamide moiety. LSD dissociates exceptionally slow from both 5-HT2BR and 5-HT2AR—a major target for its psychoactivity. Molecular dynamics (MD) simulations suggest that LSD’s slow binding kinetics may be due to a “lid” formed by extracellular loop 2 (EL2) at the entrance to the binding pocket. A mutation predicted to increase the mobility of this lid greatly accelerates LSD’s binding kinetics and selectively dampens LSD-mediated β-arrestin2 recruitment. This study thus reveals an unexpected binding mode of LSD; illuminates key features of its kinetics, stereochemistry, and signaling; and provides a molecular explanation for LSD’s actions at human serotonin receptors.

  10. Crystal Structure of an LSD-Bound Human Serotonin Receptor.

    Science.gov (United States)

    Wacker, Daniel; Wang, Sheng; McCorvy, John D; Betz, Robin M; Venkatakrishnan, A J; Levit, Anat; Lansu, Katherine; Schools, Zachary L; Che, Tao; Nichols, David E; Shoichet, Brian K; Dror, Ron O; Roth, Bryan L

    2017-01-26

    The prototypical hallucinogen LSD acts via serotonin receptors, and here we describe the crystal structure of LSD in complex with the human serotonin receptor 5-HT2B. The complex reveals conformational rearrangements to accommodate LSD, providing a structural explanation for the conformational selectivity of LSD's key diethylamide moiety. LSD dissociates exceptionally slow from both 5-HT2BR and 5-HT2AR-a major target for its psychoactivity. Molecular dynamics (MD) simulations suggest that LSD's slow binding kinetics may be due to a "lid" formed by extracellular loop 2 (EL2) at the entrance to the binding pocket. A mutation predicted to increase the mobility of this lid greatly accelerates LSD's binding kinetics and selectively dampens LSD-mediated β-arrestin2 recruitment. This study thus reveals an unexpected binding mode of LSD; illuminates key features of its kinetics, stereochemistry, and signaling; and provides a molecular explanation for LSD's actions at human serotonin receptors. PAPERCLIP. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Effect of local anesthetics on serotonin1A receptor function.

    Science.gov (United States)

    Rao, Bhagyashree D; Shrivastava, Sandeep; Chattopadhyay, Amitabha

    2016-12-01

    The fundamental mechanism behind the action of local anesthetics is still not clearly understood. Phenylethanol (PEtOH) is a constituent of essential oils with a pleasant odor and can act as a local anesthetic. In this work, we have explored the effect of PEtOH on the function of the hippocampal serotonin1A receptor, a representative neurotransmitter receptor belonging to the G protein-coupled receptor (GPCR) family. Our results show that PEtOH induces reduction in ligand binding to the serotonin1A receptor due to lowering of binding affinity, along with a concomitant decrease in the degree of G-protein coupling. Analysis of membrane order using the environment-sensitive fluorescent probe DPH revealed decrease in membrane order with increasing PEtOH concentration, as evident from reduction in rotational correlation time of the probe. Analysis of results obtained shows that the action of local anesthetics could be attributed to the combined effects of specific interaction of the receptor with anesthetics and alteration of membrane properties (such as membrane order). These results assume relevance in the perspective of anesthetic action and could be helpful to achieve a better understanding of the possible role of anesthetics in the function of membrane receptors.

  12. Serotonin 2A receptor antagonists for treatment of schizophrenia

    DEFF Research Database (Denmark)

    Ebdrup, Bjørn Hylsebeck; Rasmussen, Hans; Arnt, Jørn

    2011-01-01

    Introduction: All approved antipsychotic drugs share an affinity for the dopamine 2 (D2) receptor; however, these drugs only partially ameliorate the symptoms of schizophrenia. It is, therefore, of paramount importance to identify new treatment strategies for schizophrenia. Areas covered......: Preclinical, clinical and post-mortem studies of the serotonin 5-HT2A system in schizophrenia are reviewed. The implications of a combined D2 and 5-HT2A receptor blockade, which is obtained by several current antipsychotic drugs, are discussed, and the rationale for the development of more selective 5-HT2A...... receptor antagonists is evaluated. Moreover, the investigational pipeline of major pharmaceutical companies is examined and an Internet search conducted to identify other pharmaceutical companies investigating 5-HT2A receptor antagonists for the treatment of schizophrenia. Expert opinion: 5-HT2A receptor...

  13. Sex differences in the serotonin 1A receptor and serotonin transporter binding in the human brain measured by PET.

    Science.gov (United States)

    Jovanovic, Hristina; Lundberg, Johan; Karlsson, Per; Cerin, Asta; Saijo, Tomoyuki; Varrone, Andrea; Halldin, Christer; Nordström, Anna-Lena

    2008-02-01

    Women and men differ in serotonin associated psychiatric conditions, such as depression, anxiety and suicide. Despite this, very few studies focus on sex differences in the serotonin system. Of the biomarkers in the serotonin system, serotonin(1A) (5-HT(1A)) receptor is implicated in depression, and anxiety and serotonin transporter (5-HTT) is a target for selective serotonin reuptake inhibitors, psychotropic drugs used in the treatment of these disorders. The objective of the present study was to study sex related differences in the 5-HT(1A) receptor and 5-HTT binding potentials (BP(ND)s) in healthy humans, in vivo. Positron emission tomography and selective radioligands [(11)C]WAY100635 and [(11)C]MADAM were used to evaluate binding potentials for 5-HT(1A) receptors (14 women and 14 men) and 5-HTT (8 women and 10 men). The binding potentials were estimated both on the level of anatomical regions and voxel wise, derived by the simplified reference tissue model and wavelet/Logan plot parametric image techniques respectively. Compared to men, women had significantly higher 5-HT(1A) receptor and lower 5-HTT binding potentials in a wide array of cortical and subcortical brain regions. In women, there was a positive correlation between 5-HT(1A) receptor and 5-HTT binding potentials for the region of hippocampus. Sex differences in 5-HT(1A) receptor and 5-HTT BP(ND) may reflect biological distinctions in the serotonin system contributing to sex differences in the prevalence of psychiatric disorders such as depression and anxiety. The result of the present study may help in understanding sex differences in drug treatment responses to drugs affecting the serotonin system.

  14. In vivo imaging of cerebral serotonin transporter and serotonin(2A) receptor binding in 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") and hallucinogen users

    DEFF Research Database (Denmark)

    Erritzoe, David; Frøkjær, Vibe; Holst, Klaus K;

    2011-01-01

    Both hallucinogens and 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") have direct agonistic effects on postsynaptic serotonin(2A) receptors, the key site for hallucinogenic actions. In addition, MDMA is a potent releaser and reuptake inhibitor of presynaptic serotonin....

  15. Genetics of serotonin receptors and depression: state of the art.

    Science.gov (United States)

    Fabbri, Chiara; Marsano, Agnese; Serretti, Alessandro

    2013-05-01

    Major depression (MD) is a major health problem, partly due to the incomplete understanding of the pathogenic mechanisms of the disease. Research efforts have mainly focused on alterations in monoaminergic neurotransmission, especially in relation to the serotonergic system, due to its key role in the regulation of mood and related biological functions. Given the high heritability of MD (estimated between 31% and 42% for unipolar depression), genes coding for key regulators of the serotonergic neurotransmission have been considered as optimal candidates. The present review is focused on the role of genes coding for serotonin receptors in MD pathogenesis, since the serotonin transporter and enzymes involved in serotonin metabolism have been reviewed elsewhere. Despite the large number of candidate gene studies focusing on genes coding for serotonin receptors, results have been inconsistent. The most replicated findings are the associations between rs6295 (HTR1A gene) G allele or G/G genotype and rs6311 (HTR2A gene) A allele or A/A genotype and MD or depressive symptoms. Preclinical and imaging/post-mortem studies in humans provide strong support for the involvement of HTR1A and HTR2A genes in MD. Nevertheless, the inconsistency across previous studies clearly suggests that innovative approaches should be designed in order to overcome the limitations of candidate gene studies. To date, the most appealing methodologies seem to be full exome or genome sequencing, genome-wide pathway analyses, endophenotypes, and epigenetic biomarkers. The reported tools may assist in the detection of multiple-loci models, which could potentially explain the high percentage of MD susceptibility ascribed to genetic factors.

  16. Serotonin, neural markers and memory

    Directory of Open Access Journals (Sweden)

    Alfredo eMeneses

    2015-07-01

    Full Text Available Diverse neuropsychiatric disorders present dysfunctional memory and no effective treatment exits for them; likely as result of the absence of neural markers associated to memory. Neurotransmitter systems and signaling pathways have been implicated in memory and dysfunctional memory; however, their role is poorly understood. Hence, neural markers and cerebral functions and dysfunctions are revised. To our knowledge no previous systematic works have been published addressing these issues. The interactions among behavioral tasks, control groups and molecular changes and/or pharmacological effects are mentioned. Neurotransmitter receptors and signaling pathways, during normal and abnormally functioning memory with an emphasis on the behavioral aspects of memory are revised. With focus on serotonin, since as it is a well characterized neurotransmitter, with multiple pharmacological tools, and well characterized downstream signaling in mammals’ species. 5-HT1A, 5-HT4, 5-HT5, 5-HT6 and 5-HT7 receptors as well as SERT (serotonin transporter seem to be useful neural markers and/or therapeutic targets. Certainly, if the mentioned evidence is replicated, then the translatability from preclinical and clinical studies to neural changes might be confirmed. Hypothesis and theories might provide appropriate limits and perspectives of evidence

  17. Serotonin, neural markers, and memory.

    Science.gov (United States)

    Meneses, Alfredo

    2015-01-01

    Diverse neuropsychiatric disorders present dysfunctional memory and no effective treatment exits for them; likely as result of the absence of neural markers associated to memory. Neurotransmitter systems and signaling pathways have been implicated in memory and dysfunctional memory; however, their role is poorly understood. Hence, neural markers and cerebral functions and dysfunctions are revised. To our knowledge no previous systematic works have been published addressing these issues. The interactions among behavioral tasks, control groups and molecular changes and/or pharmacological effects are mentioned. Neurotransmitter receptors and signaling pathways, during normal and abnormally functioning memory with an emphasis on the behavioral aspects of memory are revised. With focus on serotonin, since as it is a well characterized neurotransmitter, with multiple pharmacological tools, and well characterized downstream signaling in mammals' species. 5-HT1A, 5-HT4, 5-HT5, 5-HT6, and 5-HT7 receptors as well as SERT (serotonin transporter) seem to be useful neural markers and/or therapeutic targets. Certainly, if the mentioned evidence is replicated, then the translatability from preclinical and clinical studies to neural changes might be confirmed. Hypothesis and theories might provide appropriate limits and perspectives of evidence.

  18. Serotonin receptors in suicide victims with major depression.

    Science.gov (United States)

    Stockmeier, C A; Dilley, G E; Shapiro, L A; Overholser, J C; Thompson, P A; Meltzer, H Y

    1997-02-01

    Serotonin1A (5-HT1A) and serotonin2A (5-HT2A) receptors in the brain have been implicated in the pathophysiology of suicide. Brain samples were collected at autopsy from suicide victims with a current episode of major depression and matched comparison subjects who died of natural or accidental causes. Retrospective psychiatric assessments were collected from knowledgeable informants for all suicide victims and most of the comparison subjects. Psychiatric diagnoses were determined according to DSM-III-R criteria. Any subjects with current psychoactive substance use disorders were excluded. Quantitative receptor autoradiography was used in serial sections of the right prefrontal cortex (area 10) and hippocampus to measure the binding of [3H]8-hydroxy-2-(di-n-propyl)-aminotetralin ([3H]8-OH-DPAT) to 5-HT1A receptors and [3H]ketanserin to 5-HT2A receptors. Analysis of covariance was used to compare control subjects and suicide victims with major depression. The age of subjects, the time from death to freezing the tissue (postmortem interval), and the storage time of tissues in the freezer were used as covariates in the analyses. There were no significant differences between suicide victims with major depression and comparison subjects in 5-HT1A or 5-HT2A receptors in area 10 of the right prefrontal cortex or the hippocampus. The current results suggest that the number of 5-HT1A and 5-HT2A receptors in the right prefrontal cortex (area 10) or hippocampus are not different in suicide victims with major depression.

  19. PKA regulatory subunit 1A inactivating mutation induces serotonin signaling in primary pigmented nodular adrenal disease.

    Science.gov (United States)

    Bram, Zakariae; Louiset, Estelle; Ragazzon, Bruno; Renouf, Sylvie; Wils, Julien; Duparc, Céline; Boutelet, Isabelle; Rizk-Rabin, Marthe; Libé, Rossella; Young, Jacques; Carson, Dennis; Vantyghem, Marie-Christine; Szarek, Eva; Martinez, Antoine; Stratakis, Constantine A; Bertherat, Jérôme; Lefebvre, Hervé

    2016-09-22

    Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of ACTH-independent hypercortisolism. The disease is primarily caused by germline mutations of the protein kinase A (PKA) regulatory subunit 1A (PRKAR1A) gene, which induces constitutive activation of PKA in adrenocortical cells. Hypercortisolism is thought to result from PKA hyperactivity, but PPNAD tissues exhibit features of neuroendocrine differentiation, which may lead to stimulation of steroidogenesis by abnormally expressed neurotransmitters. We hypothesized that serotonin (5-HT) may participate in the pathophysiology of PPNAD-associated hypercortisolism. We show that PPNAD tissues overexpress the 5-HT synthesizing enzyme tryptophan hydroxylase type 2 (Tph2) and the serotonin receptors types 4, 6, and 7, leading to formation of an illicit stimulatory serotonergic loop whose pharmacological inhibition in vitro decreases cortisol production. In the human PPNAD cell line CAR47, the PKA inhibitor H-89 decreases 5-HT4 and 5-HT7 receptor expression. Moreover, in the human adrenocortical cell line H295R, inhibition of PRKAR1A expression increases the expression of Tph2 and 5-HT4/6/7 receptors, an effect that is blocked by H-89. These findings show that the serotonergic process observed in PPNAD tissues results from PKA activation by PRKAR1A mutations. They also suggest that Tph inhibitors may represent efficient treatments of hypercortisolism in patients with PPNAD.

  20. PKA regulatory subunit 1A inactivating mutation induces serotonin signaling in primary pigmented nodular adrenal disease

    Science.gov (United States)

    Bram, Zakariae; Louiset, Estelle; Renouf, Sylvie; Duparc, Céline; Boutelet, Isabelle; Rizk-Rabin, Marthe; Libé, Rossella; Young, Jacques; Carson, Dennis; Vantyghem, Marie-Christine; Szarek, Eva; Martinez, Antoine; Stratakis, Constantine A.; Bertherat, Jérôme

    2016-01-01

    Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of ACTH-independent hypercortisolism. The disease is primarily caused by germline mutations of the protein kinase A (PKA) regulatory subunit 1A (PRKAR1A) gene, which induces constitutive activation of PKA in adrenocortical cells. Hypercortisolism is thought to result from PKA hyperactivity, but PPNAD tissues exhibit features of neuroendocrine differentiation, which may lead to stimulation of steroidogenesis by abnormally expressed neurotransmitters. We hypothesized that serotonin (5-HT) may participate in the pathophysiology of PPNAD-associated hypercortisolism. We show that PPNAD tissues overexpress the 5-HT synthesizing enzyme tryptophan hydroxylase type 2 (Tph2) and the serotonin receptors types 4, 6, and 7, leading to formation of an illicit stimulatory serotonergic loop whose pharmacological inhibition in vitro decreases cortisol production. In the human PPNAD cell line CAR47, the PKA inhibitor H-89 decreases 5-HT4 and 5-HT7 receptor expression. Moreover, in the human adrenocortical cell line H295R, inhibition of PRKAR1A expression increases the expression of Tph2 and 5-HT4/6/7 receptors, an effect that is blocked by H-89. These findings show that the serotonergic process observed in PPNAD tissues results from PKA activation by PRKAR1A mutations. They also suggest that Tph inhibitors may represent efficient treatments of hypercortisolism in patients with PPNAD. PMID:27699247

  1. Decreased frontal serotonin2A receptor binding in antipsychotic-naive patients with first-episode schizophrenia

    DEFF Research Database (Denmark)

    Rasmussen, Hans; Erritzoe, David; Andersen, Rune;

    2010-01-01

    Postmortem investigations and the receptor affinity profile of atypical antipsychotics have implicated the participation of serotonin(2A) receptors in the pathophysiology of schizophrenia. Most postmortem studies point toward lower cortical serotonin(2A) binding in schizophrenic patients. However...

  2. Loss of serotonin 2A receptors exceeds loss of serotonergic projections in early Alzheimer's disease

    DEFF Research Database (Denmark)

    Marner, Lisbeth; Frøkjær, Vibe; Kalbitzer, Jan

    2012-01-01

    In patients with Alzheimer's disease (AD), postmortem and imaging studies have revealed early and prominent reductions in cerebral serotonin 2A (5-HT(2A)) receptors. To establish if this was due to a selective disease process of the serotonin system, we investigated the cerebral 5-HT(2A) receptor...

  3. Dual Role of Endogenous Serotonin in 2,4,6-Trinitrobenzene Sulfonic Acid-Induced Colitis

    Science.gov (United States)

    Rapalli, Alberto; Bertoni, Simona; Arcaro, Valentina; Saccani, Francesca; Grandi, Andrea; Vivo, Valentina; Cantoni, Anna M.; Barocelli, Elisabetta

    2016-01-01

    Background and Aims: Changes in gut serotonin (5-HT) content have been described in Inflammatory Bowel Disease (IBD) and in different experimental models of colitis: the critical role of this monoamine in the pathogenesis of chronic gastrointestinal inflammation is gradually emerging. Aim of the present study was to evaluate the contribution of endogenous 5-HT through the activation of its specific receptor subtypes to the local and systemic inflammatory responses in an experimental model of IBD. Materials and Methods: Colitis was induced by intrarectal 2,4,6-TriNitroBenzene Sulfonic acid in mice subacutely treated with selective antagonists of 5-HT1A (WAY100135), 5-HT2A (Ketanserin), 5-HT3 (Ondansetron), 5-HT4 (GR125487), 5-HT7 (SB269970) receptors and with 5-HT1A agonist 8-Hydroxy-2-(di-n-propylamino)tetralin. Results: Blockade of 5-HT1A receptors worsened TNBS-induced local and systemic neutrophil recruitment while 5-HT1A agonist delayed and mitigated the severity of colitis, counteracting the increase in colonic 5-HT content. On the contrary, blockade of 5-HT2A receptors improved global health conditions, reduced colonic morphological alterations, down-regulated neutrophil recruitment, inflammatory cytokines levels and colonic apoptosis. Antagonism of 5-HT3, 5-HT4, and 5-HT7 receptor sites did not remarkably affect the progression and outcome of the pathology or only slightly improved it. Conclusion: The prevailing deleterious contribution given by endogenous 5-HT to inflammation in TNBS-induced colitis is seemingly mediated by 5-HT2A and, to a lesser extent, by 5-HT4 receptors and coexists with the weak beneficial effect elicited by 5-HT1A stimulation. These findings suggest how only a selective interference with 5-HT pro-inflammatory actions may represent an additional potential therapeutic option for intestinal inflammatory disorders. PMID:27047383

  4. A High-Resolution In Vivo Atlas of the Human Brain's Serotonin System

    DEFF Research Database (Denmark)

    Beliveau, Vincent; Ganz, Melanie; Feng, Ling

    2017-01-01

    associations between protein expression and density at high detail. This new in vivo neuroimaging atlas of the 5-HT system not only provides insight in the human brain's regional protein synthesis, transport, and density, but also represents a valuable source of information for the neuroscience community......The serotonin (5-hydroxytryptamine, 5-HT) system modulates many important brain functions and is critically involved in many neuropsychiatric disorders. Here, we present a high-resolution, multidimensional, in vivo atlas of four of the human brain's 5-HT receptors (5-HT1A, 5-HT1B, 5-HT2A, and 5-HT4...... brain by comparing the 5-HT density across the atlas with data from the Allen Human Brain atlas and identified receptor- and transporter-specific associations that show the regional relation between the two measures. Together, these data provide unparalleled insight into the serotonin system...

  5. Serotonin 2B receptor: upregulated with age and hearing loss in mouse auditory system.

    Science.gov (United States)

    Tadros, Sherif F; D'Souza, Mary; Zettel, Martha L; Zhu, XiaoXia; Lynch-Erhardt, Martha; Frisina, Robert D

    2007-07-01

    Serotonin (5-HT) is a monoamine neurotransmitter. Serotonin may modulate afferent fiber discharges in the cochlea, inferior colliculus (IC) and auditory cortex. Specific functions of serotonin are exerted upon its interaction with specific receptors; one of those receptors is the serotonin 2B receptor. The aim of this study was to investigate the differences in gene expression of serotonin 2B receptors with age in cochlea and IC, and the possible correlation between gene expression and functional hearing measurements in CBA/CaJ mice. Immunohistochemical examinations of protein expression of IC in mice of different age groups were also performed. Gene expression results showed that serotonin 2B receptor gene was upregulated with age in both cochlea and IC. A significant correlation between gene expression and functional hearing results was established. Immunohistochemical protein expression studies of IC showed more serotonin 2B receptor cells in old mice relative to young adult mice, particularly in the external nucleus. We conclude that serotonin 2B receptors may play a role in the pathogenesis of age-related hearing loss.

  6. Serotonin2C receptors and drug addiction: focus on cocaine.

    Science.gov (United States)

    Devroye, Céline; Filip, Malgorzata; Przegaliński, Edmund; McCreary, Andrew C; Spampinato, Umberto

    2013-10-01

    This review provides an overview of the role of central serotonin2C (5-HT2C) receptors in drug addiction, specifically focusing on their impact on the neurochemical and behavioral effects of cocaine, one of the most worldwide abused drug. First, we described the neurochemical and electrophysiological mechanisms underlying the interaction between 5-HT2C receptors and the mesocorticolimbic dopaminergic network, in keeping with the key role of this system in drug abuse and dependence. Thereafter, we focused on the role of 5-HT2C receptors in the effects of cocaine in various preclinical behavioral models used in drug addiction research, such as locomotor hyperactivity, locomotor sensitization, drug discrimination, and self-administration, to end with an overview of the neurochemical mechanisms underlying the interactions between 5-HT2C receptors, mesocorticolimbic dopamine system, and cocaine. On their whole, the presented data provide compelling preclinical evidence that 5-HT2C receptor agonists may have efficacy in the treatment of cocaine abuse and dependence, thereby underlying the need for additional clinical studies to ascertain whether preclinical data translate to the human.

  7. Serotonin 2a Receptor and Serotonin 1a Receptor Interact Within the Medial Prefrontal Cortex During Recognition Memory in Mice

    Science.gov (United States)

    Morici, Juan F.; Ciccia, Lucia; Malleret, Gaël; Gingrich, Jay A.; Bekinschtein, Pedro; Weisstaub, Noelia V.

    2015-01-01

    Episodic memory, can be defined as the memory for unique events. The serotonergic system one of the main neuromodulatory systems in the brain appears to play a role in it. The serotonin 2a receptor (5-HT2aR) one of the principal post-synaptic receptors for 5-HT in the brain, is involved in neuropsychiatric and neurological disorders associated with memory deficits. Recognition memory can be defined as the ability to recognize if a particular event or item was previously encountered and is thus considered, under certain conditions, a form of episodic memory. As human data suggest that a constitutively decrease of 5-HT2A signaling might affect episodic memory performance we decided to compare the performance of mice with disrupted 5-HT2aR signaling (htr2a−/−) with wild type (htr2a+/+) littermates in different recognition memory and working memory tasks that differed in the level of proactive interference. We found that ablation of 5-HT2aR signaling throughout development produces a deficit in tasks that cannot be solved by single item strategy suggesting that 5-HT2aR signaling is involved in interference resolution. We also found that in the absence of 5-HT2aR signaling serotonin has a deleterious effect on recognition memory retrieval through the activation of 5-HT1aR in the medial prefrontal cortex. PMID:26779016

  8. Serotonin 2a Receptor and serotonin 1a receptor interact within the medial prefrontal cortex during recognition memory in mice

    Directory of Open Access Journals (Sweden)

    Juan Facundo Morici

    2015-12-01

    Full Text Available Episodic memory, can be defined as the memory for unique events. The serotonergic system one of the main neuromodulatory systems in the brain appears to play a role in it. The serotonin 2a receptor (5-HT2aR one of the principal post-synaptic receptors for 5-HT in the brain, is involved in neuropsychiatric and neurological disorders associated with memory deficits. Recognition memory can be defined as the ability to recognize if a particular event or item was previously encountered and is thus considered, under certain conditions, a form of episodic memory. As human data suggest that a constitutively decrease of 5-HT2A signaling might affect episodic memory performance we decided to compare the performance of mice with disrupted 5-HT2aR signaling (htr2a -/- with wild type (htr2a+/+ littermates in different recognition memory and working memory tasks that differed in the level of proactive interference. We found that ablation of 5-HT2aR signaling throughout development produces a deficit in tasks that cannot be solved by single item strategy suggesting that 5-HT2aR signaling is involved in interference resolution. We also found that in the absence of 5-HT2aR signaling serotonin has a deleterious effect on recognition memory retrieval through the activation of 5-HT1aR in the medial prefrontal cortex.

  9. Multiple receptor subtypes mediate the effects of serotonin on rat subfornical organ neurons

    Science.gov (United States)

    Scrogin, K. E.; Johnson, A. K.; Schmid, H. A.

    1998-01-01

    The subfornical organ (SFO) receives significant serotonergic innervation. However, few reports have examined the functional effects of serotonin on SFO neurons. This study characterized the effects of serotonin on spontaneously firing SFO neurons in the rat brain slice. Of 31 neurons tested, 80% responded to serotonin (1-100 microM) with either an increase (n = 15) or decrease (n = 10) in spontaneous activity. Responses to serotonin were dose dependent and persisted after synaptic blockade. Excitatory responses could also be mimicked by the 5-hydroxytryptamine (5-HT)2A/2C receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI; 1-10 microM) and could be blocked by the 5-HT2A/2C-receptor antagonist LY-53,857 (10 microM). LY-53,857 unmasked inhibitory responses to serotonin in 56% of serotonin-excited cells tested. Serotonin-inhibited cells were also inhibited by the 5-HT1A-receptor agonist 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT; 1-10 microM; n = 7). The data indicate that SFO neurons are responsive to serotonin via postsynaptic activation of multiple receptor subtypes. The results suggest that excitatory responses to serotonin are mediated by 5-HT2A or 5-HT2C receptors and that inhibitory responses may be mediated by 5-HT1A receptors. In addition, similar percentages of serotonin-excited and -inhibited cells were also sensitive to ANG II. As such the functional relationship between serotonin and ANG II in the SFO remains unclear.

  10. The Effects of Serotonin Receptor Antagonists on Contraction and Relaxation Responses Induced by Electrical Stimulation in the Rat Small Intestine

    Directory of Open Access Journals (Sweden)

    Farajian Mashhadi

    2014-03-01

    Full Text Available Background The main source of 5-HT in body is in enterchromafin cells of intestine, different studies mentioned different roles for endogenous 5-HT and receptors involved and it is not clearified the mechanism of action of endogenous 5-HT. Objectives To study the role of endogenous 5-HT on modulation of contraction and relaxation responses induced by electrical field stimulation (EFS in different regions of the rat intestine. Materials and Methods Segments taken from the rat duodenum, jejunum, mid and terminal ileum were vertically mounted, connected to a transducer and exposed to EFS with different frequencies in the absence and presence of various inhibitors of enteric mediators i. e. specific 5-HT receptor antagonists. Results EFS-induced responses were sensitive to TTX and partly to atropine, indicating a major neuronal involvement and a cholinergic system. Pre-treatment with WAY100635 (a 5-HT1A receptor antagonist and granisetron up to 10.0 µM, GR113808 (a 5-HT4 receptor antagonist, methysergide and ritanserin up to 1.0 µM, failed to modify responses to EFS inall examined tissues. In the presence of SB258585 1.0 µM (a 5-HT6 receptor antagonist there was a trend to enhance contraction in the proximal part of the intestine and reduce contraction in the distal part. Pre-treatment with SB269970A 1.0 µM (5-HT7 receptor antagonist induced a greater contractile response to EFS at 0.4 Hz only in the duodenum. Conclusions The application of 5-HT1A, 5-HT2, 5-HT3, 5-HT4, 5-HT6 and 5-HT7 receptor antagonists, applied at concentrations lower than 1.0 µM did not modify the EFS-induced contraction and relaxation responses, whichsuggests the unlikely involvement of endogenous 5-HT in mediating responses to EFS in the described test conditions.

  11. Role of melatonin, serotonin 2B, and serotonin 2C receptors in modulating the firing activity of rat dopamine neurons.

    Science.gov (United States)

    Chenu, Franck; Shim, Stacey; El Mansari, Mostafa; Blier, Pierre

    2014-02-01

    Melatonin has been widely used for the management of insomnia, but is devoid of antidepressant effect in the clinic. In contrast, agomelatine which is a potent melatonin receptor agonist is an effective antidepressant. It is, however, a potent serotonin 2B (5-HT(2B)) and serotonin 2C (5-HT(2C)) receptor antagonist as well. The present study was aimed at investigating the in vivo effects of repeated administration of melatonin (40 mg/kg/day), the 5-HT(2C) receptor antagonist SB 242084 (0.5 mg/kg/day), the selective 5-HT(2B) receptor antagonist LY 266097 (0.6 mg/kg/day) and their combination on ventral tegmental area (VTA) dopamine (DA), locus coeruleus (LC) norepinephrine (NE), and dorsal raphe nucleus (DRN) serotonin (5-HT) firing activity. Administration of melatonin twice daily increased the number of spontaneously active DA neurons but left the firing of NE neurons unaltered. Long-term administration of melatonin and SB 242084, by themselves, had no effect on the firing rate and burst parameters of 5-HT and DA neurons. Their combination, however, enhanced only the number of spontaneously active DA neurons, while leaving the firing of 5-HT neurons unchanged. The addition of LY 266097, which by itself is devoid of effect, to the previous regimen increased for DA neurons the number of bursts per minute and the percentage of spikes occurring in bursts. In conclusion, the combination of melatonin receptor activation as well as 5-HT(2C) receptor blockade resulted in a disinhibition of DA neurons. When 5-HT(2B) receptors were also blocked, the firing and the bursting activity of DA neurons were both enhanced, thus reproducing the effect of agomelatine.

  12. Neuroticism and serotonin 5-HT1A receptors in healthy subjects

    DEFF Research Database (Denmark)

    Hirvonen, Jussi; Tuominen, Lauri; Någren, Kjell

    2015-01-01

    Neuroticism is a personality trait associated with vulnerability for mood and anxiety disorders. Serotonergic mechanisms likely contribute to neuroticism. Serotonin 5-HT1A receptors are altered in mood and anxiety disorders, but whether 5-HT1A receptors are associated with neuroticism in healthy...... and radiometabolite determination. Personality traits were assessed using the Karolinska Scales of Personality. We found a strong negative association between serotonin 5-HT1A receptor BPP and neuroticism. That is, individuals with high neuroticism tended to have lower 5-HT1A receptor binding than individuals...... with low neuroticism. This finding was confirmed with an independent voxel-based whole-brain analysis. Other personality traits did not correlate with 5-HT1A receptor BPP. Previous observations have reported lower serotonin 5-HT1A receptor density in major depression. This neurobiological finding may...

  13. In Vivo Imaging of Cerebral Serotonin Transporter and Serotonin(2A) Receptor Binding in 3,4-Methylenedioxymethamphetamine (MDMA or "Ecstasy") and Hallucinogen Users

    DEFF Research Database (Denmark)

    Erritzoe, David; Frokjaer, Vibe G.; Holst, Klaus K.

    2011-01-01

    .Objective: To assess the differential effects of MDMA and hallucinogen use on cerebral serotonin transporter (SERT) and serotonin(2A) receptor binding.Design: A positron emission tomography study of 24 young adult drug users and 21 nonusing control participants performed with carbon 11 (C-11)-labeled 3-amino-4-[2-[(di...

  14. Histamine H3 receptor-mediated inhibition of serotonin release in the rat brain cortex.

    Science.gov (United States)

    Schlicker, E; Betz, R; Göthert, M

    1988-05-01

    Rat brain cortex slices preincubated with 3H-serotonin were superfused with physiological salt solution (containing citalopram, an inhibitor of serotonin uptake) and the effect of histamine on the electrically (3 Hz) evoked 3H overflow was studied. Histamine decreased the evoked overflow in a concentration-dependent manner. The inhibitory effect of histamine was antagonized by impromidine and burimamide, but was not affected by pheniramine, ranitidine, metitepine and phentolamine. Given alone, impromidine facilitated the evoked overflow, whereas burimamide, pheniramine and ranitidine had no effect. The results suggest that histamine inhibits serotonin release in the rat brain cortex via histamine H3 receptors, which may be located presynaptically.

  15. Synergistic Impairment of Glucose Homeostasis in ob/ob Mice Lacking Functional Serotonin 2C Receptors

    OpenAIRE

    Wade, Jennifer M.; Juneja, Punita; Mackay, Adrienne W.; Graham, James; Havel, Peter J.; Tecott, Laurence H.; Goulding, Evan H.

    2007-01-01

    To investigate how serotonin and leptin interact in the regulation of energy balance and glucose homeostasis, we generated a genetic mouse model, the OB2C mouse, which lacks functional serotonin 2C receptors and the adipocyte hormone leptin. The OB2C mice exhibited a dramatic diabetes phenotype, evidenced by a synergistic increase in serum glucose levels and water intake. The severity of the animals’ diabetes phenotype would not have been predicted from the phenotypic characterization of mice...

  16. Compositions and methods related to serotonin 5-HT1A receptors

    Science.gov (United States)

    Mukherjee, Jogeshwar; Saigal, Neil

    2010-06-08

    Contemplated substituted arylpiperazinyl compounds, and most preferably 18F-Mefway, exhibit desirable in vitro and in vivo binding characteristics to the 5-HT1A receptor. Among other advantageous parameters, contemplated compounds retain high binding affinity, display optimal lipophilicity, and are radiolabeled efficiently with 18F-fluorine in a single step. Still further, contemplated compounds exhibit high target to non-target ratios in receptor-rich regions both in vitro and in vivo, and selected compounds can be effectively and sensitively displaced by serotonin, thus providing a quantitative tool for measuring 5-HT1A receptors and serotonin concentration changes in the living brain.

  17. Neuroticism and serotonin 5-HT1A receptors in healthy subjects.

    Science.gov (United States)

    Hirvonen, Jussi; Tuominen, Lauri; Någren, Kjell; Hietala, Jarmo

    2015-10-30

    Neuroticism is a personality trait associated with vulnerability for mood and anxiety disorders. Serotonergic mechanisms likely contribute to neuroticism. Serotonin 5-HT1A receptors are altered in mood and anxiety disorders, but whether 5-HT1A receptors are associated with neuroticism in healthy subjects is unclear. We measured brain serotonin 5-HT1A receptor in 34 healthy subjects in vivo using positron emission tomography (PET) and [carbonyl-(11)C]WAY-100635. Binding potential (BPP) was determined using the golden standard of kinetic compartmental modeling using arterial blood samples and radiometabolite determination. Personality traits were assessed using the Karolinska Scales of Personality. We found a strong negative association between serotonin 5-HT1A receptor BPP and neuroticism. That is, individuals with high neuroticism tended to have lower 5-HT1A receptor binding than individuals with low neuroticism. This finding was confirmed with an independent voxel-based whole-brain analysis. Other personality traits did not correlate with 5-HT1A receptor BPP. Previous observations have reported lower serotonin 5-HT1A receptor density in major depression. This neurobiological finding may be a trait-like phenomenon and partly explained by higher neuroticism in patients with affective disorders. The link between personality traits and 5-HT1A receptors should be studied in patients with major depression.

  18. Larvae of small white butterfly, Pieris rapae, express a novel serotonin receptor

    Science.gov (United States)

    The biogenic amine serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter in vertebrates and invertebrates. It acts in regulation and modulation of many physiological and behavioral processes through G protein-coupled receptors. Insects express five 5-HT receptor subtypes that share high simila...

  19. Targeting the Serotonin 5-HT7 Receptor in the Search for Treatments for CNS Disorders: Rationale and Progress to Date

    OpenAIRE

    Nikiforuk, Agnieszka

    2015-01-01

    The 5-HT7 (5-hydroxytryptamine 7, serotonin 7) receptor is one of the most recently identified members of the serotonin receptor family. Pharmacological tools, including selective antagonists and, more recently, agonists, along with 5-HT7 receptor (5-HT7R) knock-out mice have revealed the involvement of this receptor in central nervous system processes. Its well-established role in controlling body temperature and regulating sleep and circadian rhythms has implicated this receptor in mood dis...

  20. Agonist effects at putative central 5-HT4receptors in rat hippocampus by R(+)- and S(-)-zacopride; no evidence for stereo-selectivity

    NARCIS (Netherlands)

    Boddeke, H.W.G.M.; Kalkman, H.O.

    1992-01-01

    The EEG of halothane anaesthetized rats was recorded from an electrode implanted into the hippocampus. In the present study the effect of R(+)- and S(-)-zacopride, administered intra-cerebroventricularly, on different frequency bands of the EEG was investigated. Both enantiomers induced similar dose

  1. Two cases of mild serotonin toxicity via 5-hydroxytryptamine 1A receptor stimulation

    Directory of Open Access Journals (Sweden)

    Nakayama H

    2014-02-01

    Full Text Available Hiroto Nakayama,1,* Sumiyo Umeda,2,* Masashi Nibuya,3 Takeshi Terao,4 Koichi Nisijima,5 Soichiro Nomura3 1Yamaguchi Prefecture Mental Health Medical Center, Yamaguchi, Japan; 2Department of Psychiatry, NTT West Osaka Hospital, Osaka, Japan; 3Department of Psychiatry, National Defense Medical College, Saitama, Japan; 4Department of Neuropsychiatry, Oita University Faculty of Medicine, Oita, Japan; 5Department of Psychiatry, Jichi University School of Medicine, Tochigi, Japan  *These authors contributed equally to this work Abstract: We propose the possibility of 5-hydroxytryptamine (5-HT1A receptor involvement in mild serotonin toxicity. A 64-year-old woman who experienced hallucinations was treated with perospirone (8 mg/day. She also complained of depressed mood and was prescribed paroxetine (10 mg/day. She exhibited finger tremors, sweating, coarse shivering, hyperactive knee jerks, vomiting, diarrhea, tachycardia, and psychomotor agitation. After the discontinuation of paroxetine and perospirone, the symptoms disappeared. Another 81-year-old woman, who experienced delusions, was treated with perospirone (8 mg/day. Depressive symptoms appeared and paroxetine (10 mg/day was added. She exhibited tachycardia, finger tremors, anxiety, agitation, and hyperactive knee jerks. The symptoms disappeared after the cessation of paroxetine and perospirone. Recently, the effectiveness of coadministrating 5-HT1A agonistic psychotropics with selective serotonin reuptake inhibitors (SSRIs has been reported, and SSRIs with 5-HT1A agonistic activity have been newly approved in the treatment of depression. Perospirone is a serotonin–dopamine antagonist and agonistic on the 5-HT1A receptors. Animal studies have indicated that mild serotonin excess induces low body temperature through 5-HT1A, whereas severe serotonin excess induces high body temperature through 5-HT2A activation. Therefore, it could be hypothesized that mild serotonin excess induces side effects

  2. Ethanol and Mesolimbic Serotonin/Dopamine Interactions via 5HT-1B Receptors

    Science.gov (United States)

    2007-03-01

    Addiction, 101 (Suppl. 1): 23-30, 2006. 16. Kranzler HR, Hernandez -Avila CA, Gelenter J,: Polymorphism of the 5-HT1B receptor gene (HTR1B): strong within...Serotonin1B receptor stimulation enhances cocaine reinforcement, J. Neurosci., 18: 10078-10089, 1998. 25. Rojas -Corrales MO, Berrocoso E, Mico JA,: Role of...it has been reported that the effective receptor antagonist concentration of SB 216641 is similar to that of WAY 100635 ( Rojas -Corrales et al

  3. Oligonucleotide-induced alternative splicing of serotonin 2C receptor reduces food intake.

    Science.gov (United States)

    Zhang, Zhaiyi; Shen, Manli; Gresch, Paul J; Ghamari-Langroudi, Masoud; Rabchevsky, Alexander G; Emeson, Ronald B; Stamm, Stefan

    2016-08-01

    The serotonin 2C receptor regulates food uptake, and its activity is regulated by alternative pre-mRNA splicing. Alternative exon skipping is predicted to generate a truncated receptor protein isoform, whose existence was confirmed with a new antiserum. The truncated receptor sequesters the full-length receptor in intracellular membranes. We developed an oligonucleotide that promotes exon inclusion, which increases the ratio of the full-length to truncated receptor protein. Decreasing the amount of truncated receptor results in the accumulation of full-length, constitutively active receptor at the cell surface. After injection into the third ventricle of mice, the oligonucleotide accumulates in the arcuate nucleus, where it changes alternative splicing of the serotonin 2C receptor and increases pro-opiomelanocortin expression. Oligonucleotide injection reduced food intake in both wild-type and ob/ob mice. Unexpectedly, the oligonucleotide crossed the blood-brain barrier and its systemic delivery reduced food intake in wild-type mice. The physiological effect of the oligonucleotide suggests that a truncated splice variant regulates the activity of the serotonin 2C receptor, indicating that therapies aimed to change pre-mRNA processing could be useful to treat hyperphagia, characteristic for disorders like Prader-Willi syndrome.

  4. 5-Hydroxytryptamine 4 Receptor in the Endothelial Cells

    DEFF Research Database (Denmark)

    Profirovic, Jasmina; Vardya, Irina; Voyno-Yasenetskaya, Tatyana

    2006-01-01

    in the central nervous system (CNS). We have recently demonstrated that 5-HT4 receptor couples to G13 protein to induce RhoA-dependent gene transcription, neurite retraction, and neuronal cell rounding (Ponimaskin et al, 2002). Although multiple studies were focused on the function of the 5-HT4 receptor...

  5. In Vivo Imaging of Cerebral Serotonin Transporter and Serotonin(2A) Receptor Binding in 3,4-Methylenedioxymethamphetamine (MDMA or "Ecstasy") and Hallucinogen Users

    DEFF Research Database (Denmark)

    Erritzoe, David; Frokjaer, Vibe G.; Holst, Klaus K.;

    2011-01-01

    Context: Both hallucinogens and 3,4-methylenedioxy-methamphetamine( MDMA or "ecstasy") have direct agonistic effects on postsynaptic serotonin(2A) receptors, the key site for hallucinogenic actions. In addition, MDMA is a potent releaser and reuptake inhibitor of presynaptic serotonin.......Objective: To assess the differential effects of MDMA and hallucinogen use on cerebral serotonin transporter (SERT) and serotonin(2A) receptor binding.Design: A positron emission tomography study of 24 young adult drug users and 21 nonusing control participants performed with carbon 11 (C-11)-labeled 3-amino-4-[2-[(di......(methyl) amino) methyl] phenyl]sulfanylbenzonitrile (DASB) and fluorine 18 (F-18)-labeled altanserin, respectively. Scans were performed in the user group after a minimum drug abstinence period of 11 days, and the group was subdivided into hallucinogen-preferring users (n=10) and MDMA-preferring users (n=14...

  6. Serotonin receptor 5-HT5A in rat hippocampus decrease by leptin treatment.

    Science.gov (United States)

    García-Alcocer, Guadalupe; Rodríguez, Angelina; Moreno-Layseca, Paulina; Berumen, Laura C; Escobar, Jesica; Miledi, Ricardo

    2010-12-17

    5-Hydroxytryptamine (5-HT) is involved in a variety of different physiological processes and behaviors through the activation of equally diverse receptors subtypes. In this work we studied the changes on the expression of 5-HT(5A) receptors in rat hippocampus induced by leptin, an adipocyte-derived hormone that has been reported to participate in the modulation of food intake and in adult hippocampal neurogenesis. To study the effect of leptin on the 5-HT(5A) receptor gene expression a qRT-PCR was used and the distribution of those receptors in the hippocampus was visualized by immunohistochemistry. Rats were separated in four groups: control (untreated rats), leptin-treated, serotonin-treated and leptin+serotonin treated. The results showed that even though the 5-HT(5A) gene expression did not change in the hippocampus of any of the treated groups, in the rats treated with leptin and serotonin, the specific immunostaining for the 5-HT(5A) serotonin receptor decreased significantly in the dentate gyrus.

  7. Neuro-imaging the serotonin 2A receptor as a valid biomarker for canine behavioural disorders.

    Science.gov (United States)

    Vermeire, Simon; Audenaert, Kurt; De Meester, Rudy; Vandermeulen, Eva; Waelbers, Tim; De Spiegeleer, Bart; Eersels, Jos; Dobbeleir, André; Peremans, Kathelijne

    2011-12-01

    The serotonergic system is disturbed in different mood and affective disorders, with especially the serotonin (5-HT) 2A receptor involved in impulsive aggressiveness and anxiety. The aim of the study was to evaluate the involvement of the brain 5-HT 2A receptor in dogs with different behavioural disorders. Three groups of drug naive dogs were studied: 22 dogs showing impulsive aggressive behaviour, 22 showing normal behaviour, and 22 showing anxious behaviour. The serotonin 2A receptor was evaluated with Single Photon Emission Computed Tomography (SPECT) and the serotonin 2A receptor-selective radiopharmaceutical (123)I-R91150. A serotonin 2A receptor binding index (BI), proportional to the cortical receptor density, was calculated. A receiver operating characteristic (ROC) analysis was performed to determine cut-off values at which optimal sensitivity and specificity are achieved and to evaluate the general performance of the BI in reflecting the state of the dog, i.e., impulsive aggressive, normal or anxious. Significantly (Pdogs behaving abnormally, with consistently increased BI in impulsive aggressive dogs and decreased BI in anxious dogs. These results provide clear evidence for a disturbed serotonergic balance in canine impulsive aggression and anxiety disorders. A right frontal cut-off value of ≥1.92 with 86.4% sensitivity and 2.3% (1-specificity) was obtained for the impulsive aggressive dogs. Differentiating the anxious dogs from the rest of the population was possible with a cut-off value of ≤1.73 with 86.4% sensitivity and 18.2% (1-specificity). We conclude that SPECT imaging with the radioligand (123)I-R91150 can be a helpful tool in evaluating the involvement of the serotonin 2A receptor in the complex mechanisms of impulsive aggressive and anxious behaviour. The 5HT-2A binding index of the right frontal cortex appears to be a valid biomarker in differentiating the studied canine behavioural disorders.

  8. Membrane cholesterol oxidation in live cells enhances the function of serotonin1A receptors.

    Science.gov (United States)

    Jafurulla, Md; Nalli, Aswan; Chattopadhyay, Amitabha

    2017-03-01

    The serotonin1A (5-HT1A) receptor is an important neurotransmitter receptor that belongs to the G protein-coupled receptor (GPCR) family. It is implicated in a variety of cognitive and behavioral functions and serves as an important drug target for neuropsychiatric disorders such as anxiety and depression. Previous work from our laboratory has demonstrated that membrane cholesterol plays an important role in the function of the serotonin1A receptor. Our earlier results highlighted several structural features of cholesterol essential for receptor function. In order to explore the importance of the hydroxyl group of cholesterol in the function of the serotonin1A receptor, we utilized cholesterol oxidase to oxidize the hydroxyl group of cholesterol to keto group. Our results show that the oxidation of the hydroxyl group of cholesterol in live cells resulted in enhancement of agonist binding and G-protein coupling to the receptor with no appreciable change in overall membrane order. These results extend our understanding of the structural requirements of cholesterol for receptor function. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. 5-HT receptors mediate lineage-dependent effects of serotonin on adult neurogenesis in Procambarus clarkii

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    Benton Jeanne L

    2011-01-01

    Full Text Available Abstract Background Serotonin (5-HT is a potent regulator of adult neurogenesis in the crustacean brain, as in the vertebrate brain. However, there are relatively few data regarding the mechanisms of serotonin's action and which precursor cells are targeted. Therefore, we exploited the spatial separation of the neuronal precursor lineage that generates adult-born neurons in the crayfish (Procambarus clarkii brain to determine which generation(s is influenced by serotonin, and to identify and localize serotonin receptor subtypes underlying these effects. Results RT-PCR shows that mRNAs of serotonin receptors homologous to mammalian subtypes 1A and 2B are expressed in P. clarkii brain (referred to here as 5-HT1α and 5-HT2β. In situ hybridization with antisense riboprobes reveals strong expression of these mRNAs in several brain regions, including cell clusters 9 and 10 where adult-born neurons reside. Antibodies generated against the crustacean forms of these receptors do not bind to the primary neuronal precursors (stem cells in the neurogenic niche or their daughters as they migrate, but do label these second-generation precursors as they approach the proliferation zones of cell clusters 9 and 10. Like serotonin, administration of the P. clarkii 5-HT1α-specific agonist quipazine maleate salt (QMS increases the number of bromodeoxyuridine (BrdU-labeled cells in cluster 10; the P. clarkii 5-HT2β-specific antagonist methiothepin mesylate salt (MMS suppresses neurogenesis in this region. However, serotonin, QMS and MMS do not alter the rate of BrdU incorporation into niche precursors or their migratory daughters. Conclusion Our results demonstrate that the influences of serotonin on adult neurogenesis in the crayfish brain are confined to the late second-generation precursors and their descendants. Further, the distribution of 5-HT1α and 5-HT2β mRNAs and proteins indicate that these serotonergic effects are exerted directly on specific

  10. Interaction between Serotonin Transporter and Serotonin Receptor 1 B genes polymorphisms may be associated with antisocial alcoholism

    Directory of Open Access Journals (Sweden)

    Wang Tzu-Yun

    2012-07-01

    Full Text Available Abstract Background Several studies have hypothesized that genes regulating the components of the serotonin system, including serotonin transporter (5-HTTLPR and serotonin 1 B receptor (5-HT1B, may be associated with alcoholism, but their results are contradictory because of alcoholism’s heterogeneity. Therefore, we examined whether the 5-HTTLPR gene and 5-HT1B gene G861C polymorphism are susceptibility factors for a specific subtype of alcoholism, antisocial alcoholism in Han Chinese in Taiwan. Methods We recruited 273 Han Chinese male inmates with antisocial personality disorder (ASPD [antisocial alcoholism (AS-ALC group (n = 120 and antisocial non-alcoholism (AS-N-ALC group (n = 153] and 191 healthy male controls from the community. Genotyping was done using PCR-RFLP. Results There were no significant differences in the genotypic frequency of the 5-HT1B G861C polymorphism between the 3 groups. Although AS-ALC group members more frequently carried the 5-HTTLPR S/S, S/LG, and LG/LG genotypes than controls, the difference became non-significant after controlling for the covarying effects of age. However, the 5-HTTLPR S/S, S/LG, and LG/LG genotypes may have interacted with the 5-HT1B G861C C/C polymorphism and increased the risk of becoming antisocial alcoholism. Conclusion Our study suggests that neither the 5-HTTLPR gene nor the 5-HT1B G861C polymorphism alone is a risk factor for antisocial alcoholism in Taiwan’s Han Chinese population, but that the interaction between both genes may increase susceptibility to antisocial alcoholism.

  11. Characterization of a novel serotonin receptor coupled to adenylate cyclase in the hybrid neuroblastoma cell line NCB. 20

    Energy Technology Data Exchange (ETDEWEB)

    Conner, D.A.

    1988-01-01

    Pharmacological characterization of the serotonin activation of adenylate cyclase in membrane preparation using over 40 serotonergic and non-serotonergic compounds demonstrated that the receptor mediating the response was distinct from previously described mammalian serotonin receptors. Agonist activity was only observed with tryptamine and ergoline derivatives. Potent antagonism was observed with several ergoline derivatives and with compounds such as mianserin and methiothepine. A comparison of the rank order of potency of a variety of compounds for the NCB.20 cell receptor with well characterized mammalian and non-mammalian serotonin receptors showed a pharmacological similarity, but not identity, with the mammalian 5-HT{sub 1C} receptor, which modulates phosphatidylinositol metabolism, and with serotonin receptors in the parasitic trematodes Fasciola hepatica and Schistosoma mansoni, which are coupled to adenylate cyclase. Equilibrium binding analysis utilizing ({sup 3}H)serotonin, ({sup 3}H)lysergic acid diethylamide or ({sup 3}H)dihydroergotamine demonstrated that there are no abundant high affinity serotonergic sites, which implies that the serotonin activation of adenylate cyclase is mediated by receptors present in low abundance. Incubation of intact NCB.20 cells with serotinin resulted in a time and concentration dependent desensitization of the serotonin receptor.

  12. Serotonin 5HT1A receptor availability and pathological crying after stroke

    DEFF Research Database (Denmark)

    Møller, Mette; Andersen, G; Gjedde, A

    2007-01-01

    OBJECTIVES: Post-stroke depression and pathological crying (PC) implicate an imbalance of serotonergic neurotransmission. We claim that PC follows serotonin depletion that raises the binding potential (p(B)) of the 5-HT(1A) receptor antagonist [carbonyl-(11)C]WAY-100635, which is reversible...

  13. Effect of grazing seedhead-suppressed tall fescue pasture on the vasoactivity of serotonin receptors

    Science.gov (United States)

    Previous research has demonstrated that exposure to ergot alkaloids reduces vasoactivity of serotonin (5HT) receptors. Chemical suppression of tall fescue seedhead production is a tool to reduce the level of exposure to ergot alkaloids by a grazing animal. Therefore, the objective was to evaluate co...

  14. Cortical Serotonin Type-2 Receptor Density in Parents of Children with Autism Spectrum Disorders

    Science.gov (United States)

    Goldberg, Jeremy; Anderson, George M.; Zwaigenbaum, Lonnie; Hall, Geoffrey B. C.; Nahmias, Claude; Thompson, Ann; Szatmari, Peter

    2009-01-01

    Parents (N = 19) of children with autism spectrum disorders (ASD) and adult controls (N = 17) underwent positron emission tomography (PET) using [[superscript 18]F]setoperone to image cortical serotonin type-2 (5-HT2) receptors. The 5-HT2 binding potentials (BPs) were calculated by ratioing [[superscript 18]F]setoperone intensity in regions of…

  15. Associations of the 5-hydroxytryptamine (Serotonin) Receptor 1B Gene (HTR1B) with Alcohol, Cocaine, and Heroin Abuse

    OpenAIRE

    Cao, Jian; LaRocque, Emily; Li, Dawei

    2013-01-01

    Abnormal serotonergic pathways are implicated in numerous neuropsychiatric disorders including alcohol and drug dependence (abuse). The human 5-hydroxytryptamine (serotonin) receptor 1B, encoded by the HTR1B (5-HT1B) gene, is a presynaptic serotonin autoreceptor that plays an important role in regulating serotonin synthesis and release. Although there was evidence of associations of the HTR1B gene variants in the etiologies of substance use disorders, negative findings were also reported. To ...

  16. Serotonin and cholecystokinin mediate nutrient-induced segmentation in guinea pig small intestine.

    Science.gov (United States)

    Ellis, Melina; Chambers, Jordan D; Gwynne, Rachel M; Bornstein, Joel C

    2013-04-15

    Segmentation is an important process in nutrient mixing and absorption; however, the mechanisms underlying this motility pattern are poorly understood. Segmentation can be induced by luminal perfusion of fatty acid in guinea pig small intestine in vitro and mimicked by the serotonin (5-HT) reuptake inhibitor fluoxetine (300 nM) and by cholecystokinin (CCK). Serotonergic and CCK-related mechanisms underlying nutrient-induced segmentation were investigated using selective 5-HT and CCK receptor antagonists on isolated segments of small intestine luminally perfused with 1 mM decanoic acid. Motility patterns were analyzed using video imaging and spatiotemporal maps. Segmenting activity mediated by decanoic acid was depressed following luminal application of the 5-HT receptor antagonists granisetron (5-HT(3), 1 μM) and SB-207266 (5-HT(4), 10 nM) and the CCK receptor antagonists devazepide (CCK-1, 300 nM) and L-365260 (CCK-2, 300 nM), but these antagonists did not further depress segmentation when combined. The P2 receptor antagonist pyridoxal phosphate-6-azophenyl-2',4'-disulfonate (10 μM) had no effect on activity. Serosal application of 5-HT antagonists had little effect on segmentation in the duodenum but reduced activity in the jejunum when granisetron and SB-207266 were applied together. These results reveal that 5-HT(3) and 5-HT(4) receptors, as well as CCK-1 and CCK-2 receptors, are critical in regulating decanoic acid-induced segmentation. Computational simulation indicated that these data are consistent with decanoic acid activating two pathways in the mucosa that converge within the enteric neural circuitry, while contraction-induced release of 5-HT from the mucosa provides feedback into the neural circuit to set the time course of the overall contractile activity.

  17. The serotonin receptor 5-HT₇R regulates the morphology and migratory properties of dendritic cells.

    Science.gov (United States)

    Holst, Katrin; Guseva, Daria; Schindler, Susann; Sixt, Michael; Braun, Armin; Chopra, Himpriya; Pabst, Oliver; Ponimaskin, Evgeni

    2015-08-01

    Dendritic cells are potent antigen-presenting cells endowed with the unique ability to initiate adaptive immune responses upon inflammation. Inflammatory processes are often associated with an increased production of serotonin, which operates by activating specific receptors. However, the functional role of serotonin receptors in regulation of dendritic cell functions is poorly understood. Here, we demonstrate that expression of serotonin receptor 5-HT7 (5-HT7R) as well as its downstream effector Cdc42 is upregulated in dendritic cells upon maturation. Although dendritic cell maturation was independent of 5-HT7R, receptor stimulation affected dendritic cell morphology through Cdc42-mediated signaling. In addition, basal activity of 5-HT7R was required for the proper expression of the chemokine receptor CCR7, which is a key factor that controls dendritic cell migration. Consistent with this, we observed that 5-HT7R enhances chemotactic motility of dendritic cells in vitro by modulating their directionality and migration velocity. Accordingly, migration of dendritic cells in murine colon explants was abolished after pharmacological receptor inhibition. Our results indicate that there is a crucial role for 5-HT7R-Cdc42-mediated signaling in the regulation of dendritic cell morphology and motility, suggesting that 5-HT7R could be a new target for treatment of a variety of inflammatory and immune disorders.

  18. Molecular imaging of the serotonin 5-HT7 receptors: from autoradiography to positron emission tomography.

    Science.gov (United States)

    Zimmer, Luc; Billard, Thierry

    2014-01-01

    Serotonin and its various receptors are involved in numerous brain functions and neuropsychiatric disorders. Of the 14 known serotoninergic receptors, the 5-HT7 receptor is the most recently identified and characterized. It is closely involved in the pathogenesis of depression, anxiety, epilepsy and pain and is therefore an important target for drug therapy. It is a crucial target in neuroscience, and there is a clear need for radioligands for in vitro and in vivo visualization and quantification, first in animal models and ultimately in humans. This review focuses on the main radioligands suggested for in vitro and in vivo imaging of the 5-HT7 receptor.

  19. Kinetics of the membrane current mediated by serotonin 5-HT3 receptors in cultured mouse neuroblastoma cells.

    NARCIS (Netherlands)

    Neijt, H.C.; Plomp, J.J.; Vijverberg, H.P.M.

    1989-01-01

    1. Ionic currents mediated by serotonin 5-HT3 receptors were studied in the mouse neuroblastoma cell line N1E-115, using suction pipettes for intracellular perfusion and voltage clamp recording. The dependence of the kinetics of the membrane current on serotonin concentration was investigated. 2. At

  20. Interplay between serotonin 5-HT1A and 5-HT7 receptors in depressive disorders.

    Science.gov (United States)

    Naumenko, Vladimir S; Popova, Nina K; Lacivita, Enza; Leopoldo, Marcello; Ponimaskin, Evgeni G

    2014-07-01

    Serotonin (5-hydroxytryptamine or 5-HT) is an important neurotransmitter regulating a wide range of physiological and pathological functions via activation of heterogeneously expressed 5-HT receptors. Besides the important role of 5-HT receptors in the pathogenesis of depressive disorders and in their clinical medications, underlying mechanisms are far from being completely understood. This review focuses on possible cross talk between two serotonin receptors, 5-HT1A and the 5-HT7 . Although these receptors are highly co-expressed in brain regions implicated in depression, and most agonists developed for the 5-HT1A or 5-HT7 receptors have cross-reactivity, their functional interaction has not been yet established. It has been recently shown that 5-HT1A and 5-HT7 receptors form homo- and heterodimers both in vitro and in vivo. From the functional point of view, heterodimerization has been shown to play an important role in regulation of receptor-mediated signaling and internalization, suggesting the implication of heterodimerization in the development and maintenance of depression. Interaction between these receptors is also of clinical interest, because both receptors represent an important pharmacological target for the treatment of depression and anxiety.

  1. Serotonin/dopamine interactions in a hyperactive mouse: reduced serotonin receptor 1B activity reverses effects of dopamine transporter knockout.

    Directory of Open Access Journals (Sweden)

    Frank Scott Hall

    Full Text Available Knockout (KO mice that lack the dopamine transporter (SL6A3; DAT display increased locomotion that can be attenuated, under some circumstances, by administration of drugs that normally produce psychostimulant-like effects, such as amphetamine and methylphenidate. These results have led to suggestions that DAT KO mice may model features of attention deficit hyperactivity disorder (ADHD and that these drugs may act upon serotonin (5-HT systems to produce these unusual locomotor decreasing effects. Evidence from patterns of brain expression and initial pharmacologic studies led us to use genetic and pharmacologic approaches to examine the influence of altered 5-HT1B receptor activity on hyperactivity in DAT KO mice. Heterozygous 5-HT1B KO and pharmacologic 5-HT1B antagonism both attenuated locomotor hyperactivity in DAT KO mice. Furthermore, DAT KO mice with reduced, but not eliminated, 5-HT1B receptor expression regained cocaine-stimulated locomotion, which was absent in DAT KO mice with normal levels of 5-HT1B receptor expression. Further experiments demonstrated that the degree of habituation to the testing apparatus determined whether cocaine had no effect on locomotion in DAT KO or reduced locomotion, helping to resolve differences among prior reports. These findings of complementation of the locomotor effects of DAT KO by reducing 5-HT1B receptor activity underscore roles for interactions between specific 5-HT receptors and dopamine (DA systems in basal and cocaine-stimulated locomotion and support evaluation of 5-HT1B antagonists as potential, non-stimulant ADHD therapeutics.

  2. Serotonin decreases aggression via 5-HT1A receptors in the fighting fish Betta splendens.

    Science.gov (United States)

    Clotfelter, Ethan D; O'Hare, Erin P; McNitt, Meredith M; Carpenter, Russ E; Summers, Cliff H

    2007-01-01

    The role of the monoamine neurotransmitter serotonin (5-HT) in the modulation of conspecific aggression in the fighting fish (Betta splendens) was investigated using pharmacological manipulations. We used a fish's response to its mirror image as our index of aggressive behavior. We also investigated the effects of some manipulations on monoamine levels in the B. splendens brain. Acute treatment with 5-HT and with the 5-HT1A receptor agonist 8-OH-DPAT both decreased aggressive behavior; however, treatment with the 5-HT1A receptor antagonist WAY-100635 did not increase aggression. Chronic treatment with the selective serotonin reuptake inhibitor fluoxetine caused no significant changes in aggressive behavior and a significant decline in 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) concentrations. Treatment with the serotonin synthesis inhibitor p-chlorophenylalanine resulted in no change in aggression, yet serotonergic activity decreased significantly. Finally, a diet supplemented with L-tryptophan (Trp), the precursor to 5-HT, showed no consistent effects on aggressive behavior or brain monoamine concentrations. These results suggest a complex role for serotonin in the expression of aggression in teleost fishes, and that B. splendens may be a useful model organism in pharmacological and toxicological studies.

  3. Functional Selectivity and Antidepressant Activity of Serotonin 1A Receptor Ligands

    Science.gov (United States)

    Chilmonczyk, Zdzisław; Bojarski, Andrzej Jacek; Pilc, Andrzej; Sylte, Ingebrigt

    2015-01-01

    Serotonin (5-HT) is a monoamine neurotransmitter that plays an important role in physiological functions. 5-HT has been implicated in sleep, feeding, sexual behavior, temperature regulation, pain, and cognition as well as in pathological states including disorders connected to mood, anxiety, psychosis and pain. 5-HT1A receptors have for a long time been considered as an interesting target for the action of antidepressant drugs. It was postulated that postsynaptic 5-HT1A agonists could form a new class of antidepressant drugs, and mixed 5-HT1A receptor ligands/serotonin transporter (SERT) inhibitors seem to possess an interesting pharmacological profile. It should, however, be noted that 5-HT1A receptors can activate several different biochemical pathways and signal through both G protein-dependent and G protein-independent pathways. The variables that affect the multiplicity of 5-HT1A receptor signaling pathways would thus result from the summation of effects specific to the host cell milieu. Moreover, receptor trafficking appears different at pre- and postsynaptic sites. It should also be noted that the 5-HT1A receptor cooperates with other signal transduction systems (like the 5-HT1B or 5-HT2A/2B/2C receptors, the GABAergic and the glutaminergic systems), which also contribute to its antidepressant and/or anxiolytic activity. Thus identifying brain specific molecular targets for 5-HT1A receptor ligands may result in a better targeting, raising a hope for more effective medicines for various pathologies. PMID:26262615

  4. LP-211 is a brain penetrant selective agonist for the serotonin 5-HT7 receptor

    OpenAIRE

    Hedlund, Peter B.; Leopoldo, Marcello; Caccia, Silvio; Sarkisyan, Gor; Fracasso, Claudia; Martelli, Giuliana; Lacivita, Enza; Berardi, Francesco; Perrone, Roberto

    2010-01-01

    We have determined the pharmacological profile of the new serotonin 5-HT7 receptor agonist N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide (LP-211). Radioligand binding assays were performed on a panel of 5-HT receptor subtypes. The compound was also evaluated in vivo by examining its effect on body temperature regulation in mice lacking the 5-HT7 receptor (5-HT7−/−) and their 5-HT7+/+ sibling controls. Disposition studies were performed in mice of both genotypes. It was found t...

  5. Serotonin stimulates lateral habenula via activation of the post-synaptic serotonin 2/3 receptors and transient receptor potential channels.

    Science.gov (United States)

    Zuo, Wanhong; Zhang, Yong; Xie, Guiqin; Gregor, Danielle; Bekker, Alex; Ye, Jiang-Hong

    2016-02-01

    There is growing interest on the role of the lateral habenula (LHb) in depression, because it closely and bilaterally connects with the serotoninergic raphe nuclei. The LHb sends glutamate efferents to the raphe nuclei, while it receives serotoninergic afferents, and expresses a high density of serotonin (5-HT) receptors. Recent studies suggest that 5-HT receptors exist both in the presynaptic and postsynaptic sites of LHb neurons, and activation of these receptors may have different effects on the activity of LHb neurons. The current study focused on the effect of 5-HT on the postsynaptic membrane. We found that 5-HT initiated a depolarizing inward current (I((5-HTi))) and accelerated spontaneous firing in ∼80% of LHb neurons in rat brain slices. I((5-HTi)) was also induced by the 5-HT uptake blocker citalopram, indicating activity of endogenous 5-HT. I((5-HTi)) was diminished by 5-HT(2/3) receptor antagonists (ritanserin, SB-200646 or ondansetron), and activated by the selective 5-HT(2/3) agonists 1-(3-Chlorophenyl) piperazine hydrochloride or 1-(3-Chlorophenyl) biguanide hydrochloride. Furthermore, I((5-HTi)) was attenuated by 2-Aminoethyl diphenylborinate, a blocker of transient receptor potential channels, and an IP3 receptor inhibitor, indicating the involvement of transient receptor potential channels. These results demonstrate that the reciprocal connection between the LHb and the 5-HT system highlights a key role for 5-HT stimulation of LHb neurons that may be important in the pathogenesis of depression.

  6. Serotonin receptors and heart valve disease--it was meant 2B.

    Science.gov (United States)

    Hutcheson, Joshua D; Setola, Vincent; Roth, Bryan L; Merryman, W David

    2011-11-01

    Carcinoid heart disease was one of the first valvular pathologies studied in molecular detail, and early research identified serotonin produced by oncogenic enterochromaffin cells as the likely culprit in causing changes in heart valve tissue. Researchers and physicians in the mid-1960s noted a connection between the use of several ergot-derived medications with structures similar to serotonin and the development of heart valve pathologies similar to those observed in carcinoid patients. The exact serotonergic target that mediated valvular pathogenesis remained a mystery for many years until similar cases were reported in patients using the popular diet drug Fen-Phen in the late 1990s. The Fen-Phen episode sparked renewed interest in serotonin-mediated valve disease, and studies led to the identification of the 5-HT(2B) receptor as the likely molecular target leading to heart valve tissue fibrosis. Subsequent studies have identified numerous other activators of the 5-HT(2B) receptor, and consequently, the use of many of these molecules has been linked to heart valve disease. Herein, we: review the molecular properties of the 5-HT(2B) receptor including factors that differentiate the 5-HT(2B) receptor from other 5-HT receptor subtypes, discuss the studies that led to the identification of the 5-HT(2B) receptor as the mediator of heart valve disease, present current efforts to identify potential valvulopathogens by screening for 5-HT(2B) receptor activity, and speculate on potential therapeutic benefits of 5-HT(2B) receptor targeting. Copyright © 2011. Published by Elsevier Inc.

  7. Effect of dopamine and serotonin receptor antagonists on fencamfamine-induced abolition of latent inhibition.

    Science.gov (United States)

    de Aguiar, Cilene Rejane Ramos Alves; de Aguiar, Marlison José Lima; DeLucia, Roberto; Silva, Maria Teresa Araujo

    2013-01-05

    The purpose of this investigation was to verify the role of dopamine and serotonin receptors in the effect of fencamfamine (FCF) on latent inhibition. FCF is a psychomotor stimulant with an indirect dopaminergic action. Latent inhibition is a model of attention. Latent inhibition is blocked by dopaminergic agents and facilitated by dopamine receptor agonists. FCF has been shown to abolish latent inhibition. The serotonergic system may also participate in the neurochemical mediation of latent inhibition. The selective dopamine D(1) receptor antagonist SCH 23390 (7-chloro-3-methyl-1-phenyl-1,2,4,5-tetrahydro-3-benzazepin-8-ol), D(2) receptor antagonists pimozide (PIM) and methoclopramide (METH), and serotonin 5-HT(2A/C) receptor antagonist ritanserin (RIT) were used in the present study. Latent inhibition was evaluated using a conditioned emotional response procedure. Male Wistar rats that were water-restricted were subjected to a three-phase procedure: preexposure to a tone, tone-shock conditioning, and a test of the effect of the tone on licking frequency. All of the drugs were administered before the preexposure and conditioning phases. The results showed that FCF abolished latent inhibition, and this effect was clearly antagonized by PIM and METH and moderately attenuated by SCH 23390. At the doses used in the present study, RIT pretreatment did not affect latent inhibition and did not eliminate the effect of FCF, suggesting that the FCF-induced abolition of latent inhibition is not mediated by serotonin 5-HT(2A/C) receptors. These results suggest that the effect of FCF on latent inhibition is predominantly related to dopamine D(2) receptors and that dopamine D(2) receptors participate in attention processes.

  8. Serotonin 2A receptors contribute to the regulation of risk-averse decisions

    DEFF Research Database (Denmark)

    Macoveanu, Julian; Rowe, James B; Hornboll, Bettina

    2013-01-01

    -averse choice behavior was abolished by 5-HT2A receptor blockade. The results provide the first evidence for a critical role of 5-HT2A receptor function in regulating risk-averse behavior. We suggest that the 5-HT2A receptor system facilitates risk-taking behavior by modulating the outcome evaluation of "missed......Pharmacological studies point to a role of the neurotransmitter serotonin (5-HT) in regulating the preference for risky decisions, yet the functional contribution of specific 5-HT receptors remains to be clarified. We used pharmacological fMRI to investigate the role of the 5-HT2A receptors...... in processing negative outcomes and regulating risk-averse behavior. During fMRI, twenty healthy volunteers performed a gambling task under two conditions: with or without blocking the 5-HT2A receptors. The volunteers repeatedly chose between small, likely rewards and large, unlikely rewards. Choices were...

  9. Serotonin mediation of early memory formation via 5-HT2B receptor-induced glycogenolysis in the day-old chick

    OpenAIRE

    Marie Elizabeth Gibbs; Leif eHertz

    2014-01-01

    Investigation of the effects of serotonin on memory formation in the chick revealed an action on at least two 5-HT receptors. Serotonin injected intracerebrally produced a biphasic effect on memory consolidation with enhancement at low doses and inhibition at higher doses. The non-selective 5-HT receptor antagonist methiothepin and the selective 5-HT2B/C receptor antagonist SB221284 both inhibited memory, suggesting actions of serotonin on at least two different receptor subtypes. The 5-HT2B/...

  10. Serotonergic system and its role in epilepsy and neuropathic pain treatment: a review based on receptor ligands.

    Science.gov (United States)

    Panczyk, Katarzyna; Golda, Sylwia; Waszkielewicz, Anna; Zelaszczyk, Dorota; Gunia-Krzyzak, Agnieszka; Marona, Henryk

    2015-01-01

    The serotonergic system is involved in pathomechanisms of both epilepsy and neuropathic pain. So far, participation in the epileptogenesis and maintenance of epilepsy was proved for 5-HT1A, 5-HT2C, 5-HT3, 5-HT4 and 5-HT7 receptors as well as 5-HTT serotonin transporter. Depending on the receptor type or its localization, its stimulation may increase or decrease neuronal excitability. According to the available data, neuropathic pain mechanisms involve 5-HT1A/1B/1D, 5-HT2A/2B/2C, 5-HT3, 5-HT4, 5-HT6, 5-HT7 receptors and 5-HTT serotonin transporter. Changes in their expression modulate pain mainly by affecting the transmission through serotonergic descending pathways. Several compounds, whose mechanisms of action base on influence on the serotonergic system, are already in use. These are 5-HT3 agonists (triptans) in case of migraine, tricyclic antidepressants or monoamine reuptake inhibitors in neuropathic pain treatment. In addition, selective and non-selective ligands are tested for their anticonvulsant or analgesic properties. Some ED50 values have been already obtained in such animal models as maximal electroshock (MES)-induced seizures (epilepsy), spinal nerve ligation (SNL), chronic constriction injury (CCI) or formalin (neuropathic pain). This review shows that in case of drug discovery within the serotonergic system one must take into account special significance of factors such as: the species, the type of model, the route of administration, and the dose range.

  11. Brain serotonin 2A receptor binding: Relations to body mass index, tobacco and alcohol use

    DEFF Research Database (Denmark)

    Erritzoe, D.; Frokjaer, V. G.; Haugbol, S.

    2009-01-01

    Manipulations of the serotonin levels in the brain can affect impulsive behavior and influence our reactivity to conditioned reinforcers. Eating, tobacco smoking, and alcohol consumption are reinforcers that are influenced by serotonergic neurotransmission; serotonergic hypofunction leads...... to increased food and alcohol intake, and conversely, stimulation of the serotonergic system induces weight reduction and decreased food/alcohol intake as well as tobacco smoking. To investigate whether body weight, alcohol intake and tobacco smoking were related to the regulation of the cerebral serotonin 2A...... receptor (5-HT(2A)) in humans, we tested in 136 healthy human subjects if body mass index (BMI), degree of alcohol consumption and tobacco smoking was associated to the cerebral in vivo 5-HT(2A) receptor binding as measured with (18)F-altanserin PET. The subjects' BMI's ranged from 18.4 to 42.8 (25...

  12. Dm5-HT2B: Pharmacological Characterization of the Fifth Serotonin Receptor Subtype of Drosophila melanogaster

    Directory of Open Access Journals (Sweden)

    Wolfgang Blenau

    2017-05-01

    Full Text Available Serotonin (5-hydroxytryptamine, 5-HT is an important regulator of physiological and behavioral processes in both protostomes (e.g., insects and deuterostomes (e.g., mammals. In insects, serotonin has been found to modulate the heart rate and to control secretory processes, development, circadian rhythms, aggressive behavior, as well as to contribute to learning and memory. Serotonin exerts its activity by binding to and activating specific membrane receptors. The clear majority of these receptors belong to the superfamily of G-protein-coupled receptors. In Drosophila melanogaster, a total of five genes have been identified coding for 5-HT receptors. From this family of proteins, four have been pharmacologically examined in greater detail, so far. While Dm5-HT1A, Dm5-HT1B, and Dm5-HT7 couple to cAMP signaling cascades, the Dm5-HT2A receptor leads to Ca2+ signaling in an inositol-1,4,5-trisphosphate-dependent manner. Based on sequence similarity to homologous genes in other insects, a fifth D. melanogaster gene was uncovered coding for a Dm5-HT2B receptor. Knowledge about this receptor’s pharmacological properties is very limited. This is quite surprising because Dm5-HT2B has been attributed to distinct physiological functions based on genetic interference with its gene expression. Mutations were described reducing the response of the larval heart to 5-HT, and specific knockdown of Dm5-HT2B mRNA in hemocytes resulted in a higher susceptibility of the flies to bacterial infection. To gain deeper understanding of Dm5-HT2B’s pharmacology, we evaluated the receptor’s response to a series of established 5-HT receptor agonists and antagonists in a functional cell-based assay. Metoclopramide and mianserin were identified as two potent antagonists that may allow pharmacological interference with Dm5-HT2B signaling in vitro and in vivo.

  13. Headache, Raynaud's syndrome and serotonin receptor agonists in systemic lupus erythematosus.

    Science.gov (United States)

    Bernatsky, S; Pineau, C A; Lee, J L; Clarke, A E

    2006-01-01

    There are potential concerns regarding serotonin receptor agonists in SLE patients with migraine, particularly patients with concomitant Raynaud's syndrome. We estimated the prevalence of lupus-related headache and Raynaud's syndrome in the Montreal General Hospital SLE clinic cohort and evaluated the relationship between these two variables in multivariable logistic regression models, controlling for age, sex, race, SLE duration and the presence of lupus anticoagulant and antibodies to cardiolipin and beta2 glycoprotein I. We also assessed, through chart review in those individuals with both Raynaud's syndrome and migraine, a history of serotonin receptor agonist use, and any associated worsening vasospasm. Based on Systemic Lupus Activity Measure (SLAM) scores, the cumulative incidence of lupus-related headache in our sample (n = 391) was 46.1%; the prevalence of Raynaud's syndrome was 49.4%. The adjusted odds ratio (OR) for lupus-related headache and Raynaud's syndrome was 1.7 (95% CI 1.1, 2.5). In addition, there was a strong independent relationship between headache and anti-beta2 glycoprotein I antibodies (adjusted OR 5.6 [95% CI 1.8, 17.0]). The data from our chart review suggest that careful use of serotonin receptor agonists in patients with both Raynaud's syndrome and migraines may be undertaken, although caution would necessitate that these agents not be used in individuals with very severe Raynaud's (eg, digital ulcerations, and so on).

  14. Serotonin type-1A receptor imaging in depression

    Energy Technology Data Exchange (ETDEWEB)

    Drevets, Wayne C. E-mail: drevets@pet.upmc.edu; Frank, Ellen; Price, Julie C.; Kupfer, David J.; Greer, Phil J.; Mathis, Chester

    2000-07-01

    Regional 5-hydroxytryptamine{sub 1A} (5-HT{sub 1A}) receptor binding potential (BP) of depressed subjects with primary, recurrent, familial mood disorders was compared to that of healthy controls by using positron emission tomography and [carbonyl-{sup 11}C]WAY-100635 {l_brace}[{sup 11}C]N-(2-(4-(2-methoxyphenyl)-1-piperazin-1-yl)ethyl)-N-(2-pyridyl) cyclohexanecarboxamide{r_brace}. The mean 5-HT{sub 1A} receptor BP was reduced 42% in the midbrain raphe and 25-33% in limbic and neocortical areas in the mesiotemporal, occipital, and parietal cortex. The magnitude of these abnormalities was most prominent in bipolar depressives and unipolar depressives who had bipolar relatives. These abnormal reductions in 5-HT{sub 1A} receptor BP are consistent with in vivo evidence that 5-HT{sub 1A} receptor sensitivity is reduced in major depressive disorder and postmortem data showing a widespread deficit of 5-HT{sub 1A} receptor expression in primary mood disorders.

  15. Serotonin 5-HT2A Receptor Function as a Contributing Factor to Both Neuropsychiatric and Cardiovascular Diseases

    Directory of Open Access Journals (Sweden)

    Charles D. Nichols

    2009-01-01

    Full Text Available There are high levels of comorbidity between neuropsychiatric and cardiovascular disorders. A key molecule central to both cognitive and cardiovascular function is the molecule serotonin. In the brain, serotonin modulates neuronal activity and is actively involved in mediating many cognitive functions and behaviors. In the periphery, serotonin is involved in vasoconstriction, inflammation, and cell growth, among other processes. It is hypothesized that one component of the serotonin system, the 5-HT2A receptor, is a common and contributing factor underlying aspects of the comorbidity between neuropsychiatric and cardiovascular disorders. Within the brain this receptor participates in processes such as cognition and working memory, been implicated in effective disorders such as schizophrenia, and mediate the primary effects of hallucinogenic drugs. In the periphery, 5-HT2A receptors have been linked to vasoconstriction and hypertension, and to inflammatory processes that can lead to atherosclerosis.

  16. Affinity of cyamemazine metabolites for serotonin, histamine and dopamine receptor subtypes.

    Science.gov (United States)

    Benyamina, Amine; Arbus, Christophe; Nuss, Philippe; Garay, Ricardo P; Neliat, Gervais; Hameg, Ahcène

    2008-01-14

    Animal and human pharmacological studies indicate that the antipsychotic action of cyamemazine results from blockade of dopamine D(2) receptors, its anxiolytic properties from serotonin 5-HT(2C) receptor antagonism and the low incidence of extrapyramidal side effects from a potent 5-HT(2A) receptor antagonistic action. Cyamemazine is metabolized in monodesmethyl cyamemazine and cyamemazine sulfoxide, which are not known for their affinities for serotonin, dopamine and other brain receptor types considered to mediate central nervous systems effects of drugs. Hence, metabolite affinities were determined in human recombinant receptors expressed in CHO cells (hD(2) and hD4.4 receptors, h5-HT(1A), h5-HT(2A), h5-HT(2C) and h5-HT(7) receptors and hM(1), hM(2) and hM(3) receptors) and HEK-293 cells (h5-HT(3) receptors) or natively present in rat cerebral cortex (non-specific alpha(1)- and alpha(2)-adrenoceptors, GABA(A) and GABA(B) receptors) and guinea pig cerebellum (H(1) central histamine receptors) membranes. Monodesmethyl cyamemazine showed a neurotransmitter receptor profile similar to that of its parent compound cyamemazine, i.e.: high affinity for h5-HT(2A) receptors (K(i)=1.5 nM), h5-HT(2C) receptors (K(i)=12 nM) and hD(2) receptors (K(i)=12 nM). Cyamemazine sulfoxide showed high affinity for h5-HT(2A) receptors (K(i)=39 nM) and histamine H(1) receptors (K(i)=15 nM) and a reduced affinity for D(2) and 5-HT(2C) receptors. Therefore, monodesmethyl cyamemazine can contribute to enhance and prolong the therapeutic actions of cyamemazine. Further investigation is required to see if the high affinities of cyamemazine sulfoxide for H(1) and 5-HT(2A) receptors are of therapeutic benefit against sleep onset insomnia and/or sleep maintenance insomnia respectively.

  17. Activation and modulation of recombinantly expressed serotonin receptor type 3A by terpenes and pungent substances.

    Science.gov (United States)

    Ziemba, Paul M; Schreiner, Benjamin S P; Flegel, Caroline; Herbrechter, Robin; Stark, Timo D; Hofmann, Thomas; Hatt, Hanns; Werner, Markus; Gisselmann, Günter

    2015-11-27

    Serotonin receptor type 3 (5-HT3 receptor) is a ligand-gated ion channel that is expressed in the central nervous system (CNS) as well as in the peripheral nervous system (PNS). The receptor plays an important role in regulating peristalsis of the gastrointestinal tract and in functions such as emesis, cognition and anxiety. Therefore, a variety of pharmacologically active substances target the 5-HT3 receptor to treat chemotherapy-induced nausea and vomiting. The 5-HT3 receptors are activated, antagonized, or modulated by a wide range of chemically different substances, such as 2-methyl-serotonin, phenylbiguanide, setrones, or cannabinoids. Whereas the action of all of these substances is well described, less is known about the effect of terpenoids or fragrances on 5-HT3A receptors. In this study, we screened a large number of natural odorous and pungent substances for their pharmacological action on recombinantly expressed human 5-HT3A receptors. The receptors were functionally expressed in Xenopus oocytes and characterized by electrophysiological recordings using the two-electrode voltage-clamp technique. A screening of two odorous mixes containing a total of 200 substances revealed that the monoterpenes, thymol and carvacrol, act as both weak partial agonists and positive modulators on the 5-HT3A receptor. In contrast, the most effective blockers were the terpenes, citronellol and geraniol, as well as the pungent substances gingerol, capsaicin and polygodial. In our study, we identified new modulators of 5-HT3A receptors out of the classes of monoterpenes and vanilloid substances that frequently occur in various plants.

  18. Effect of meta-chlorophenylpiperazine (mCPP), a central serotonin agonist and vascular serotonin receptor antagonist, on blood pressure in SHR.

    Science.gov (United States)

    Cohen, M L; Kurz, K D; Fuller, R W

    1987-01-01

    mCPP (meta-chlorophenylpiperazine) has agonist activity at some central serotonin receptors and antagonist activity at peripheral vascular 5HT2 receptors, both effects that have been postulated to lower blood pressure. mCPP (10 and 30 mg/kg, i.p. 1 hr after administration) increased serotonin and decreased 5-hydroxy-indolacetic acid (5-HIAA) brain concentrations and elevated serum corticosterone and prolactin, indications of central serotonergic agonist activities. The same doses of mCPP also antagonized vascular 5HT2 receptors as measured by blockade of pressor responses to serotonin in pithed rats. Although mCPP could be demonstrated to activate central serotonergic receptors and block peripheral vascular 5HT2 receptors, mCPP (10 and 30 mg/kg, i.p.) produced little effect on blood pressure in either the anesthetized or conscious spontaneously hypertensive rat (SHR) up to 1 hr after intraperitoneal administration. The findings are consistent with initial studies in normotensive humans that have not demonstrated a reduction in blood pressure clinically after mCPP in doses that produce elevations in serum cortisol and prolactin levels.

  19. High-throughput chemiluminometric genotyping of single nucleotide polymorphisms of histamine, serotonin, and adrenergic receptor genes.

    Science.gov (United States)

    Toubanaki, Dimitra K; Christopoulos, Theodore K; Ioannou, Penelope C; Flordellis, Christodoulos S

    2009-02-01

    Several pharmacogenetic studies are focused on the investigation of the relation between the efficacy of various antipsychotic agents (e.g., clozapine) and the genetic profile of the patient with an emphasis on genes that code for neurotransmitter receptors such as histamine, serotonin, and adrenergic receptors. We report a high-throughput method for genotyping of single nucleotide polymorphisms (SNPs) within the genes of histamine H2 receptor (HRH2), serotonin receptor (HTR2A1 and HTR2A2), and beta(3) adrenergic receptor (ADRB3). The method combines the high specificity of allele discrimination by oligonucleotide ligation reaction (OLR) and the superior sensitivity and simplicity of chemiluminometric detection in a microtiter well assay configuration. The genomic region that spans the locus of interest is first amplified by polymerase chain reaction (PCR). Subsequently, an oligonucleotide ligation reaction is performed using a biotinylated common probe and two allele-specific probes that are labeled at the 3' end with digoxigenin and fluorescein. The ligation products are immobilized in polystyrene wells via biotin-streptavidin interaction, and the hybrids are denatured. Detection is accomplished by the addition of alkaline phosphatase-conjugated anti-digoxigenin or anti-fluorescein antibodies in combination with a chemiluminogenic substrate. The ratio of the luminescence signals obtained from digoxigenin and fluorescein indicates the genotype of the sample. The method was applied successfully to the genotyping of 23 blood samples for all four SNPs. The results were in concordance with both PCR-restriction fragment length polymorphism analysis and sequencing.

  20. Neocortical serotonin2A receptor binding predicts quetiapine associated weight gain in antipsychotic-naive first-episode schizophrenia patients

    DEFF Research Database (Denmark)

    Rasmussen, Hans; Ebdrup, Bjørn H; Oranje, B

    2014-01-01

    Antipsychotic-induced weight gain is of major clinical importance since it is associated with severe metabolic complications and increased mortality. The serotonin2A receptor system has been suggested to be implicated in weight gain and obesity. However, no previous in vivo imaging data have...... binding as measured with positron emission tomography (PET) and [18F]altanserin and change in body mass index (BMI). Quetiapine was chosen because it is characterized by a moderately high affinity for the serotonin2A receptor and a fast dissociation rate from the dopamine D2 receptor. At baseline the mean...... to treatment and subsequent increase in BMI (rho = 0.59, p = 0.022). At follow-up, the serotonin2A receptor occupancy was positively correlated with BMI increase (rho = 0.54, p = 0.038). To our knowledge, these are the first in vivo receptor imaging data in initially antipsychotic-naive first...

  1. Functional characterization of serotonin receptor subtypes in human duodenal secretion

    DEFF Research Database (Denmark)

    Engelmann, Bodil Elisabeth; Bindslev, Niels; Poulsen, Steen Seier;

    2006-01-01

    of dyspeptic patients with or without Helicobacter pylori infection, and to determine the 5-HT receptor subtypes functionally involved. Biopsies from the second part of duodenum were obtained from 43 dyspeptic patients during routine endoscopy. Biopsies were mounted in modified Ussing chambers with air suction......: ketanserin, ondansetron, or SB-204070 (1-butyl-4 piperidinmethyl-8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-carboxylate HCl). Histological examination was performed on duodenal biopsies. Helicobacter urease testing and histological examination determined Helicobacter pylori infection. 5-HT induced a dose......-dependent and bumetanide-sensitive short-circuit current, which was independent of the presence of Helicobacter pylori infection. All the three 5-HT receptor antagonists failed to significantly effect basal and 5-HT-induced short-circuit current. Our results indicate that in human duodenum 1) 5-HT is a potent stimulator...

  2. A nonlinear relationship between cerebral serotonin transporter and 5-HT(2A) receptor binding: an in vivo molecular imaging study in humans

    DEFF Research Database (Denmark)

    Erritzoe, David; Holst, Klaus; Frokjaer, Vibe G.;

    2010-01-01

    Serotonergic neurotransmission is involved in the regulation of physiological functions such as mood, sleep, memory, and appetite. Within the serotonin transmitter system, both the postsynaptically located serotonin 2A (5-HT2A) receptor and the presynaptic serotonin transporter (SERT) are sensitive...

  3. A Novel Role of Serotonin Receptor 2B Agonist as an Anti-Melanogenesis Agent

    Directory of Open Access Journals (Sweden)

    Eun Ju Oh

    2016-04-01

    Full Text Available BW723C86, a serotonin receptor 2B agonist, has been investigated as a potential therapeutic for various conditions such as anxiety, hyperphagia and hypertension. However, the functional role of BW723C86 against melanogenesis remains unclear. In this study, we investigate the effect of serotonin receptor 2B (5-HTR2B agonist on melanogenesis and elucidate the mechanism involved. BW723C86 reduced melanin synthesis and intracellular tyrosinase activity in melan-A cells and normal human melanocytes. The expression of melanogenesis-related proteins (tyrosinase, TRP-1 and TRP-2 and microphthalmia-associated transcription factor (MITF in melan-A cells decreased after BW723C86 treatment. The promoter activity of MITF was also reduced by BW723C86 treatment. The reduced level of MITF was associated with inhibition of protein kinase A (PKA and cAMP response element-binding protein (CREB activation by BW723C86 treatment. These results suggest that the serotonin agonist BW723C86 could be a potential therapeutic agent for skin hyperpigmentation disorders.

  4. Activation, internalization, and recycling of the serotonin 2A receptor by dopamine

    Science.gov (United States)

    Bhattacharyya, Samarjit; Raote, Ishier; Bhattacharya, Aditi; Miledi, Ricardo; Panicker, Mitradas M.

    2006-01-01

    Serotonergic and dopaminergic systems, and their functional interactions, have been implicated in the pathophysiology of various CNS disorders. Here, we use recombinant serotonin (5-HT) 2A (5-HT2A) receptors to further investigate direct interactions between dopamine and 5-HT receptors. Previous studies in Xenopus oocytes showed that dopamine, although not the cognate ligand for the 5-HT2A receptor, acts as a partial-efficacy agonist. At micromolar concentrations, dopamine also acts as a partial-efficacy agonist on 5-HT2A receptors in HEK293 cells. Like 5-HT, dopamine also induces receptor-internalization in these cells, although at significantly higher concentrations than 5-HT. Interestingly, if the receptors are first sensitized or “primed” by subthreshold concentrations of 5-HT, then dopamine-induced internalization occurs at concentrations ≈10-fold lower than when dopamine is used alone. Furthermore, unlike 5-HT-mediated internalization, dopamine-mediated receptor internalization, alone, or after sensitization by 5-HT, does not depend on PKC. Dopamine-internalized receptors recycle to the surface at rates similar to those of 5-HT-internalized receptors. Our results suggest a previously uncharacterized role for dopamine in the direct activation and internalization of 5-HT2A receptors that may have clinical relevance to the function of serotonergic systems in anxiety, depression, and schizophrenia and also to the treatment of these disorders. PMID:17005723

  5. Similar serotonin-2A receptor binding in rats with different coping styles or levels of aggression

    DEFF Research Database (Denmark)

    Visser, Anniek Kd; Ettrup, Anders; Klein, Anders Bue

    2015-01-01

    Individual differences in coping style emerge as a function of underlying variability in the activation of a mesocorticolimbic brain circuitry. Particularly serotonin seems to play an important role. For this reason, we assessed serotonin-2A receptor (5-HT2A R) binding in the brain of rats...... with different coping styles. We compared proactive and reactive males of two rat strains, Wild-type Groningen (WTG) and Roman high- and low avoidance (RHA, RLA). 5-HT2A R binding in (pre)frontal cortex (FC) and hippocampus was investigated using a radiolabeled antagonist ([(3) H]MDL-100907) and agonist ([(3) H...... is not an important molecular marker for coping style. Since neither an antagonist nor an agonist tracer showed any binding differences, it is unlikely that the affinity state of the 5-HT2A R is co-varying with levels of aggression or active avoidance in WTG, RHA and RLA. This article is protected by copyright. All...

  6. The Structure of the Mouse Serotonin 5-HT3 Receptor in Lipid Vesicles.

    Science.gov (United States)

    Kudryashev, Mikhail; Castaño-Díez, Daniel; Deluz, Cédric; Hassaine, Gherici; Grasso, Luigino; Graf-Meyer, Alexandra; Vogel, Horst; Stahlberg, Henning

    2016-01-01

    The function of membrane proteins is best understood if their structure in the lipid membrane is known. Here, we determined the structure of the mouse serotonin 5-HT3 receptor inserted in lipid bilayers to a resolution of 12 Å without stabilizing antibodies by cryo electron tomography and subtomogram averaging. The reconstruction reveals protein secondary structure elements in the transmembrane region, the extracellular pore, and the transmembrane channel pathway, showing an overall similarity to the available X-ray model of the truncated 5-HT3 receptor determined in the presence of a stabilizing nanobody. Structural analysis of the 5-HT3 receptor embedded in a lipid bilayer allowed the position of the membrane to be determined. Interactions between the densely packed receptors in lipids were visualized, revealing that the interactions were maintained by the short horizontal helices. In combination with methodological improvements, our approach enables the structural analysis of membrane proteins in response to voltage and ligand gating.

  7. Functional Selectivity and Antidepressant Activity of Serotonin 1A Receptor Ligands

    Directory of Open Access Journals (Sweden)

    Zdzisław Chilmonczyk

    2015-08-01

    Full Text Available Serotonin (5-HT is a monoamine neurotransmitter that plays an important role in physiological functions. 5-HT has been implicated in sleep, feeding, sexual behavior, temperature regulation, pain, and cognition as well as in pathological states including disorders connected to mood, anxiety, psychosis and pain. 5-HT1A receptors have for a long time been considered as an interesting target for the action of antidepressant drugs. It was postulated that postsynaptic 5-HT1A agonists could form a new class of antidepressant drugs, and mixed 5-HT1A receptor ligands/serotonin transporter (SERT inhibitors seem to possess an interesting pharmacological profile. It should, however, be noted that 5-HT1A receptors can activate several different biochemical pathways and signal through both G protein-dependent and G protein-independent pathways. The variables that affect the multiplicity of 5-HT1A receptor signaling pathways would thus result from the summation of effects specific to the host cell milieu. Moreover, receptor trafficking appears different at pre- and postsynaptic sites. It should also be noted that the 5-HT1A receptor cooperates with other signal transduction systems (like the 5-HT1B or 5-HT2A/2B/2C receptors, the GABAergic and the glutaminergic systems, which also contribute to its antidepressant and/or anxiolytic activity. Thus identifying brain specific molecular targets for 5-HT1A receptor ligands may result in a better targeting, raising a hope for more effective medicines for various pathologies.

  8. Sleep deprivation increases cerebral serotonin 2A receptor binding in humans.

    Science.gov (United States)

    Elmenhorst, David; Kroll, Tina; Matusch, Andreas; Bauer, Andreas

    2012-12-01

    Serotonin and its cerebral receptors play an important role in sleep-wake regulation. The aim of the current study is to investigate the effect of 24-h total sleep deprivation on the apparent serotonin 2A receptor (5-HT(2A)R) binding capacity in the human brain to test the hypothesis that sleep deprivation induces global molecular alterations in the cortical serotonergic receptor system. Volunteers were tested twice with the subtype-selective radiotracer [(18)F]altanserin and positron emission tomography (PET) for imaging of 5-HT(2A)Rs at baseline and after 24 h of sleep deprivation. [(18)F]Altanserin binding potentials were analyzed in 13 neocortical regions of interest. The efficacy of sleep deprivation was assessed by questionnaires, waking electroencephalography, and cognitive performance measurements. Sleep laboratory and neuroimaging center. Eighteen healthy volunteers. Sleep deprivation. A total of 24 hours of sleep deprivation led to a 9.6% increase of [(18)F]altanserin binding on neocortical 5-HT(2A) receptors. Significant region-specific increases were found in the medial inferior frontal gyrus, insula, and anterior cingulate, parietal, sensomotoric, and ventrolateral prefrontal cortices. This study demonstrates that a single night of total sleep deprivation causes significant increases of 5-HT(2A)R binding potentials in a variety of cortical regions although the increase declines as sleep deprivation continued. It provides in vivo evidence that total sleep deprivation induces adaptive processes in the serotonergic system of the human brain.

  9. Interaction of psychoactive tryptamines with biogenic amine transporters and serotonin receptor subtypes

    Science.gov (United States)

    Blough, Bruce E.; Landavazo, Antonio; Decker, Ann M.; Partilla, John S.; Baumann, Michael H.; Rothman, Richard B.

    2014-01-01

    Rationale Synthetic hallucinogenic tryptamines, especially those originally described by Alexander Shulgin, continue to be abused in the United States. The range of subjective experiences produced by different tryptamines suggests that multiple neurochemical mechanisms are involved in their actions, in addition to the established role of agonist activity at serotonin-2A (5-HT2A) receptors. Objectives This study evaluated the interaction of a series of synthetic tryptamines with biogenic amine neurotransmitter transporters and with serotonin (5-HT) receptor subtypes implicated in psychedelic effects. Methods Neurotransmitter transporter activity was determined in rat brain synaptosomes. Receptor activity was determined using calcium mobilization and DiscoveRx PathHunter® assays in HEK293, Gα16-CHO, and CHOk1 cells transfected with human receptors. Results Twenty-one tryptamines were analyzed in transporter uptake and release assays, and 5-HT2A, serotonin 1A (5-HT1A), and 5-HT2A β-arrestin functional assays. Eight of the compounds were found to have 5-HT-releasing activity. Thirteen compounds were found to be 5-HT uptake inhibitors or were inactive. All tryptamines were 5-HT2A agonists with a range of potencies and efficacies, but only a few compounds were 5-HT1A agonists. Most tryptamines recruited β-arrestin through 5-HT2A activation. Conclusions All psychoactive tryptamines are 5-HT2A agonists, but 5-HT transporter (SERT) activity may contribute significantly to the pharmacology of certain compounds. The in vitro transporter data confirm structure-activity trends for releasers and uptake inhibitors whereby releasers tend to be structurally smaller compounds. Interestingly, two tertiary amines were found to be selective substrates at SERT, which dispels the notion that 5-HT-releasing activity is limited only to primary or secondary amines. PMID:24800892

  10. Effects of age of serotonin 5-HT2 receptors in cocaine abusers and normal subjects

    Energy Technology Data Exchange (ETDEWEB)

    Wang, G.J.; Volkow, N.D.; Logan, J. [Brookhaven National Laboratory, Upton, NY (United States)] [and others

    1995-05-01

    We measured the effect of age on serotonin 5-HT2 receptor availability and compared it with the effects on dopamine D2 receptors on 19 chronic cocaine abusers (35.2{plus_minus}9.8 years, range 18-54 years old) and 19 age matched normal controls using positron emission tomography (PET) and F-18 N-methylspiperone (NMS). 5-HT2 Receptor availability was measure din frontal (FR), occipital (OC), cingulate (CI) and orbitofrontal (OF) cortices using the ratio of the distribution volume in the region of interest to that in the cerebelium (CB) which is a function of Bmax/Kd. D2 receptor availability in the basal ganglia was measured using the {open_quotes}ratio index{close_quotes} (slope of striatum/CB versus time over 180 min of the scan) which is a function of Bmax. 5-HT2 Receptor availability differed among regions and were as follows: CI>OF>OC>FC.5-HT2 Receptor availability decreased significantly with age. This effect was more accentuated for 5-HT2 receptor availability in FR than in OC(df=1, p<0.025). Striatal dopamine D2 receptors were also found to decrease significantly with age (r=0.63, p<0.007). In a given subject, D2 receptor availability was significantly correlated with 5-HT2 receptor availability in FR (r=0.51, p<0.035) but not in OC. The values for 5-HT2 receptor availability were not different in normal subjects and cocaine abusers. These results document a decline in 5-HT2 and D2 receptors with age and document an association between frontal 5-HT2 and striatal D2 receptor availability. These results did not show any changes in 5-HT2 receptor availability in cocaine abusers as compared to control subjects.

  11. Signalling properties and pharmacology of a 5-HT7 -type serotonin receptor from Tribolium castaneum.

    Science.gov (United States)

    Vleugels, R; Lenaerts, C; Vanden Broeck, J; Verlinden, H

    2014-04-01

    In the last decade, genome sequence data and gene structure information on invertebrate receptors has been greatly expanded by large sequencing projects and cloning studies. This information is of great value for the identification of receptors; however, functional and pharmacological data are necessary for an accurate receptor classification and for practical applications. In insects, an important group of neurotransmitter and neurohormone receptors, for which ample sequence information is available but pharmacological information is missing, are the biogenic amine G protein-coupled receptors (GPCRs). In the present study, we investigated the sequence information, pharmacology and signalling properties of a 5-HT7 -type serotonin receptor from the red flour beetle, Tribolium castaneum (Trica5-HT7 ). The receptor encoding cDNA shows considerable sequence similarity with cognate 5-HT7 receptors and phylogenetic analysis also clusters the receptor within this 5-HT receptor group. Real-time reverse transcription PCR demonstrated high expression levels in the brain, indicating the possible importance of this receptor in neural processes. Trica5-HT7 was dose-dependently activated by 5-HT, which induced elevated intracellular cyclic AMP levels but had no effect on calcium signalling. The synthetic agonists, α-methyl 5-HT, 5-methoxytryptamine, 5-carboxamidotryptamine and 8-hydroxy-2-(dipropylamino)tetralin hydrobromide, showed a response, although with a much lower potency and efficacy than 5-HT. Ketanserin and methiothepin were the most potent antagonists. Both showed characteristics of competitive inhibition on Trica5-HT7 . The signalling pathway and pharmacological profile offer important information that will facilitate functional and comparative studies of 5-HT receptors in insects and other invertebrates. The pharmacology of invertebrate 5-HT receptors differs considerably from that of vertebrates. The present study may therefore contribute to establishing a more

  12. Serotonin 5-HT2C receptor-mediated inhibition of the M-current in hypothalamic POMC neurons

    OpenAIRE

    Roepke, T. A.; Smith, A W; Rønnekleiv, O. K.; Kelly, M. J.

    2012-01-01

    Hypothalamic proopiomelanocortin (POMC) neurons are controlled by many central signals, including serotonin. Serotonin increases POMC activity and reduces feeding behavior via serotonion [5-hydroxytryptamine (5-HT)] receptors by modulating K+ currents. A potential K+ current is the M-current, a noninactivating, subthreshold outward K+ current. Previously, we found that M-current activity was highly reduced in fasted vs. fed states in neuropeptide Y neurons. Because POMC neurons also respond t...

  13. Serotonin-1A receptor imaging in recurrent depression: replication and literature review

    Energy Technology Data Exchange (ETDEWEB)

    Drevets, Wayne C. [Mood and Anxiety Disorders Program, MINH Molecular Imaging Branch, Bethesda, MD 20892 (United States); Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 19213 (United States); Department of Radiology, University of Pittsburgh, Pittsburgh, PA 19213 (United States)], E-mail: drevetsw@mail.nih.gov; Thase, Michael E. [Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 19213 (United States); Department of Psychiatry, University of Pennsylvania, School of Medicine and Philadelphia Veterans Affairs Medical Center, Philadelphia, PA 19104 (United States); Moses-Kolko, Eydie L. [Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 19213 (United States); Price, Julie [Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 19213 (United States); Department of Radiology, University of Pittsburgh, Pittsburgh, PA 19213 (United States); Frank, Ellen; Kupfer, David J. [Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 19213 (United States); Mathis, Chester [Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 19213 (United States); Department of Radiology, University of Pittsburgh, Pittsburgh, PA 19213 (United States)

    2007-10-15

    Introduction: Serotonin-1A receptor (5-HT{sub 1A}R) function appears to be decreased in major depressive disorder (MDD) based on physiological responses to 5-HT{sub 1A}R agonists in vivo and to 5-HT{sub 1A}R binding in brain tissues postmortem or antemortem. We have previously assessed 5-HT{sub 1A}R binding potential (BP) in depression using positron emission tomography (PET) and [carbonyl-{sup 11}C]WAY-100635, and we have demonstrated reduced 5-HT{sub 1A}R BP in the mesiotemporal cortex (MTC) and raphe in depressives with primary recurrent familial mood disorders (n=12) versus controls (n=8) [Drevets WC, Frank E, Price JC, Kupfer DJ, Holt D, Greer PJ, Huang Y, Gautier C, Mathis C. PET imaging of serotonin 1A receptor binding in depression. Biol Psychiatry 1999;46(10):1375-87]. These findings were replicated by some, but not other, studies performed in depressed samples that were more generally selected using criteria for MDD. In the current study, we attempted to replicate our previous findings in an independent sample of subjects selected according to the criteria for primary recurrent depression applied in our prior study. Methods: Using PET and [carbonyl-{sup 11}C]WAY-100635, 5-HT{sub 1A}R BP was assessed in 16 depressed subjects and 8 healthy controls. Results: Mean 5-HT{sub 1A}R BP was reduced by 26% in the MTC (P < .005) and by 43% in the raphe (P < .001) in depressives versus controls. Conclusions: These data replicate our original findings, which showed that BP was reduced by 27% in the MTC (P < .025) and by 42% in the raphe (P < .02) in depression. The magnitudes of these reductions in 5-HT{sub 1A}R binding were similar to those found postmortem in 5-HT{sub 1A}R mRNA concentrations in the hippocampus in MDD [Lopez JF, Chalmers DT, Little KY, Watson SJ. Regulation of serotonin 1A, glucocorticoid, and mineralocorticoid receptor in rat and human hippocampus: implications for neurobiology of depression. Biol Psychiatry 1998;43:547-73] and in 5-HT{sub 1A

  14. Pharmacological and genetic interventions in serotonin (5-HT)(2C) receptors to alter drug abuse and dependence processes

    NARCIS (Netherlands)

    Filip, Malgorzata; Spampinato, Umberto; McCreary, Andrew C.; Przegalinski, Edmund

    2012-01-01

    The present review provides an overview on serotonin (5-hydroxytryptamine; 5-HT)(2C) receptors and their relationship to drug dependence. We have focused our discussion on the impact of 5-HT2C receptors on the effects of different classes of addictive drugs, illustrated by reference to data using ph

  15. Serotonin receptor agonist quipazine promotes proliferation and apoptosis of human hepatocyte strain of L-02 strain

    Institute of Scientific and Technical Information of China (English)

    Yang Liu; Zhi-Yong Zhang

    2009-01-01

    BACKGROUND:Liver disease is commonly seen in the clinic and its pathological characteristic is combined hepatocellular death and apoptosis. Promoting hepatocyte regeneration is one of the main methods of treating liver disease. Serotonin (5-HT) is an important compound which participates in various life process, and 95% of it is carried by platelets in the blood. A recent ifnding showed that platelet-derived serotonin is the key factor in liver regeneration, which fails without serotonin. This study aimed to investigate the effects of quipazine, a selective 5-HT receptor agonist, on proliferation and apoptosis in the human hepatocyte strain L-02. METHODS:L-02 cells were cultured in medium with 5-HT and quipazine, and samples were collected at 24, 48, and 72 hours. The methyl thiazolyl tetrazolium (MTT) method was used to test viability, lfow cytometry to assess the cell cycle, the Annexin-V/PI method to evaluate apoptosis, and immunohistochemistry to detect proliferating cell nuclear antigen (PCNA). RESULTS:Compared with the control group, the viability of L-02 cells was improved in the 10, 50, and 250 μg/ml quipazine groups (P0.05); and no difference in the percentage of apoptotic cells was found between the 50μg/ml quipazine and control groups (P>0.05).CONCLUSION:Quipazine improves proliferation of a human hepatocyte strainin vitro, and this is not based on the inhibition of apoptosis.

  16. Molecular dynamics simulation of the structure and dynamics of 5-HT3 serotonin receptor

    Science.gov (United States)

    Antonov, M. Yu.; Popinako, A. V.; Prokopiev, G. A.

    2016-10-01

    In this work, we investigated structure, dynamics and ion transportation in transmembrane domain of the 5-HT3 serotonin receptor. High-resolution (0.35 nm) structure of the 5-HT3 receptor in complex with stabilizing nanobodies was determined by protein crystallography in 2014 (Protein data bank (PDB) code 4PIR). Transmembrane domain of the structure was prepared in complex with explicit membrane environment (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC)) and solvent (TIP3P water model). Molecular dynamics protocols for simulation and stabilization of the transmembrane domain of the 5-HT3 receptor model were developed and 60 ns simulation of the structure was conducted in order to explore structural parameters of the system. We estimated the mean force profile for Na+ ions using umbrella sampling method.

  17. In vivo regulation of the serotonin-2 receptor in rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Stockmeier, C.A.; Kellar, K.J.

    1986-01-13

    Serotonin-2 (5-HT-2) receptors in brain were measured using (/sup 3/H)ketanserin. The authors examined the effects of amitriptyline, an anti-depressant drug, of electroconvulsive shock (ECS) and of drug-induced alterations in presynaptic 5-HT function on (/sup 3/H)ketanserin binding to 5-HT-2 receptors in rat brain. The importance of intact 5-HT axons to the up-regulation of 5-HT-2 receptors by ECS was also investigated, and an attempt was made to relate the ECS-induced increase in this receptor to changes in 5-HT presynaptic mechanisms. Twelve days of ECS increased the number of 5-HT-2 receptors in frontal cortex. Neither the IC/sub 50/ nor the Hill coefficient of 5-HT in competing for (/sup 3/H)ketanserin binding sites was altered by ECS. Repeated injections of amitriptyline reduced the number of 5-HT-2 receptors in frontal cortex. Reserpine, administered daily for 12 days, caused a significant increase in 5-HT-2 receptors, but neither daily injections of p-chlorophenylalanine (PCPA) nor lesions of 5-HT axons with 5,7-dihydroxytryptamine (5,7-DHT) affected 5-HT-2 receptors. However, regulation of 5-HT-2 receptors by ECS was dependent on intact 5-HT axons since ECS could not increase the number of 5-HT-2 receptors in rats previously lesioned with 5,7-DHT. Repeated ECS, however, does not appear to affect either the high-affinity uptake of (/sup 3/H)5-HT or (/sup 3/H)imipramine binding, two presynaptic markers of 5-HT neuronal function. 5-HT-2 receptors appear to be under complex control. ECS or drug treatments such as reserpine or amitriptyline, which affect several monoamine neurotransmission systems including 5-HT, can alter 5-HT-2 receptors. 28 references, 1 figure, 7 tables.

  18. Anterior cingulate serotonin 1B receptor binding is associated with emotional response inhibition

    DEFF Research Database (Denmark)

    da Cunha-Bang, Sofi; Hjordt, Liv Vadskjær; Dam, Vibeke Høyrup

    2017-01-01

    -HT1BR would be positively associated with false alarms (failures to inhibit nogo responses) in the context of aversive (angry and fearful) facial expressions. Across groups, we found that frontal cortex 5-HT1BR binding was positively correlated with false alarms when angry faces were go stimuli......-offender controls, completed an emotional Go/NoGo task requiring inhibition of prepotent motor responses to emotional facial expressions. We also measured cerebral serotonin 1B receptor (5-HT1BR) binding with [(11)C]AZ10419369 positron emission tomography within regions of the frontal cortex. We hypothesized that 5...

  19. A High-Resolution In Vivo Atlas of the Human Brain's Serotonin System.

    Science.gov (United States)

    Beliveau, Vincent; Ganz, Melanie; Feng, Ling; Ozenne, Brice; Højgaard, Liselotte; Fisher, Patrick M; Svarer, Claus; Greve, Douglas N; Knudsen, Gitte M

    2017-01-04

    The serotonin (5-hydroxytryptamine, 5-HT) system modulates many important brain functions and is critically involved in many neuropsychiatric disorders. Here, we present a high-resolution, multidimensional, in vivo atlas of four of the human brain's 5-HT receptors (5-HT1A, 5-HT1B, 5-HT2A, and 5-HT4) and the 5-HT transporter (5-HTT). The atlas is created from molecular and structural high-resolution neuroimaging data consisting of positron emission tomography (PET) and magnetic resonance imaging (MRI) scans acquired in a total of 210 healthy individuals. Comparison of the regional PET binding measures with postmortem human brain autoradiography outcomes showed a high correlation for the five 5-HT targets and this enabled us to transform the atlas to represent protein densities (in picomoles per milliliter). We also assessed the regional association between protein concentration and mRNA expression in the human brain by comparing the 5-HT density across the atlas with data from the Allen Human Brain atlas and identified receptor- and transporter-specific associations that show the regional relation between the two measures. Together, these data provide unparalleled insight into the serotonin system of the human brain.

  20. Serotonin 2A receptor mRNA levels in the neonatal dopamine-depleted rat striatum remain upregulated following suppression of serotonin hyperinnervation.

    Science.gov (United States)

    Basura, G J; Walker, P D

    1999-08-05

    Sixty days after bilateral dopamine (DA) depletion (>98%) with 6-hydroxydopamine (6-OHDA) in neonatal rats, serotonin (5-HT) content doubled and 5-HT(2A) receptor mRNA expression rose 54% within the rostral striatum. To determine if striatal 5-HT(2A) receptor mRNA upregulation is dependent on increased 5-HT levels following DA depletion, neonatal rats received dual injections of 6-OHDA and 5,7-dihydroxytryptamine (5,7-DHT) which suppressed 5-HT content by approximately 90%. In these 6-OHDA/5,7-DHT-treated rats, striatal 5-HT(2A) receptor mRNA expression was still elevated (87% above vehicle controls). Comparative analysis of 5-HT(2C) receptor mRNA expression yielded no significant changes in any experimental group. These results demonstrate that upregulated 5-HT(2A) receptor biosynthesis in the DA-depleted rat is not dependent on subsequent 5-HT hyperinnervation.

  1. Crucial interactions between selective serotonin uptake inhibitors and sigma-1 receptor in heart failure.

    Science.gov (United States)

    Bhuiyan, Md Shenuarin; Tagashira, Hideaki; Fukunaga, Kohji

    2013-01-01

    Depression is associated with a substantial increase in the risk of developing heart failure and is independently associated with increased cardiovascular morbidity and mortality. Inversely, cardiovascular disease can lead to severe depression. Thus, therapy with selective serotonin reuptake inhibitors (SSRIs) is strongly recommended to reduce cardiovascular disease-induced morbidity and mortality. However, molecular mechanisms to support evidence-based SSRI treatment of cardiovascular disease have not been elucidated. We recently found very high expression of the sigma-1 receptor, an orphan receptor, in rat heart tissue and defined the cardiac sigma-1 receptor as a direct SSRI target in eliciting cardioprotection in both pressure overload (PO)induced and transverse aortic constriction (TAC)-induced myocardial hypertrophy models in rodents. Our findings suggest that SSRIs such as fluvoxamine protect against PO- and TAC-induced cardiac dysfunction by upregulating sigma-1 receptor expression and stimulating sigma-1 receptor-mediated Akt-eNOS signaling. Here, we discuss the association of depression and cardiovascular diseases, the protective mechanism of SSRIs in heart failure patients, and the pathophysiological relevance of sigma-1 receptors to progression of heart failure. These findings should promote development of clinical therapeutics targeting the sigma-1 receptor in cardiovascular diseases.

  2. 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.

  3. Investigation of serotonin-1A receptor function in the human psychopharmacology of MDMA.

    Science.gov (United States)

    Hasler, F; Studerus, E; Lindner, K; Ludewig, S; Vollenweider, F X

    2009-11-01

    Serotonin (5-HT) release is the primary pharmacological mechanism of 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') action in the primate brain. Dopamine release and direct stimulation of dopamine D2 and serotonin 5-HT2A receptors also contributes to the overall action of MDMA. The role of 5-HT1A receptors in the human psychopharmacology of MDMA, however, has not yet been elucidated. In order to reveal the consequences of manipulation at the 5-HT1A receptor system on cognitive and subjective effects of MDMA, a receptor blocking study using the mixed beta-adrenoreceptor blocker/5-HT1A antagonist pindolol was performed. Using a double-blind, placebo-controlled within-subject design, 15 healthy male subjects were examined under placebo (PL), 20 mg pindolol (PIN), MDMA (1.6 mg/kg b.wt.), MDMA following pre-treatment with pindolol (PIN-MDMA). Tasks from the Cambridge Neuropsychological Test Automated Battery were used for the assessment of cognitive performance. Psychometric questionnaires were applied to measure effects of treatment on core dimensions of Altered States of Consciousness, mood and state anxiety. Compared with PL, MDMA significantly impaired sustained attention and visual-spatial memory, but did not affect executive functions. Pre-treatment with PIN did not significantly alter MDMA-induced impairment of cognitive performance and only exerted a minor modulating effect on two psychometric scales affected by MDMA treatment ('positive derealization' and 'dreaminess'). Our findings suggest that MDMA differentially affects higher cognitive functions, but does not support the hypothesis from animal studies, that some of the MDMA effects are causally mediated through action at the 5-HT1A receptor system.

  4. Effects of systemic injections of vilazodone, a selective serotonin reuptake inhibitor and serotonin 1A receptor agonist, on anxiety induced by predator stress in rats.

    Science.gov (United States)

    Adamec, Robert; Bartoszyk, Gerd D; Burton, Paul

    2004-11-03

    We examined the effect of Vilazodone, a selective serotonin reuptake inhibitor (SSRI) and serotonin 1A (5-HT(1A)) receptor agonist [Bartoszyk, G.D., Hegenbart, R., Ziegler, H., 1997. EMD 68843, a serotonin reuptake inhibitor with selective presynaptic 5-HT1A receptor agonistic properties. Eur. J. Pharmacol. 322, 147-153.], on change in affect following predator stress. Vilazodone and vehicle injection (intraperitoneal) occurred either 10 min after predator stress (prophylactic testing), or 90 min prior to behavioral testing for the effects of predator stress (therapeutic testing). Predator stress involved unprotected exposure of rats to a domestic cat. Behavioral effects of stress were evaluated with hole board, plus-maze, and acoustic startle tests 1 week after stress. Predator stress increased anxiety-like behavior in the plus-maze and elevated response to acoustic startle. In prophylactic testing, Vilazodone affected stress potentiation of startle at doses above 5 mg/kg. Vilazodone increased stress elevation of startle at 10 mg/kg. Higher doses of Vilazodone (20 and 40 mg/kg) blocked stress potentiation of startle. In contrast, Vilazodone had no effect on stress potentiation of anxiety in the plus-maze. In therapeutic testing, Vilazodone increased stress elevation of startle at all doses. In contrast, therapeutic Vilazodone had no effect on stress potentiation of anxiety in the plus-maze. Taken together, the data suggest a prophylactic potential for Vilazodone in the treatment of changes in hypervigilance following severe stress.

  5. Postnatal handling reverses social anxiety in serotonin receptor 1A knockout mice.

    Science.gov (United States)

    Zanettini, C; Carola, V; Lo Iacono, L; Moles, A; Gross, C; D'Amato, F R

    2010-02-01

    Mice lacking the serotonin receptor 1A (Htr1a knockout, Htr1a(KO)) show increased innate and conditioned anxiety. This phenotype depends on functional receptor activity during the third through fifth weeks of life and thus appears to be the result of long-term changes in brain function as a consequence of an early deficit in serotonin signaling. To evaluate whether this phenotype can be influenced by early environmental factors, we subjected Htr1a knockout mice to postnatal handling, a procedure known to reduce anxiety-like behavior and stress responses in adulthood. Offspring of heterozygous Htr1a knockout mice were separated from their mother and exposed 15 min each day from postnatal day 1 (PD1) to PD14 to clean bedding. Control animals were left undisturbed. Maternal behavior was observed during the first 13 days of life. Adult male offspring were tested in the open field, social approach and resident-intruder tests and assessed for corticosterone response to restraint stress. Knockout mice showed increased anxiety in the open field and in the social approach test as well as an enhanced corticosterone response to stress. However, while no effect of postnatal handling was seen in wild-type mice, handling reduced anxiety-like behavior in the social interaction test and the corticosterone response to stress in knockout mice. These findings extend the anxiety phenotype of Htr1a(KO) mice to include social anxiety and demonstrate that this phenotype can be moderated by early environmental factors.

  6. The acute anorexic effect of liraglutide, a GLP-1 receptor agonist, does not require functional leptin receptor, serotonin, and hypothalamic POMC and CART activities in mice.

    Science.gov (United States)

    Nonogaki, Katsunori; Kaji, Takao

    2016-10-01

    The acute anorexic effect of liraglutide, a GLP-1 receptor agonist, did not require functional leptin receptor, serotonin, and hypothalamic proopiomelanocortin and cocaine amphetamine regulated transcript activities in mice, although decrease in functional hypothalamic orexin activity might be involved in the acute anorexic effect of liraglutide.

  7. Serotonin modulation of cortical neurons and networks

    Directory of Open Access Journals (Sweden)

    Pau eCelada

    2013-04-01

    Full Text Available The serotonergic pathways originating in the dorsal and median raphe nuclei (DR and MnR, respectively are critically involved in cortical function. Serotonin (5-HT, acting on postsynaptic and presynaptic receptors, is involved in cognition, mood, impulse control and motor functions by 1 modulating the activity of different neuronal types, and 2 varying the release of other neurotransmitters, such as glutamate, GABA, acetylcholine and dopamine. Also, 5-HT seems to play an important role in cortical development. Of all cortical regions, the frontal lobe is the area most enriched in serotonergic axons and 5-HT receptors. 5-HT and selective receptor agonists modulate the excitability of cortical neurons and their discharge rate through the activation of several receptor subtypes, of which the 5-HT1A, 5-HT1B, 5-HT2A and 5-HT3 subtypes play a major role. Little is known, however, on the role of other excitatory receptors moderately expressed in cortical areas, such as 5-HT2C, 5-HT4, 5-HT6 and 5-HT7. In vitro and in vivo studies suggest that 5-HT1A and 5-HT2A receptors are key players and exert opposite effects on the activity of pyramidal neurons in the medial prefrontal cortex (mPFC. The activation of 5-HT1A receptors in mPFC hyperpolarizes pyramidal neurons whereas that of 5-HT2A receptors results in neuronal depolarization, reduction of the afterhyperpolarization and increase of excitatory postsynaptic currents (EPSCs and of discharge rate. 5-HT can also stimulate excitatory (5-HT2A and 5-HT3 and inhibitory (5-HT1A receptors in GABA interneurons to modulate synaptic GABA inputs onto pyramidal neurons. Likewise, the pharmacological manipulation of various 5-HT receptors alters oscillatory activity in PFC, suggesting that 5-HT is also involved in the control of cortical network activity. A better understanding of the actions of 5-HT in PFC may help to develop treatments for mood and cognitive disorders associated with an abnormal function of the

  8. The serotonin 5-HT₁A receptor agonist tandospirone improves executive function in common marmosets.

    Science.gov (United States)

    Baba, Satoko; Murai, Takeshi; Nakako, Tomokazu; Enomoto, Takeshi; Ono, Michiko; Shimizu, Isao; Ikeda, Kazuhito

    2015-01-01

    Previous pilot clinical studies have shown that the serotonin 5-HT1A receptor agonist tandospirone has beneficial effect on cognitive deficits associated with schizophrenia. In the present study, we evaluated the cognitive efficacy of tandospirone, given alone or in combination with the antipsychotic blonanserin, risperidone or haloperidol, on executive function in marmosets using the object retrieval with detour (ORD) task. Treatment with tandospirone alone at 20 and 40 mg/kg increased the number of correct responses in the difficult trial, while risperidone (0.3mg/kg) and haloperidol (0.3mg/kg) decreased the number of correct responses in this trial. On the other hand, blonanserin (0.1-0.3mg/kg), an atypical antipsychotic highly selective for dopamine D2/D3 and serotonin 5-HT2A receptors, did not affect the number of correct responses in both the easy and difficult trials. Co-treatment with tandospirone (20mg/kg) and risperidone (0.1-0.3mg/kg) or haloperidol (0.1-0.3mg/kg) did not improve animals' performance in the difficult trial. However, co-treatment with tandospirone and blonanserin (0.1-0.3mg/kg) increased the number of correct responses in the difficult trial. In addition, treatment with the dopamine D1 receptor agonist SKF-81297 at 1mg/kg increased marmosets correct responses in the difficult trial. These results suggest that tandospirone is a promising candidate for the treatment of cognitive deficits associated with schizophrenia and that adjunctive treatment with tandospirone and blonanserin is more appropriate for cognitive deficits than combination therapy with tandospirone and risperidone or haloperidol. The results of this study also indicate that the putative mechanism of action of tandospirone might be related to enhancement of dopamine neurotransmission via activation of the 5-HT1A receptor. Copyright © 2015 Elsevier B.V. All rights reserved.

  9. The role of serotonin 5-HT7 receptor in regulating sleep and wakefulness.

    Science.gov (United States)

    Monti, Jaime M; Jantos, Héctor

    2014-01-01

    Different approaches have been followed to characterize the role of 5-hydroxytryptamine (serotonin) receptor 7 (5-HT7) in the regulation of sleep-wake behavior: (1) 5-HT7 receptor knockout mice spend less time in rapid eye movement sleep than their wild-type counterparts, mainly during the light period. In contrast, there is no difference between the genotypes in time spent in wakefulness or slow-wave sleep. (2) Systemic administration of the selective 5-HT7 receptor agonist LP-211 significantly increased wakefulness (time spent awake) and reduced rapid eye movement sleep in the rat. Direct infusion of LP-211 into the dorsal raphe nucleus, locus coeruleus nucleus, basal forebrain (horizontal limb of the diagonal band of Broca), or laterodorsal tegmental nucleus also produced a decrease in rapid eye movement sleep. Additionally, microinjection of the 5-HT7 receptor agonist into the basal forebrain augmented the time animals remained awake. Local injection of the 5-HT7 receptor agonist LP-44 into the dorsal raphe nucleus also suppressed rapid eye movement sleep in the rat. (3) A similar reduction of rapid eye movement sleep has been described following intraperitoneal injection of the selective 5-HT7 receptor antagonists SB-269970 and SB-656104 in the rat and oral administration of the 5-HT7 receptor antagonist NJ-18038683 to rat and man. Local microinjection of SB-269970 into the dorsal raphe nucleus and basal forebrain also induced a decrease in rapid eye movement sleep in the rat. This tends to suggest that the on-off (activation/blockade), two-state ligand-receptor interaction model is not tenable for the 5-HT7 receptor.

  10. Expression Changes of Serotonin Receptor Gene Subtype 5HT3a in Peripheral Blood Mononuclear Cells from Schizophrenic Patients Treated with Haloperidol and Olanzapin

    Directory of Open Access Journals (Sweden)

    Gholam Reza Shariati

    2009-09-01

    Full Text Available Serotonin receptors are involved in pathophysiology of schizophrenia and may mediate other neurotransmitter effects. We investigated serotonin receptors gene expression in peripheral blood mononuclear cells (PBMC of naïve schizophrenic patients, before and after treatment. Also serotonin receptor gene expression was compared in two treatment groups including Haloperidol and Olanzapine. The PBMC was separated from whole blood by Ficoll-hypaque. The total cellular RNA was extracted and the cDNA was synthesized. This process was followed by real-time PCR using primer pairs specific for 5HT3a serotonin receptor mRNA and beta-actin as internal control. The results showed the presence of subtype of serotonin receptor in lymphocytes. Serotonin gene expression showed significant changes in Olanzapine treatment group which correlated with Clinical Global Impression (CGI score improvement. In conclusion, the present study has shown that human PBMC express serotonin receptors 5HT3a. Moreover, clinical symptom improvement of Olanzapin may be demonstrated by a change in serotonin receptor gene expression.

  11. Selective agonists for serotonin 7 (5-HT7) receptor and their applications in preclinical models: an overview.

    Science.gov (United States)

    Di Pilato, Pantaleo; Niso, Mauro; Adriani, Walter; Romano, Emilia; Travaglini, Domenica; Berardi, Francesco; Colabufo, Nicola A; Perrone, Roberto; Laviola, Giovanni; Lacivita, Enza; Leopoldo, Marcello

    2014-01-01

    The serotonin 7 (5-HT7) receptor was the last serotonin receptor subtype to be discovered in 1993. This receptor system has been implicated in several central nervous system (CNS) functions, including circadian rhythm, rapid eye movement sleep, thermoregulation, nociception, memory and neuropsychiatric symptoms and pathologies, such as anxiety, depression and schizophrenia. In 1999, medicinal chemistry efforts led to the identification of SB-269970, which became the gold standard selective 5-HT7 receptor antagonist, and later of various selective agonists such as AS-19, LP-44, LP-12, LP-211 and E-55888. In this review, we summarize the preclinical pharmacological studies performed using these agonists, highlighting their strengths and weaknesses. The data indicate that 5-HT7 receptor agonists can have neuroprotective effects against N-methyl-d-aspartate-induced toxicity, modulate neuronal plasticity in rats, enhance morphine-induced antinociception and alleviate hyperalgesia consecutive to nerve lesion in neuropathic animals.

  12. Serotonin(2) receptors mediate respiratory recovery after cervical spinal cord hemisection in adult rats.

    Science.gov (United States)

    Zhou, S Y; Basura, G J; Goshgarian, H G

    2001-12-01

    The aim of the present study was to specifically investigate the involvement of serotonin [5-hydroxytryptamine (5-HT(2))] receptors in 5-HT-mediated respiratory recovery after cervical hemisection. Experiments were conducted on C(2) spinal cord-hemisected, anesthetized (chloral hydrate, 400 mg/kg ip), vagotomized, pancuronium- paralyzed, and artificially ventilated female Sprague-Dawley rats in which CO(2) levels were monitored and maintained. Twenty-four hours after spinal hemisection, the ipsilateral phrenic nerve displayed no respiratory-related activity indicative of a functionally complete hemisection. Intravenous administration of the 5-HT(2A/2C)-receptor agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) induced respiratory-related activity in the phrenic nerve ipsilateral to hemisection under conditions in which CO(2) was maintained at constant levels and augmented the activity induced under conditions of hypercapnia. The effects of DOI were found to be dose dependent, and the recovery of activity could be maintained for up to 2 h after a single injection. DOI-induced recovery was attenuated by the 5-HT(2)-receptor antagonist ketanserin but not with the 5-HT(2C)-receptor antagonist RS-102221, suggesting that 5-HT(2A) and not necessarily 5-HT(2C) receptors may be involved in the induction of respiratory recovery after cervical spinal cord injury.

  13. Frontolimbic serotonin 2A receptor binding in healthy subjects is associated with personality risk factors for affective disorder

    DEFF Research Database (Denmark)

    Frokjaer, Vibe G.; Mortensen, Erik L.; Nielsen, Finn Årup

    2008-01-01

    Background: Serotonergic dysfunction has been associated with affective disorders. High trait neuroticism, as measured on personality inventories, is a risk factor for major depression. In this study we investigated whether neuroticism is associated with serotonin 2A receptor binding in brain...... regions of relevance for affective disorders. Methods: Eighty-three healthy volunteers completed the standardized personality questionnaire NEO-PI-R (Revised NEO Personality Inventory) and underwent [F-18]altanserin positron emission tomography imaging for assessment of serotonin 2A receptor binding...... remained significant after correction for multiple comparisons (r = .35, p = .009). Conclusions: In healthy subjects the personality dimension neuroticism and particularly its constituent trait, vulnerability, are positively associated with frontolimbic serotonin 2A binding. Our findings point...

  14. 5-HT7 receptor modulates GABAergic transmission in the rat dorsal raphe nucleus and controls cortical release of serotonin

    OpenAIRE

    Magdalena eKusek; Joanna eSowa; Katarzyna eKamińska; Krystyna eGołembiowska; Krzysztof eTokarski; Grzegorz eHess

    2015-01-01

    The 5-HT7 receptor is one of the several serotonin (5-HT) receptor subtypes that are expressed in the dorsal raphe nucleus (DRN). Some earlier findings suggested that 5-HT7 receptors in the DRN were localized on GABAergic interneurons modulating the activity of 5-HT projection neurons. The aim of the present study was to find out how the 5-HT7 receptor modulates the GABAergic synaptic input to putative 5-HT DRN neurons, and whether blockade of the 5-HT7 receptor would affect the release of 5-...

  15. Contribution of brain serotonin subtype 1B receptors in levodopa-induced motor complications.

    Science.gov (United States)

    Morin, Nicolas; Morissette, Marc; Grégoire, Laurent; Rajput, Alex; Rajput, Ali H; Di Paolo, Thérèse

    2015-12-01

    L-DOPA-induced dyskinesias (LID) are abnormal involuntary movements limiting the chronic use of L-DOPA, the main pharmacological treatment of Parkinson's disease. Serotonin receptors are implicated in the development of LID and modulation of basal ganglia 5-HT1B receptors is a potential therapeutic alternative in Parkinson's disease. In the present study, we used receptor-binding autoradiography of the 5-HT1B-selective radioligand [3H]GR125743 to investigate possible contributions of changes in ligand binding of this receptor in LID in post-mortem brain specimens from Parkinson's disease patients (n=14) and control subjects (n=11), and from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys treated with saline (n=5), L-DOPA (n=4) or L-DOPA+2-methyl-6-(phenylethynyl)pyridine (MPEP) (n=5), and control monkeys (n=4). MPEP is the prototypal metabotropic glutamate 5 (mGlu5) receptor antagonist and has been shown to reduce the development of LID in these monkeys in a chronic treatment of one month. [3H]GR125743 specific binding to striatal and pallidal 5-HT1B receptors respectively were only increased in L-DOPA-treated MPTP monkeys (dyskinetic monkeys) as compared to controls, saline and L-DOPA+MPEP MPTP monkeys; dyskinesias scores correlated positively with this binding. Parkinson's disease patients with motor complications (L-DOPA-induced dyskinesias and wearing-off) had higher [3H]GR125743 specific binding compared to those without motor complications and controls in the basal ganglia. Reduction of motor complications was associated with normal striatal 5-HT1B receptors, suggesting the potential of this receptor for the management of motor complications in Parkinson's disease.

  16. Serotonin (5-HT3 receptor antagonists for the reduction of symptoms of low anterior resection syndrome

    Directory of Open Access Journals (Sweden)

    Itagaki R

    2014-03-01

    Full Text Available Ryohei Itagaki, Keiji Koda, Masato Yamazaki, Kiyohiko Shuto, Chihiro Kosugi, Atsushi Hirano, Hidehito Arimitsu, Risa Shiragami, Yukino Yoshimura, Masato Suzuki Department of Surgery, Teikyo University Chiba Medical Center, Anesaki, Ichihara, Chiba, Japan Purpose: Serotonin (5-hydroxytryptamine [5-HT]3 receptor antagonists are effective for the treatment of diarrhea-predominant irritable bowel syndrome (IBS-D, in which exaggerated intestinal/colonic hypermotility is often observed. Recent studies have suggested that the motility disorder, especially spastic hypermotility, seen in the neorectum following sphincter-preserving operations for rectal cancer may be the basis of the postoperative defecatory malfunction seen in these patients. We investigated the efficacy of 5-HT3 receptor antagonists in patients suffering from severe low anterior resection syndrome. Patients and methods: A total of 25 male patients with complaints of uncontrollable urgency or fecal incontinence following sphincter-preserving operations were enrolled in this study. Defecatory status, assessed on the basis of incontinence score (0–20, urgency grade (0–3, and number of toilet visits per day, was evaluated using a questionnaire before and 1 month after the administration of the 5-HT3 antagonist ramosetron. Results: All the parameters assessed improved significantly after taking ramosetron for 1 month. The effect was more prominent in cases whose anastomotic line was lower, ie, inside the anal canal. Defecatory function was better in patients who commenced ramosetron therapy within 6 months postoperatively, as compared to those who were not prescribed ramosetron for more than 7 months postoperatively. Conclusion: These results suggest that 5-HT3 antagonists are effective for the treatment of low anterior resection syndrome, as in diarrhea-predominant irritable bowel syndrome. The improvement in symptoms is not merely time dependent, but it is related to treatment with 5

  17. Serotonin syndrome

    Science.gov (United States)

    Hyperserotonemia; Serotonergic syndrome; Serotonin toxicity; SSRI - serotonin syndrome; MAO - serotonin syndrome ... two medicines that affect the body's level of serotonin are taken together at the same time. The ...

  18. Effect of serotonin receptor blockade on endocrine and cardiovascular responses to head-up tilt in humans

    DEFF Research Database (Denmark)

    Matzen, S; Secher, N H; Knigge, U

    1993-01-01

    Effects of blockade of serotonin (5-HT) receptors on the integrated cardiovascular and endocrine adaptations during head-up tilt were investigated in normal men. In control experiments 50 degrees head-up tilt increased heart rate (HR), total peripheral resistance (TPR), plasma renin activity (PRA...

  19. Effects of ergot alkaloid exposure on serotonin receptor mRNA in the smooth muscle of the bovine gastrointestinal tract

    Science.gov (United States)

    Various serotonin (5HT) receptor subtypes have been located in the gastrointestinal tract and some are associated with gut motility. Cattle exposed to ergot alkaloids through consumption of contaminated feedstuffs have demonstrated signs (e.g. - increased rumen DM content and total content) that sug...

  20. Serotonin 2C receptor activates a distinct population of arcuate pro-opiomelanocortin neurons via TRPC channels

    Science.gov (United States)

    Serotonin 2C receptors (5-HT2CRs) expressed by pro-opiomelanocortin (POMC) neurons of hypothalamic arcuate nucleus regulate food intake, energy homeostasis ,and glucose metabolism. However, the cellular mechanisms underlying the effects of 5-HT to regulate POMC neuronal activity via 5-HT2CRs have no...

  1. Oxytocin receptor (OXTR) and serotonin transporter (5-HTT) genes associated with observed parenting.

    Science.gov (United States)

    Bakermans-Kranenburg, Marian J; van Ijzendoorn, Marinus H

    2008-06-01

    Both oxytocin and serotonin modulate affiliative responses to partners and offspring. Animal studies suggest a crucial role of oxytocin in mammalian parturition and lactation but also in parenting and social interactions with offspring. The serotonergic system may also be important through its influence on mood and the release of oxytocin. We examined the role of serotonin transporter (5-HTT) and oxytocin receptor (OXTR) genes in explaining differences in sensitive parenting in a community sample of 159 Caucasian, middle-class mothers with their 2-year-old toddlers at risk for externalizing behavior problems, taking into account maternal educational level, maternal depression and the quality of the marital relationship. Independent genetic effects of 5-HTTLPR SCL6A4 and OXTR rs53576 on observed maternal sensitivity were found. Controlling for differences in maternal education, depression and marital discord, parents with the possibly less efficient variants of the serotonergic (5-HTT ss) and oxytonergic (AA/AG) system genes showed lower levels of sensitive responsiveness to their toddlers. Two-way and three-way interactions with marital discord or depression were not significant. This first study on the role of both OXTR and 5-HTT genes in human parenting points to molecular genetic differences that may be implicated in the production of oxytocin explaining differences in sensitive parenting.

  2. Serotonin1A receptors in the pathophysiology of schizophrenia: development of novel cognition-enhancing therapeutics.

    Science.gov (United States)

    Sumiyoshi, Tomiki; Bubenikova-Valesova, Vera; Horacek, Jiri; Bert, Bettina

    2008-10-01

    Serotonin (5-HT) receptors have been suggested to play key roles in psychosis, cognition, and mood via influence on neurotransmitters, synaptic integrity, and neural plasticity. Specifically, genetic evidence indicates that 5-HT(1A), 5-HT(2A), and 5-HT(2C) receptor single-nucleotide polymorphisms (SNPs) are related to psychotic symptoms, cognitive disturbances, and treatment response in schizophrenia. Data from animal research suggest the role of 5-HT in cognition via its influence on dopaminergic, cholinergic, glutamatergic, and GABAergic function. This article provides up-to-date findings on the role of 5-HT receptors in endophenotypic variations in schizophrenia and the development of newer cognition-enhancing medications, based on basic science and clinical evidence. Imaging genetics studies on associations of polymorphisms of several 5-HT receptor subtypes with brain structure, function, and metabolism suggest a role for the prefrontal cortex and the parahippocampal gyrus in cognitive impairments of schizophrenia. Data from animal experiments to determine the effect of agonists/antagonists at 5-HT(1A), 5-HT(2A), and 5-HT(2C) receptors on behavioral performance in animal models of schizophrenia based on the glutamatergic hypothesis provide useful information. For this purpose, standard as well as novel cognitive tasks provide a measure of memory/information processing and social interaction. In order to scrutinize mixed evidence for the ability of 5-HT(1A) agonists/antagonists to improve cognition, behavioral data in various paradigms from transgenic mice overexpressing 5-HT(1A) receptors provide valuable insights. Clinical trials reporting the advantage of 5-HT(1A) partial agonists add to efforts to shape pharmacologic perspectives concerning cognitive enhancement in schizophrenia by developing novel compounds acting on 5-HT receptors. Overall, these lines of evidence from translational research will facilitate the development of newer pharmacologic strategies

  3. Decreased serotonin2C receptor responses in male patients with schizophrenia.

    Science.gov (United States)

    Lee, Myung Ae; Jayathilake, Karuna; Sim, Min Young; Meltzer, Herbert Y

    2015-03-30

    Serotonin (5-HT)2C receptors in brain affect psychosis, reward, substance abuse, anxiety, other behaviors, appetite, body temperature, and other physiological measures. They also have been implicated in antipsychotic drug efficacy and side effects. We previously reported that the hyperthermia following administration of MK-212, a predominantly 5-HT(2C) receptor agonist, was diminished in a small sample of patients with schizophrenia (SCH), suggesting decreased 5-HT(2C) receptor responsiveness. We have now studied the responses to oral MK-212 and placebo in a larger sample of unmedicated male SCH (n = 69) and normal controls (CON) (n = 33), and assessed the influence of comorbid substance abuse (SA) on oral body temperature, behavioral responses, etc. The placebo-adjusted oral body temperature response to MK-212 was significantly lower in SCH compared to CON and not significantly different between the SCH with or without SA. Some behavioral responses to MK-212, e.g. self-rated feelings of increased anxiety, depression and decreased calmness, or good overall feeling, were significantly lower in the SCH patients compared to CON. These results add to the evidence for diminished 5-HT(2C) receptor responsiveness in SCH patients compared to CON and are consistent with reported association of HTR(2C) polymorphisms, leading to decreased expression or function of the HTR(2C) in patients with SCH.

  4. Design and Discovery of Functionally Selective Serotonin 2C (5-HT2C) Receptor Agonists.

    Science.gov (United States)

    Cheng, Jianjun; McCorvy, John D; Giguere, Patrick M; Zhu, Hu; Kenakin, Terry; Roth, Bryan L; Kozikowski, Alan P

    2016-11-10

    On the basis of the structural similarity of our previous 5-HT2C agonists with the melatonin receptor agonist tasimelteon and the putative biological cross-talk between serotonergic and melatonergic systems, a series of new (2,3-dihydro)benzofuran-based compounds were designed and synthesized. The compounds were evaluated for their selectivity toward 5-HT2A, 5-HT2B, and 5-HT2C receptors in the calcium flux assay with the ultimate goal to generate selective 5-HT2C agonists. Selected compounds were studied for their functional selectivity by comparing their transduction efficiency at the G protein signaling pathway versus β-arrestin recruitment. The most functionally selective compound (+)-7e produced weak β-arrestin recruitment and also demonstrated less receptor desensitization compared to serotonin in both calcium flux and phosphoinositide (PI) hydrolysis assays. We report for the first time that selective 5-HT2C agonists possessing weak β-arrestin recruitment can produce distinct receptor desensitization properties.

  5. Structure-based discovery of selective serotonin 5-HT(1B) receptor ligands.

    Science.gov (United States)

    Rodríguez, David; Brea, José; Loza, María Isabel; Carlsson, Jens

    2014-08-05

    The development of safe and effective drugs relies on the discovery of selective ligands. Serotonin (5-hydroxytryptamine [5-HT]) G protein-coupled receptors are therapeutic targets for CNS disorders but are also associated with adverse drug effects. The determination of crystal structures for the 5-HT1B and 5-HT2B receptors provided an opportunity to identify subtype selective ligands using structure-based methods. From docking screens of 1.3 million compounds, 22 molecules were predicted to be selective for the 5-HT1B receptor over the 5-HT2B subtype, a requirement for safe serotonergic drugs. Nine compounds were experimentally verified as 5-HT1B-selective ligands, with up to 300-fold higher affinities for this subtype. Three of the ligands were agonists of the G protein pathway. Analysis of state-of-the-art homology models of the two 5-HT receptors revealed that the crystal structures were critical for predicting selective ligands. Our results demonstrate that structure-based screening can guide the discovery of ligands with specific selectivity profiles.

  6. Caracterização fisiológica de receptores serotoninérgicos no caranguejo Neohelice granulata

    OpenAIRE

    Elen Thegla Sander Inohara

    2013-01-01

    A serotonina está presente no Sistema Nervoso Central (SNC), gânglios perifé-ricos, e órgãos neuroendócrinos de crustáceos, participando de muitos processos fisi-ológicos. Receptores serotoninérgicos com perfil farmacológico similar ao dos recep-tores 5-HT1 e 5-HT2 de vertebrados já foram identificados em crustáceos, assim como os efeitos de vários agonistas e antagonistas destes receptores. O objetivo geral deste trabalho foi investigar a localização dos receptores serotoninérgicos nos tecid...

  7. Tryptophan hydroxylase and serotonin receptor 1A expression in the retina of the sea lamprey.

    Science.gov (United States)

    Cornide-Petronio, María Eugenia; Anadón, Ramón; Barreiro-Iglesias, Antón; Rodicio, María Celina

    2015-06-01

    The dual development of the retina of lampreys is exceptional among vertebrates and offers an interesting EvoDevo (evolutionary developmental biology) model for understanding the origin and evolution of the vertebrate retina. Only a single type of photoreceptor, ganglion cell and bipolar cell are present in the early-differentiated central retina of lamprey prolarvae. A lateral retina appears later in medium-sized larvae (about 3 years after hatching in the sea lamprey), growing and remaining largely neuroblastic until metamorphosis. In this lateral retina, only ganglion cells and optic fibers differentiate in larvae, whereas differentiation of amacrine, horizontal, photoreceptor and bipolar cells mainly takes place during metamorphosis, which gives rise to the adult retina. Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter found in the retina of vertebrates whose synthesis is mediated by the rate-limiting enzyme tryptophan hydroxylase (TPH). TPH is also the first enzyme in the biosynthetic pathways of melatonin in photoreceptor cells. The serotonin 1A receptor (5-HT1A) is a major determinant of the activity of both serotonergic cells and their targets due to its pre- and post-synaptic location. Here, we report the developmental pattern of expression of tph and 5-ht1a transcripts in the sea lamprey retina by means of in situ hybridization. In larvae, strong tph mRNA signal was observed in photoreceptors and putative ganglion cells of the central retina, and in some neuroblasts of the lateral retina. In adults, strong tph expression was observed in bipolar, amacrine and ganglion cells and in photoreceptors. In the prolarval (central) retina, all the differentiated retinal cells expressed 5-ht1a transcripts, which were not observed in undifferentiated cells. In larvae, photoreceptors, bipolar cells and ganglion cells in the central retina, and neuroblasts in the lateral retina, showed 5-ht1a expression. In the adult retina, expression of 5-ht1a transcript

  8. Novel aza-analogous ergoline derived scaffolds as potent serotonin 5-HT6 and dopamine D2 receptor ligands

    DEFF Research Database (Denmark)

    Krogsgaard-Larsen, Niels; Jensen, Anders A.; Schrøder, T.J.

    2014-01-01

    By introducing distal substituents on a tetracyclic scaffold resembling the ergoline structure, two series of analogues were achieved exhibiting subnanomolar receptor binding affinities for the dopamine D2 and serotonin 5-HT6 receptor subtype, respectively. While the 5-HT6 ligands were antagonists......, the D2 ligands displayed intrinsic activities ranging from full agonism to partial agonism with low intrinsic activity. These structures could potentially be interesting for treatment of neurological diseases such as schizophrenia, Parkinson’s disease, and cognitive deficits....

  9. Lorcaserin: a selective serotonin receptor (5-HT2C agonist for the treatment of obesity

    Directory of Open Access Journals (Sweden)

    Bhaven C. Kataria

    2012-02-01

    Full Text Available Lorcaserin is a selective serotonin receptor (5-HT2C agonist that recently received the U.S. Food and Drug Administration (FDA approval for chronic weight management. The efficacy of this drug in reducing body weight and improving metabolic parameters of obese patients has been demonstrated in three phase-3 clinical trials. The available evidence indicates that this drug does not show heart valve abnormalities, and the treatment improves the risk factors for type 2 diabetes and cardiovascular diseases. However, the drug's manufacturer will be required to conduct postmarketing studies, including a long-term cardiovascular outcomes trial to assess the effect of Lorcaserin on the risk for major adverse cardiac events such as heart attack and stroke. [Int J Basic Clin Pharmacol 2012; 1(1.000: 45-47

  10. [Antagonists of the type 3 serotonin receptor (5 -HT3) in IBS].

    Science.gov (United States)

    Komoto, Shunsuke; Miura, Soichiro

    2006-08-01

    Irritable bowel syndrome (IBS) is a common chronic gastrointestinal (GI) disorder, but its pathophysiology remains unknown. 5-hydroxytryptamine (5-HT, serotonin) is an important neurotransmitter involved in the brain-gut connection. Alosetron, a 5-HT3 receptor antagonist, has been demonstrated in randomized, placebo-controlled trials (RCT) to be effective in diarrhea-predominant IBS(IBS-D). Constipation is the most common adverse event. Alosetron improved abdominal pain and discomfort and stool consistency in both female and male patients, but it did not improve other symptoms (sense of urgency, stool frequency and bloating) in male patients. Although less is known about the gender differences in therapeutic benefit, a new 5-HT3 antagonist, cilansetron, has demonstrated effectiveness in male and female IBS-D patients and is currently under clinical trials.

  11. Contribution of non-genetic factors to dopamine and serotonin receptor availability in the adult human brain

    DEFF Research Database (Denmark)

    Borg, J; Cervenka, S; Kuja-Halkola, R

    2016-01-01

    The dopamine (DA) and serotonin (5-HT) neurotransmission systems are of fundamental importance for normal brain function and serve as targets for treatment of major neuropsychiatric disorders. Despite central interest for these neurotransmission systems in psychiatry research, little is known about...... and environmental factors, respectively, on dopaminergic and serotonergic markers in the living human brain. Eleven monozygotic and 10 dizygotic healthy male twin pairs were examined with PET and [(11)C]raclopride binding to the D2- and D3-dopamine receptor and [(11)C]WAY100635 binding to the serotonin 5-HT1A...

  12. Structure-activity relationships for hallucinogenic N,N-dialkyltryptamines: photoelectron spectra and serotonin receptor affinities of methylthio and methylenedioxy derivatives

    Energy Technology Data Exchange (ETDEWEB)

    Kline, T.B.; Benington, F.; Morin, R.D.; Beaton, J.M.; Glennon, R.A.; Domelsmith, L.N.; Houk, K.N.; Rozeboom, M.D.

    1982-11-01

    Serotonin receptor affinity and photelectron spectral data were obtained on a number of substituted N,N-dimethyltryptamines. Evidence is presented that electron-donating substituents in the 5-position lead to enhanced behavioral disruption activity and serotonin receptor affinity as compared to unsubstituted N,N-dimethyltryptamine and analogues substituted in the 4- or 6-position. Some correlation was found between ionization potentials and behavioral activity, which may have implications concerning the mechanism of receptor binding.

  13. Serotonin receptor antagonists discriminate between PKA- and PKC-mediated plasticity in aplysia sensory neurons.

    Science.gov (United States)

    Dumitriu, Bogdan; Cohen, Jonathan E; Wan, Qin; Negroiu, Andreea M; Abrams, Thomas W

    2006-04-01

    Highly selective serotonin (5-hydroxytryptamine, 5-HT) receptor antagonists developed for mammals are ineffective in Aplysia due to the evolutionary divergence of neurotransmitter receptors and because the higher ionic strength of physiological saline for marine invertebrates reduces antagonist affinity. It has therefore been difficult to identify antagonists that specifically block individual signaling cascades initiated by 5-HT. We studied two broad-spectrum 5-HT receptor antagonists that have been characterized biochemically in Aplysia CNS: methiothepin and spiperone. Methiothepin is highly effective in inhibiting adenylyl cyclase (AC)-coupled 5-HT receptors in Aplysia. Spiperone, which blocks phospholipase C (PLC)-coupled 5-HT receptors in mammals, does not block AC-coupled 5-HT receptors in Aplysia. In electrophysiological studies, we explored whether methiothepin and spiperone can be used in parallel to distinguish between the AC-cAMP and PLC-protein kinase C (PKC) modulatory cascades that are initiated by 5-HT. 5-HT-induced broadening of the sensory neuron action potential in the presence of tetraethylammonium/nifedipine, which is mediated by modulation of the S-K+ currents, was used an assay for the AC-cAMP cascade. Spike broadening initiated by 5 microM 5-HT was unaffected by 100 microM spiperone, whereas it was effectively blocked by 100 microM methiothepin. Facilitation of highly depressed sensory neuron-to-motor neuron synapses by 5-HT was used as an assay for the PLC-PKC cascade. Spiperone completely blocked facilitation of highly depressed synapses by 5 microM 5-HT. In contrast, methiothepin produced a modest, nonsignificant, reduction in the facilitation of depressed synapses. Interestingly, these experiments revealed that the PLC-PKC cascade undergoes desensitization during exposure to 5-HT.

  14. Mast cell expression of the serotonin1A receptor in guinea pig and human intestine.

    Science.gov (United States)

    Wang, Guo-Du; Wang, Xi-Yu; Zou, Fei; Qu, Meihua; Liu, Sumei; Fei, Guijun; Xia, Yun; Needleman, Bradley J; Mikami, Dean J; Wood, Jackie D

    2013-05-15

    Serotonin [5-hydroxytryptamine (5-HT)] is released from enterochromaffin cells in the mucosa of the small intestine. We tested a hypothesis that elevation of 5-HT in the environment of enteric mast cells might degranulate the mast cells and release mediators that become paracrine signals to the enteric nervous system, spinal afferents, and secretory glands. Western blotting, immunofluorescence, ELISA, and pharmacological analysis were used to study expression of 5-HT receptors by mast cells in the small intestine and action of 5-HT to degranulate the mast cells and release histamine in guinea pig small intestine and segments of human jejunum discarded during Roux-en-Y gastric bypass surgeries. Mast cells in human and guinea pig preparations expressed the 5-HT1A receptor. ELISA detected spontaneous release of histamine in guinea pig and human preparations. The selective 5-HT1A receptor agonist 8-hydroxy-PIPAT evoked release of histamine. A selective 5-HT1A receptor antagonist, WAY-100135, suppressed stimulation of histamine release by 5-HT or 8-hydroxy-PIPAT. Mast cell-stabilizing drugs, doxantrazole and cromolyn sodium, suppressed the release of histamine evoked by 5-HT or 8-hydroxy-PIPAT in guinea pig and human preparations. Our results support the hypothesis that serotonergic degranulation of enteric mast cells and release of preformed mediators, including histamine, are mediated by the 5-HT1A serotonergic receptor. Association of 5-HT with the pathophysiology of functional gastrointestinal disorders (e.g., irritable bowel syndrome) underlies a question of whether selective 5-HT1A receptor antagonists might have therapeutic application in disorders of this nature.

  15. Aging-induced changes in brain regional serotonin receptor binding: Effect of Carnosine.

    Science.gov (United States)

    Banerjee, S; Poddar, M K

    2016-04-05

    Monoamine neurotransmitter, serotonin (5-HT) has its own specific receptors in both pre- and post-synapse. In the present study the role of carnosine on aging-induced changes of [(3)H]-5-HT receptor binding in different brain regions in a rat model was studied. The results showed that during aging (18 and 24 months) the [(3)H]-5-HT receptor binding was reduced in hippocampus, hypothalamus and pons-medulla with a decrease in their both Bmax and KD but in cerebral cortex the [(3)H]-5-HT binding was increased with the increase of its only Bmax. The aging-induced changes in [(3)H]-5-HT receptor binding with carnosine (2.0 μg/kg/day, intrathecally, for 21 consecutive days) attenuated in (a) 24-month-aged rats irrespective of the brain regions with the attenuation of its Bmax except hypothalamus where both Bmax and KD were significantly attenuated, (b) hippocampus and hypothalamus of 18-month-aged rats with the attenuation of its Bmax, and restored toward the [(3)H]-5-HT receptor binding that observed in 4-month-young rats. The decrease in pons-medullary [(3)H]-5-HT binding including its Bmax of 18-month-aged rats was promoted with carnosine without any significant change in its cerebral cortex. The [(3)H]-5-HT receptor binding with the same dosages of carnosine in 4-month-young rats (a) increased in the cerebral cortex and hippocampus with the increase in their only Bmax whereas (b) decreased in hypothalamus and pons-medulla with a decrease in their both Bmax and KD. These results suggest that carnosine treatment may (a) play a preventive role in aging-induced brain region-specific changes in serotonergic activity (b) not be worthy in 4-month-young rats in relation to the brain regional serotonergic activity.

  16. Serotonin and dopamine receptors in cognitive and motivational disturbances of psychiatric disorders

    Directory of Open Access Journals (Sweden)

    Tomiki eSumiyoshi

    2014-12-01

    Full Text Available Negative symptoms (e.g. decreased spontaneity, social withdrawal, blunt affect and disturbances of cognitive function (e.g. several types of memory, attention, processing speed, executive function, fluency provide a major determinant of long-term outcome in patients with schizophrenia. Specifically, motivation deficits, a type of negative symptoms, have been attracting interest as a moderator of cognitive performance in schizophrenia and related disorders, and also a modulating factor of cognitive enhancers/remediation. These considerations suggest the need to clarify neurobiological substrates regulating motivation. Genetic studies indicate a role for the monoamine systems in motivation and key cognitive domains. For example, polymorphism of genes encoding catecholamine-O-methyltransferase, an enzyme catabolizing dopamine (DA, affects performance on tests of working memory and executive function in a phenotype (schizophrenia vs. healthy controls-dependent fashion. On the other hand, motivation to maximize rewards has been shown to be influenced by other DA-related genes, such as DARPP-32 and DA-D2 receptors. Serotonin (5-HT receptors may also play a key role in cognitive and motivational disabilities in psychoses and mood disorders. For example, mutant mice over-expressing D2 receptors in the striatum, an animal model of schizophrenia, exhibit both decreased willingness to work for reward and up-regulation of 5-HT2C receptors. Taken together, genetic predisposition related to 5-HT receptors may mediate the diversity of incentive motivation that is impaired in patients receiving biological and/or psychosocial treatments. Taken together, research into genetic and neurobiological measures of motivation, in association with 5-HT receptors, is likely to facilitate intervention into patients seeking better social consequences.

  17. Serotonin 1A receptor binding and treatment response in late-life depression.

    Science.gov (United States)

    Meltzer, Carolyn Cidis; Price, Julie C; Mathis, Chester A; Butters, Meryl A; Ziolko, Scott K; Moses-Kolko, Eydie; Mazumdar, Sati; Mulsant, Benoit H; Houck, Patricia R; Lopresti, Brian J; Weissfeld, Lisa A; Reynolds, Charles F

    2004-12-01

    Depression in late life carries an increased risk of dementia and brittle response to treatment. There is growing evidence to support a key role of the serotonin type 1A (5-HT(1A)) receptor as a regulator of treatment response, particularly the 5-HT(1A) autoreceptor in the dorsal raphe nucleus (DRN). We used [11C]WAY 100635 and positron emission tomography (PET) to test our hypothesis that 5-HT(1A) receptor binding in the DRN and prefrontal cortex is altered in elderly depressives and that these measures relate to treatment responsivity. We studied 17 elderly subjects with untreated (nonpsychotic, nonbipolar) major depression (four men, 13 women; mean age: 71.4+/-5.9) and 17 healthy control subjects (eight men, nine women; mean age: 70.0+/-6.7). Patients were subsequently treated with paroxetine as part of a clinical trial of maintenance therapies in geriatric depression. [11C]WAY 100635 PET imaging was acquired and binding potential (BP) values derived using compartmental modeling. We observed significantly diminished [11C]WAY 100635 binding in the DRN in depressed (BP = 2.31+/-0.90) relative to control (BP = 3.69+/-1.56) subjects (p = 0.0016). Further, the DRN BP was correlated with pretreatment Hamilton Depression Rating Scores (r = 0.60, p = 0.014) in the depressed cohort. A trend level correlation between DRN binding and time to remission (r = 0.52, p = 0.067) was observed in the 14 depressed patients for whom these data were available. Our finding of decreased [11C]WAY 100635 binding in the brainstem region of the DRN in elderly depressed patients supports evidence of altered 5-HT(1A) autoreceptor function in depression. Further, this work indicates that dysfunction in autoreceptor activity may play a central role in the mechanisms underlying treatment response to selective serotonin reuptake inhibitors in late-life depression.

  18. The serotonin receptor 7 and the structural plasticity of brain circuits

    Directory of Open Access Journals (Sweden)

    Floriana eVolpicelli

    2014-09-01

    Full Text Available Serotonin (5-hydroxytryptamine, 5-HT modulates numerous physiological processes in the nervous system. Together with its function as neurotrasmitter, 5-HT regulates neurite outgrowth, dendritic spine shape and density, growth cone motility and synapse formation during development. In the mammalian brain 5-HT innervation is virtually ubiquitous and the diversity and specificity of its signaling and function arise from at least 20 different receptors, grouped in 7 classes. Here we will focus on the role 5-HT7 receptor (5-HT7R in the correct establishment of neuronal cytoarchitecture during development, as also suggested by its involvement in several neurodevelopmental disorders. The emerging picture shows that this receptor is a key player contributing not only to shape brain networks during development but also to remodel neuronal wiring in the mature brain, thus controlling cognitive and emotional responses. The activation of 5-HT7R might be one of the mechanisms underlying the ability of the CNS to respond to different stimuli by modulation of its circuit configuration.

  19. Adenosine, dopamine and serotonin receptors imbalance in lymphocytes of Lesch-Nyhan patients.

    Science.gov (United States)

    García, Marta G; Puig, Juan G; Torres, Rosa J

    2012-11-01

    Lesch-Nyhan disease (LND) is caused by complete deficiency of the hypoxanthine-guanine phosphoribosyltransferase enzyme. It is characterized by overproduction of uric acid, jointly with severe motor disability and self-injurious behaviour which physiopathology is unknown. These neurological manifestations suggest a dysfunction in the basal ganglia, and three neurotransmitters have been implicated in the pathogenesis of the disease: dopamine, adenosine and serotonin. All of them are implicated in motor function and behaviour, and act by binding to specific G-protein coupled receptors in the synaptic membrane where they seem to be integrated through receptor-receptor interactions. In this work we have confirmed at protein level the previously reported increased expression of DRD5 and the variably aberrant expression of ADORA2A, in LND PBL respect to control PBL. We have also described, for the first time, a decreased expression and protein level of 5-HTR1A in LND PBL respect to control PBL. If these results were confirmed in the Lesch-Nyhan patients basal ganglia cells, this would support the hypothesis that pathogenesis of neurological manifestations of Lesch-Nyhan patients may be related to an imbalance of neurotransmitters, rather than to the isolated disturbance of one of the neurotransmitters, and this fact should be taken into account in the design of pharmacologic treatment for their motor and behavioural disturbances.

  20. Pharmacogenetics of parkinsonism, rigidity, rest tremor, and bradykinesia in African-Caribbean inpatients : Differences in association with dopamine and serotonin receptors

    NARCIS (Netherlands)

    Al Hadithy, Asmar F.; Wilffert, Bob; Stewart, Roy E.; Looman, Nicole M.; Bruggeman, Richard; Brouwers, Jacobus R.; Matroos, Glenn E.; van Os, Jim; Hoek, Hans W.; van Harten, Peter N.

    2008-01-01

    We studied the association between polymorphisms of genes coding for dopamine D-2 (DRD2), dopamine D-3 (DRD3), serotonin 2(a) (HTR2A), and serotonin 2(c) (HTR2C) receptors and Antipsychotic-Induced Parkinsonism (AIP), rigidity, bradykinesia, and rest-tremor in African-Caribbeans treated with antipsy

  1. Opposite control of mesocortical and mesoaccumbal dopamine pathways by serotonin2B receptor blockade: Involvement of medial prefrontal cortex serotonin1A receptors.

    Science.gov (United States)

    Devroye, Céline; Haddjeri, Nasser; Cathala, Adeline; Rovera, Renaud; Drago, Filippo; Piazza, Pier Vincenzo; Artigas, Francesc; Spampinato, Umberto

    2017-06-01

    Recent studies have shown that serotonin2B receptor (5-HT2BR) antagonists exert opposite facilitatory and inhibitory effects on dopamine (DA) release in the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAc), respectively, thereby leading to the proposal that these compounds could provide an interesting pharmacological tool for treating schizophrenia. Although the mechanisms underlying these effects remain unknown, several data in the literature suggest that 5-HT1ARs located into the mPFC could participate in this interaction. The present study, using in vivo microdialysis and electrophysiological recordings in rats, assessed this hypothesis by means of two selective 5-HT1AR (WAY 100635) and 5-HT2BR (RS 127445) antagonists. WAY 100635, administered either subcutaneously (0.16 mg/kg, s.c) or locally into the mPFC (0.1 μM), blocked the changes of mPFC and NAc DA release induced by the intraperitoneal administration of RS 127445 (0.16 mg/kg, i.p.). The administration of RS 127445 (0.16 mg/kg, i.p.) increased both dorsal raphe nucleus (DRN) 5-HT neuron firing rate and 5-HT outflow in the mPFC. Likewise, mPFC 5-HT outflow was increased following the intra-DRN injection of RS 127445 (0.032 μg/0.2 μl). Finally, intra-DRN injection of RS 127445 increased and decreased DA outflow in the mPFC and the NAc, respectively, these effects being reversed by the intra-mPFC perfusion of WAY 100635. These results demonstrate the existence of a functional interplay between mPFC 5-HT1ARs and DRN 5-HT2BRs in the control of the DA mesocorticolimbic system, and highlight the clinical interest of this interaction, as both receptors represent an important pharmacological target for the treatment of schizophrenia. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. The antidepressant 5-HT2A receptor antagonists pizotifen and cyproheptadine inhibit serotonin-enhanced platelet function.

    Directory of Open Access Journals (Sweden)

    Olivia A Lin

    Full Text Available There is considerable interest in defining new agents or targets for antithrombotic purposes. The 5-HT2A receptor is a G-protein coupled receptor (GPCR expressed on many cell types, and a known therapeutic target for many disease states. This serotonin receptor is also known to regulate platelet function. Thus, in our FDA-approved drug repurposing efforts, we investigated the antiplatelet activity of cyproheptadine and pizotifen, two antidepressant 5-HT2A Receptor antagonists. Our results revealed that cyproheptadine and pizotifen reversed serotonin-enhanced ADP-induced platelet aggregation in vitro and ex vivo. And the inhibitory effects of these two agents were found to be similar to that of EMD 281014, a 5-HT2A Receptor antagonist under development. In separate experiments, our studies revealed that these 5-HT2A receptor antagonists have the capacity to reduce serotonin-enhanced ADP-induced elevation in intracellular calcium levels and tyrosine phosphorylation. Using flow cytometry, we also observed that cyproheptadine, pizotifen, and EMD 281014 inhibited serotonin-enhanced ADP-induced phosphatidylserine (PS exposure, P-selectin expression, and glycoprotein IIb-IIIa activation. Furthermore, using a carotid artery thrombosis model, these agents prolonged the time for thrombotic occlusion in mice in vivo. Finally, the tail-bleeding time was investigated to assess the effect of cyproheptadine and pizotifen on hemostasis. Our findings indicated prolonged bleeding time in both cyproheptadine- and pizotifen-treated mice. Notably, the increases in occlusion and bleeding times associated with these two agents were comparable to that of EMD 281014, and to clopidogrel, a commonly used antiplatelet drug, again, in a fashion comparable to clopidogrel and EMD 281014. Collectively, our data indicate that the antidepressant 5-HT2A antagonists, cyproheptadine and pizotifen do exert antiplatelet and thromboprotective effects, but similar to clopidogrel and

  3. Enhanced central serotonin release from slices of rat hypothalamus following repeated nialamide administration: evidence supporting the overactive serotonin receptor theory of depression

    Energy Technology Data Exchange (ETDEWEB)

    Offord, S.J.

    1986-01-01

    Researchers are suggesting unipolar affective disorders may be related to an abnormality in biogenic amine receptor-sensitivity. This abnormality may be a result of a dysfunction in central serotonin (5-HT) release mechanisms. 5-HT neurotransmission is modulated by presynaptic autoreceptors, which are members of the 5-HT/sub 1/ receptor subtype. The autoreceptor is thought to play an important role in the homeostasis of the central 5-HT synapse and could be a site at which some antidepressants mediate their therapeutic effect. The number of 5-HT/sub 1/ type receptor binding sites are reduced and behavior mediated by this receptor is abolished following repeated injections of monoamine oxidase inhibitor type antidepressants. These changes did not occur following a single injection. It was hypothesized that repeated treatment with a monoamine oxidase inhibitor would reduce the sensitivity of 5-HT autoreceptors and enhance 5-HT release. Rats were pretreated with single or repeated (twice daily for 7 days) intraperitoneal injections of nialamide (40 mg/kg) or chlorimipramine (10 mg/kg) and the ability of the autoreceptor agonist to inhibit potassium-induced /sup 3/H-5-HT release was evaluated using an in vitro superfusion system. These changes in 5-HT autoreceptor activity are consistent with other reports evaluating monoamine oxidase inhibitors on 5-HT/sub 1/ type receptors. It is hypothesized that the changes in 5-HT neurotransmission are related to the antidepressant mechanism of monoamine oxidase inhibitors.

  4. Intestinal Serotonin Transporter Inhibition by Toll-Like Receptor 2 Activation. A Feedback Modulation

    Science.gov (United States)

    Layunta, Elena; Grasa, Laura; Castro, Marta; Pardo, Julián; Gomollón, Fernando; Mesonero, José E.

    2016-01-01

    TLR2 is a microbiota recognition receptor that has been described to contribute to intestinal homeostasis and to ameliorate inflammatory intestinal injury. In this context, serotonin (5-HT) has shown to be an essential intestinal physiological neuromodulator that is also involved in intestinal inflammatory diseases. Since the interaction between TLR2 activation and the intestinal serotoninergic system remains non-investigated, our main aim was to analyze the effect of TLR2 on intestinal serotonin transporter (SERT) activity and expression and the intracellular pathways involved. Caco-2/TC7 cells were used to analyze SERT and TLR2 molecular expression and SERT activity by measuring 5-HT uptake. The results showed that apical TLR2 activation inhibits SERT activity in Caco-2/TC7 cells mainly by reducing SERT protein level either in the plasma membrane, after short-term TLR2 activation or in both the plasma membrane and cell lysate, after long-term activation. cAMP/PKA pathway appears to mediate short-term inhibitory effect of TLR2 on SERT; however, p38 MAPK pathway has been shown to be involved in both short- and long-term TLR2 effect. Reciprocally, 5-HT long-term treatment yielded TLR2 down regulation in Caco-2/TC7 cells. Finally, results from in vivo showed an augmented intestinal SERT expression in mice Tlr2-/-, thus confirming our inhibitory effect of TLR2 on intestinal SERT in vitro. The present work infers that TLR2 may act in intestinal pathophysiology, not only by its inherent innate immune role, but also by regulating the intestinal serotoninergic system. PMID:28033388

  5. Serotonin-1A receptor polymorphism (rs6295 associated with thermal pain perception.

    Directory of Open Access Journals (Sweden)

    Fredrik Lindstedt

    Full Text Available BACKGROUND: Serotonin (5-HT is highly involved in pain regulation and serotonin-1A (5-HT1A receptors are important in determining central 5-HT tone. Accordingly, variation in the 5-HT1A receptor gene (HTR1A may contribute to inter-individual differences in human pain sensitivity. The minor G-allele of the HTR1A single nucleotide polymorphism (SNP rs6295 attenuates firing of serotonergic neurons and reduces postsynaptic expression of the receptor. Experiments in rodents suggest that 5-HT1A-agonism modulates pain in opposite directions at mild compared to high noxious intensities. Based upon this and several other similar observations, we hypothesized that G-carriers would exhibit a relative hypoalgesia at mild thermal stimuli but tend towards hyperalgesia at higher noxious intensities. METHODS: Fourty-nine healthy individuals were selectively genotyped for rs6295. Heat- and cold-pain thresholds were assessed along with VAS-ratings of a range of suprathreshold noxious heat intensities (45°C-49°C. Nociceptive-flexion reflex (NFR thresholds were also assessed. RESULTS: Volunteers did not deviate significantly from Hardy-Weinberg equilibrium. G-carriers were less sensitive to threshold-level thermal pain. This relative hypoalgesia was abolished at suprathreshold noxious intensities where G-carriers instead increased their ratings of heat-pain significantly more than C-homozygotes. No differences with regard to NFR-thresholds emerged. CONCLUSION/SIGNIFICANCE: To the best of our knowledge this is the first study of human pain perception on the basis of variation in HTR1A. The results illustrate the importance of including a range of stimulus intensities in assessments of pain sensitivity. In speculation, we propose that an attenuated serotonergic tone may be related to a 'hypo- to hyperalgesic' response-pattern. The involved mechanisms could be of clinical interest as variation in pain regulation is known to influence the risk of developing pain

  6. Effects of serotonin 2A/1A receptor stimulation on social exclusion processing.

    Science.gov (United States)

    Preller, Katrin H; Pokorny, Thomas; Hock, Andreas; Kraehenmann, Rainer; Stämpfli, Philipp; Seifritz, Erich; Scheidegger, Milan; Vollenweider, Franz X

    2016-05-03

    Social ties are crucial for physical and mental health. However, psychiatric patients frequently encounter social rejection. Moreover, an increased reactivity to social exclusion influences the development, progression, and treatment of various psychiatric disorders. Nevertheless, the neuromodulatory substrates of rejection experiences are largely unknown. The preferential serotonin (5-HT) 2A/1A receptor agonist, psilocybin (Psi), reduces the processing of negative stimuli, but whether 5-HT2A/1A receptor stimulation modulates the processing of negative social interactions remains unclear. Therefore, this double-blind, randomized, counterbalanced, cross-over study assessed the neural response to social exclusion after the acute administration of Psi (0.215 mg/kg) or placebo (Pla) in 21 healthy volunteers by using functional magnetic resonance imaging (fMRI) and resting-state magnetic resonance spectroscopy (MRS). Participants reported a reduced feeling of social exclusion after Psi vs. Pla administration, and the neural response to social exclusion was decreased in the dorsal anterior cingulate cortex (dACC) and the middle frontal gyrus, key regions for social pain processing. The reduced neural response in the dACC was significantly correlated with Psi-induced changes in self-processing and decreased aspartate (Asp) content. In conclusion, 5-HT2A/1A receptor stimulation with psilocybin seems to reduce social pain processing in association with changes in self-experience. These findings may be relevant to the normalization of negative social interaction processing in psychiatric disorders characterized by increased rejection sensitivity. The current results also emphasize the importance of 5-HT2A/1A receptor subtypes and the Asp system in the control of social functioning, and as prospective targets in the treatment of sociocognitive impairments in psychiatric illnesses.

  7. Effects of serotonin 2A/1A receptor stimulation on social exclusion processing

    Science.gov (United States)

    Preller, Katrin H.; Pokorny, Thomas; Hock, Andreas; Kraehenmann, Rainer; Stämpfli, Philipp; Seifritz, Erich; Scheidegger, Milan; Vollenweider, Franz X.

    2016-01-01

    Social ties are crucial for physical and mental health. However, psychiatric patients frequently encounter social rejection. Moreover, an increased reactivity to social exclusion influences the development, progression, and treatment of various psychiatric disorders. Nevertheless, the neuromodulatory substrates of rejection experiences are largely unknown. The preferential serotonin (5-HT) 2A/1A receptor agonist, psilocybin (Psi), reduces the processing of negative stimuli, but whether 5-HT2A/1A receptor stimulation modulates the processing of negative social interactions remains unclear. Therefore, this double-blind, randomized, counterbalanced, cross-over study assessed the neural response to social exclusion after the acute administration of Psi (0.215 mg/kg) or placebo (Pla) in 21 healthy volunteers by using functional magnetic resonance imaging (fMRI) and resting-state magnetic resonance spectroscopy (MRS). Participants reported a reduced feeling of social exclusion after Psi vs. Pla administration, and the neural response to social exclusion was decreased in the dorsal anterior cingulate cortex (dACC) and the middle frontal gyrus, key regions for social pain processing. The reduced neural response in the dACC was significantly correlated with Psi-induced changes in self-processing and decreased aspartate (Asp) content. In conclusion, 5-HT2A/1A receptor stimulation with psilocybin seems to reduce social pain processing in association with changes in self-experience. These findings may be relevant to the normalization of negative social interaction processing in psychiatric disorders characterized by increased rejection sensitivity. The current results also emphasize the importance of 5-HT2A/1A receptor subtypes and the Asp system in the control of social functioning, and as prospective targets in the treatment of sociocognitive impairments in psychiatric illnesses. PMID:27091970

  8. Positive association of the serotonin 5-HT7 receptor gene with schizophrenia in a Japanese population.

    Science.gov (United States)

    Ikeda, Masashi; Iwata, Nakao; Kitajima, Tsuyoshi; Suzuki, Tatsuyo; Yamanouchi, Yoshio; Kinoshita, Yoko; Ozaki, Norio

    2006-04-01

    Several lines of evidence suggest that abnormalities in the serotonin system may be related to the pathophysiology of schizophrenia. The 5-HT7 receptor is considered to be a possible schizophrenia-susceptibility factor, based on findings from binding, animal, postmortem, and genomewide linkage studies. In this study, we conducted linkage disequilibrium (LD) mapping of the human 5-HT7 receptor gene (HTR7) and selected four 'haplotype-tagging (ht) SNPs'. Using these four htSNPs, we then conducted an LD case-control association analysis in 383 Japanese schizophrenia patients and 351 controls. Two htSNPs (SNP2 and SNP5) and haplotypes were found to be associated with schizophrenia. A promoter SNP (SNP2) was further assessed in a dual-luciferase reporter assay, but it was not found to have any functional relevance. Although we failed to find an actual susceptibility variant that could modify the function of HTR7, our results support the supposition that HTR7 is a susceptibility gene for schizophrenia in this ethnic group.

  9. Involvement of presynaptic H3 receptors in the inhibitory effect of histamine on serotonin release in the rat brain cortex.

    Science.gov (United States)

    Fink, K; Schlicker, E; Neise, A; Göthert, M

    1990-11-01

    Rat brain cortex slices or synaptosomes preincubated with 3H-serotonin were superfused with physiological salt solution (which, in the case of slices, contained citalopram, an inhibitor of serotonin uptake), and the effects of histamine and related drugs on the evoked tritium overflow were studied. The electrically (3 Hz) evoked tritium overflow from slices was inhibited by histamine and the H3 receptor agonists R-(-)-alpha-methylhistamine and N alpha-methylhistamine (pIC12.5 values: 6.41, 7.28 and 6.12, respectively), but not affected by the H1 receptor agonist 2-(2-thiazolyl)ethylamine and the H2 receptor agonist dimaprit (each at 10 mumol/l). The concentration-response curve for histamine was shifted to the right by the H3 receptor antagonists impromidine, burimamide and thioperamide (apparent pA2 values: 7.45, 5.97 and 7.88, respectively); the concentration-response curve of serotonin for its inhibitory effect on the electrically evoked overflow was not affected by the three drugs (apparent pA2 values: less than 5.5, less than 5.5 and less than 6.5). Given alone, impromidine, thioperamide and a low concentration of burimamide facilitated the electrically evoked overflow. In slices superfused with K(+)-rich, Ca2(+)-free solution containing tetrodotoxin throughout and in synaptosomes superfused with Ca2(+)-free solution, histamine inhibited the overflow evoked by introduction of Ca2+ (in synaptosomes, simultaneously with an increased amount of K+). In either tissue, the effect of histamine was counteracted by thioperamide. The results provide evidence that exogenous and probably also endogenous histamine inhibits serotonin release in the rat brain cortex via presynaptic histamine H3 receptors.

  10. Antagonism of serotonin receptor 1B decreases viability and promotes apoptosis in the COS canine osteosarcoma cell line.

    Science.gov (United States)

    Viall, A K; Goodall, C P; Stang, B; Marley, K; Chappell, P E; Bracha, S

    2016-06-01

    Serotonin receptor 1B (5HTR1B) traditionally exhibits anti-proliferative activity in osteoblasts. We examined the expression and function of 5HTR1B in the COS canine osteosarcoma cell line and normal canine osteoblasts. Equal levels of 5HTR1B gene and protein expression were found between normal and malignant osteoblasts. Treatment with serotonin enhanced viability of osteosarcoma cells but not normal osteoblasts. Challenge with the 5HTR1B agonist anpirtoline caused no change in cell viability. Rather incubation with the specific receptor antagonist SB224289 caused reduction in osteoblast viability, with this effect more substantial in osteosarcoma cells. Investigation of this inhibitory activity showed 5HTR1B antagonism induces apoptosis in malignant cells. Evaluation of phosphorylated levels of CREB and ERK, transcriptional regulators associated with serotonin receptor signalling in osteoblasts, revealed aberrant 5HTR1B signalling in COS. Our results confirm the presence of 5HTR1B in a canine osteosarcoma cell line and highlight this receptor as a possible novel therapeutic target.

  11. Internalization and recycling of 5-HT2A receptors activated by serotonin and protein kinase C-mediated mechanisms

    Science.gov (United States)

    Bhattacharyya, Samarjit; Puri, Sapna; Miledi, Ricardo; Panicker, Mitradas M.

    2002-01-01

    Serotonin (5-HT), a major neurotransmitter, has a large number of G protein-coupled receptors in mammals. On activation by exposure to their ligand, 5-HT2 receptor subtypes increase IP3 levels and undergo desensitization and internalization. To visualize the receptor in cells during these processes, we have constructed a 5-HT2A-enhanced GFP (SR2-GFP) fusion receptor. We show that this fusion receptor undergoes internalization on exposure to its natural ligand, 5-HT. Because 5-HT2A receptors activate the phospholipase C pathway, we studied the effect of protein kinase C (PKC) on the internalization process and found that activation of PKC by its specific activator phorbol 12-myristate 13-acetate, in the absence of 5-HT, leads to internalization of the receptor. Moreover, inhibition of PKC by its inhibitor sphingosine in the presence of 5-HT prevents the internalization process, suggesting that activation of PKC is sufficient and necessary for the internalization of 5-HT2A receptors. We also show that SR2-GFP recycles back to the plasma membrane after 5-HT-dependent internalization, suggesting a mechanism for resensitization. In addition, receptors that have been internalized on addition of phorbol 12-myristate 13-acetate in the absence of 5-HT also recycle to the surface, with a time course similar to that seen after activation of the receptors by 5-HT. Our study suggests that 5-HT2A receptors internalize and return to the surface after both serotonin- and PKC-mediated processes. This study reveals a role for PKC in receptor internalization and also shows that 5-HT2A receptors are recycled. PMID:12388782

  12. Caveolin-1 interacts with 5-HT2A serotonin receptors and profoundly modulates the signaling of selected Galphaq-coupled protein receptors.

    Science.gov (United States)

    Bhatnagar, Anushree; Sheffler, Douglas J; Kroeze, Wesley K; Compton-Toth, BethAnn; Roth, Bryan L

    2004-08-13

    5-Hydroxytryptamine 2A (5-HT(2A)) serotonin receptors are important for a variety of functions including vascular smooth muscle contraction, platelet aggregation, and the modulation of perception, cognition, and emotion. In a search for 5-HT(2A) receptor-interacting proteins, we discovered that caveolin-1 (Cav-1), a scaffolding protein enriched in caveolae, complexes with 5-HT(2A) receptors in a number of cell types including C6 glioma cells, transfected HEK-293 cells, and rat brain synaptic membrane preparations. To address the functional significance of this interaction, we performed RNA interference-mediated knockdown of Cav-1 in C6 glioma cells, a cell type that endogenously expresses both 5-HT(2A) receptors and Cav-1. We discovered that the in vitro knockdown of Cav-1 in C6 glioma cells nearly abolished 5-HT(2A) receptor-mediated signal transduction as measured by calcium flux assays. RNA interference-mediated knockdown of Cav-1 also greatly attenuated endogenous Galpha(q)-coupled P2Y purinergic receptor-mediated signaling without altering the signaling of PAR-1 thrombin receptors. Cav-1 appeared to modulate 5-HT(2A) signaling by facilitating the interaction of 5-HT(2A) receptors with Galpha(q). These studies provide compelling evidence for a prominent role of Cav-1 in regulating the functional activity of not only 5-HT(2A) serotonin receptors but also selected Galpha(q)-coupled receptors.

  13. [Serotonin syndrome].

    Science.gov (United States)

    Lheureux, P; Penaloza, A; De Cottenier, V; Ullmann, U; Gris, M

    2002-10-01

    The serotonin syndrome is a hyperserotoninergic state resulting from an excess of intrasynaptic 5-hydroxytryptamine, induced by multiple psychotropic agents, but also non psychiatric drugs. It is a potentially dangerous and sometimes lethal condition. The clinical manifestations usually include cognitive, neuromuscular and autonomic features and are mediated by the action of serotonin on various subtypes of receptors. The main differential diagnosis is the neuroleptic malignant syndrome. Treatment is mainly supportive. No pharmacological agent has been definitely demonstrated really effective. However, reports of cases treated with the 5-HT2 blockers, including cyproheptadine or chlorpromazine have suggested that these agents could have some efficacy. Serotonin syndrome is a toxic condition which requires heightened clinical awareness among physicians in order to prevent, recognize, and treat the condition promptly.

  14. Alterations in serotonin receptors and transporter immunoreactivities in the hippocampus in the rat unilateral hypoxic-induced epilepsy model.

    Science.gov (United States)

    An, Sung-Jin; Kim, Duk-Soo

    2011-11-01

    Unilateral hypoxic-ischemia results in the frequent occurrence of interictal spikes, and occasionally sustained ictal discharges accompanied by a reduction in paired-pulse inhibition within the non-lesioned dentate gyrus. To elucidate the roles of serotonin (5-hydroxytryptamine [5-HT]) in an epileptogenic insult, we investigated the changes in 5-HT receptors and serotonin transporter (5-HTT) immunoreactivities within the lesioned and contralateral hippocampus following unilateral hypoxic-ischemia. During epileptogenic periods following hypoxic-ischemia, both 5-HT(1A) and 5HT(1B) receptor immunoreactivities were decreased within the lesioned and the non-lesioned hippocampus. However, 5-HTT immunoreactivity was transiently increased within the hippocampus bilaterally. These findings indicate that alteration of the 5-HT system results in a "diaschisis" pattern, and may contribute to neuronal death and the development of emotional disorders in epileptic patients accompanied by psychological stress.

  15. Cross-regulation between colocalized nicotinic acetylcholine and 5-HT3 serotonin receptors on presynaptic nerve terminals

    Institute of Scientific and Technical Information of China (English)

    John J DOUGHERTY; Robert A NICHOLS

    2009-01-01

    Aim: Substantial colocalization of functionally independent a4 nicotinic acetylcholine receptors and 5-HT3 serotonin receptors on presynaptic terminals has been observed in brain. The present study was aimed at addressing whether nicotinic acetylcholine receptors and 5-HT3 serotonin receptors interact on the same presynaptic terminal, suggesting a convergence of cholinergic and serotonergic regulation.Methods: Ca2+ responses in individual, isolated nerve endings purified from rat striatum were measured using confocal imaging.Results: Application of 500 nmol/L nicotine following sustained stimulation with the highly selective 5-HT3 receptor agonist m-chlorophenylbiguanide at 100 nmol/L resulted in markedly reduced Ca2* responses (28% of control) in only those striatal nerve endings that originally responded to m-chlorophenylbiguanide. The cross-regulation developed over several minutes. Presynaptic nerve endings that had not responded to m-chlorophenylbiguanide, indicating that 5-HT3 receptors were not present, displayed typical responses to nicotine. Application of m-chlorophenylbiguanide following sustained stimulation with nicotine resulted in partially attenuated Ca2* responses (49% of control). Application of m-chlorophenylbiguanide following sustained stimulation with m-chlorophenylbiguanide also resulted in a strong attenuation of Ca2+ responses (12% of control), whereas nicotine-induced Ca2t responses following sustained stimulation with nicotine were not significantly different from control.Conclusion: These results indicate that the presynaptic Ca2+ increases evoked by either 5-HT, receptor or nicotinic acetylcholine receptor activation regulate subsequent responses to 5-HT3 receptor activation, but that only 5-HT3 receptors cross-regulate subsequent nicotinic acetylcholine receptor-mediated responses. The findings suggest a specific interaction between the two receptor systems in the same striatal nerve terminal, likely involving Ca2+-dependent

  16. Serotonin receptor 3A polymorphism c.-42C > T is associated with severe dyspepsia

    Directory of Open Access Journals (Sweden)

    Grobbee Diederick E

    2011-10-01

    Full Text Available Abstract Background The association between anxiety and depression related traits and dyspepsia may reflect a common genetic predisposition. Furthermore, genetic factors may contribute to the risk of having increased visceral sensitivity, which has been implicated in dyspeptic symptom generation. Serotonin (5-HT modulates visceral sensitivity by its action on 5-HT3 receptors. Interestingly, a functional polymorphism in HTR3A, encoding the 5-HT3 receptor A subunit, has been reported to be associated with depression and anxiety related traits. A functional polymorphism in the serotonin transporter (5-HTT, which terminates serotonergic signalling, was also found associated with these psychiatric comorbidities and increased visceral sensitivity in irritable bowel syndrome, which coexistence is associated with higher dyspeptic symptom severity. We investigated the association between these functional polymorphisms and dyspeptic symptom severity. Methods Data from 592 unrelated, Caucasian, primary care patients with dyspepsia participating in a randomised clinical trial comparing step-up and step-down antacid drug treatment (The DIAMOND trial were analysed. Patients were genotyped for HTR3A c.-42C > T SNP and the 44 bp insertion/deletion polymorphism in the 5-HTT promoter (5-HTTLPR. Intensity of 8 dyspeptic symptoms at baseline was assessed using a validated questionnaire (0 = none; 6 = very severe. Sum score ≥20 was defined severe dyspepsia. Results HTR3A c.-42T allele carriers were more prevalent in patients with severe dyspepsia (OR 1.50, 95% CI 1.06-2.20. This association appeared to be stronger in females (OR 2.05, 95% CI 1.25-3.39 and patients homozygous for the long (L variant of the 5-HTTLPR genotype (OR 2.00, 95% CI 1.01-3.94. Females with 5-HTTLPR LL genotype showed the strongest association (OR = 3.50, 95% CI = 1.37-8.90. Conclusions The HTR3A c.-42T allele is associated with severe dyspeptic symptoms. The stronger association among

  17. Alpha-smooth muscle actin and serotonin receptors 2A and 2B in dogs with myxomatous mitral valve disease

    DEFF Research Database (Denmark)

    Cremer, Signe Emilie; Moesgaard, S. G.; Rasmussen, C. E.

    2015-01-01

    Canine Myxomatous mitral valve disease (MMVD) is an age-related disease. Serotonin (5-HT) is implicated in the pathogenesis as locally-produced or platelet-derived. Involvement of the 5-HT2A receptor (R) and 5-HT2BR in the induction of myxomatous-mediating valvular myofibroblasts (MF) has been su...... a functional relationship, perhaps perpetuation of clinical MMVD. 5-HT2AR-expression and serum 5-HT showed no differences between groups....

  18. Serotonin receptors expressed in Drosophila mushroom bodies differentially modulate larval locomotion.

    Directory of Open Access Journals (Sweden)

    Bryon Silva

    Full Text Available Drosophila melanogaster has been successfully used as a simple model to study the cellular and molecular mechanisms underlying behaviors, including the generation of motor programs. Thus, it has been shown that, as in vertebrates, CNS biogenic amines (BA including serotonin (5HT participate in motor control in Drosophila. Several evidence show that BA systems innervate an important association area in the insect brain previously associated to the planning and/or execution of motor programs, the Mushroom Bodies (MB. The main objective of this work is to evaluate the contribution of 5HT and its receptors expressed in MB to motor behavior in fly larva. Locomotion was evaluated using an automated tracking system, in Drosophila larvae (3(rd-instar exposed to drugs that affect the serotonergic neuronal transmission: alpha-methyl-L-dopa, MDMA and fluoxetine. In addition, animals expressing mutations in the 5HT biosynthetic enzymes or in any of the previously identified receptors for this amine (5HT1AR, 5HT1BR, 5HT2R and 5HT7R were evaluated in their locomotion. Finally, RNAi directed to the Drosophila 5HT receptor transcripts were expressed in MB and the effect of this manipulation on motor behavior was assessed. Data obtained in the mutants and in animals exposed to the serotonergic drugs, suggest that 5HT systems are important regulators of motor programs in fly larvae. Studies carried out in animals pan-neuronally expressing the RNAi for each of the serotonergic receptors, support this idea and further suggest that CNS 5HT pathways play a role in motor control. Moreover, animals expressing an RNAi for 5HT1BR, 5HT2R and 5HT7R in MB show increased motor behavior, while no effect is observed when the RNAi for 5HT1AR is expressed in this region. Thus, our data suggest that CNS 5HT systems are involved in motor control, and that 5HT receptors expressed in MB differentially modulate motor programs in fly larvae.

  19. Targeting the Serotonin 5-HT7 Receptor in the Search for Treatments for CNS Disorders: Rationale and Progress to Date.

    Science.gov (United States)

    Nikiforuk, Agnieszka

    2015-04-01

    The 5-HT7 (5-hydroxytryptamine 7, serotonin 7) receptor is one of the most recently identified members of the serotonin receptor family. Pharmacological tools, including selective antagonists and, more recently, agonists, along with 5-HT7 receptor (5-HT7R) knock-out mice have revealed the involvement of this receptor in central nervous system processes. Its well-established role in controlling body temperature and regulating sleep and circadian rhythms has implicated this receptor in mood disorders. Thus, the 5-HT7R has gained much attention as a possible target for the treatment of depression. Although preclinical data support the antidepressant-like actions of 5-HT7R antagonists, their clinical efficacy has not been yet established. Other evidence has implicated the 5-HT7R in learning and memory. Preclinical findings suggest that blockade of this receptor may be beneficial against schizophrenia-like cognitive deficits. Other possible indications include nociception, epilepsy, migraine, autism spectrum disorders, and Rett Syndrome. However, the question is whether the beneficial effects may be achieved by activation or blockade of 5-HT7Rs. Hence, this review briefly summarises the recent findings on the role of 5-HT7Rs and their ligands in CNS disorders.

  20. Mifepristone modulates serotonin transporter function

    Institute of Scientific and Technical Information of China (English)

    Chaokun Li; Linlin Shan; Xinjuan Li; Linyu Wei; Dongliang Li

    2014-01-01

    Regulating serotonin expression can be used to treat psychotic depression. Mifepristone, a glu-cocorticoid receptor antagonist, is an effective candidate for psychotic depression treatment. However, the underlying mechanism related to serotonin transporter expression is poorly un-derstood. In this study, we cloned the human brain serotonin transporter into Xenopus oocytes, to establish an in vitro expression system. Two-electrode voltage clamp recordings were used to detect serotonin transporter activity. Our results show that mifepristone attenuates serotonin transporter activity by directly inhibiting the serotonin transporter, and suggests that the se-rotonin transporter is a pharmacological target of mifepristone for the treatment of psychotic depression.

  1. Auraptenol attenuates vincristine-induced mechanical hyperalgesia through serotonin 5-HT1A receptors.

    Science.gov (United States)

    Wang, Yunfei; Cao, Shu-e; Tian, Jianmin; Liu, Guozhe; Zhang, Xiaoran; Li, Pingfa

    2013-11-29

    Common chemotherapeutic agents such as vincristine often cause neuropathic pain during cancer treatment in patients. Such neuropathic pain is refractory to common analgesics and represents a challenging clinical issue. Angelicae dahuricae radix is an old traditional Chinese medicine with demonstrated analgesic efficacy in humans. However, the active component(s) that attribute to the analgesic action have not been identified. This work described the anti-hyperalgesic effect of one coumarin component, auraptenol, in a mouse model of chemotherapeutic agent vincristine-induced neuropathic pain. We reported that auraptenol dose-dependently reverted the mechanical hyperalgesia in mice within the dose range of 0.05-0.8 mg/kg. In addition, the anti-hyperalgesic effect of auraptenol was significantly blocked by a selective serotonin 5-HT1A receptor antagonist WAY100635 (1 mg/kg). Within the dose range studied, auraptenol did not significantly alter the general locomotor activity in mice. Taken together, this study for the first time identified an active component from the herbal medicine angelicae dahuricae radix that possesses robust analgesic efficacy in mice. These data support further studies to assess the potential of auraptenol as a novel analgesic for the management of neuropathic pain.

  2. Genetic variation of the serotonin 2a receptor affects hippocampal novelty processing in humans.

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    Björn H Schott

    Full Text Available Serotonin (5-hydroxytryptamine, 5-HT is an important neuromodulator in learning and memory processes. A functional genetic polymorphism of the 5-HT 2a receptor (5-HTR2a His452Tyr, which leads to blunted intracellular signaling, has previously been associated with explicit memory performance in several independent cohorts, but the underlying neural mechanisms are thus far unclear. The human hippocampus plays a critical role in memory, particularly in the detection and encoding of novel information. Here we investigated the relationship of 5-HTR2a His452Tyr and hippocampal novelty processing in 41 young, healthy subjects using functional magnetic resonance imaging (fMRI. Participants performed a novelty/familiarity task with complex scene stimuli, which was followed by a delayed recognition memory test 24 hours later. Compared to His homozygotes, Tyr carriers exhibited a diminished hippocampal response to novel stimuli and a higher tendency to judge novel stimuli as familiar during delayed recognition. Across the cohort, the false alarm rate during delayed recognition correlated negatively with the hippocampal novelty response. Our results suggest that previously reported effects of 5-HTR2a on explicit memory performance may, at least in part, be mediated by alterations of hippocampal novelty processing.

  3. Genetic variation of the serotonin 2a receptor affects hippocampal novelty processing in humans.

    Science.gov (United States)

    Schott, Björn H; Seidenbecher, Constanze I; Richter, Sylvia; Wüstenberg, Torsten; Debska-Vielhaber, Grazyna; Schubert, Heike; Heinze, Hans-Jochen; Richardson-Klavehn, Alan; Düzel, Emrah

    2011-01-18

    Serotonin (5-hydroxytryptamine, 5-HT) is an important neuromodulator in learning and memory processes. A functional genetic polymorphism of the 5-HT 2a receptor (5-HTR2a His452Tyr), which leads to blunted intracellular signaling, has previously been associated with explicit memory performance in several independent cohorts, but the underlying neural mechanisms are thus far unclear. The human hippocampus plays a critical role in memory, particularly in the detection and encoding of novel information. Here we investigated the relationship of 5-HTR2a His452Tyr and hippocampal novelty processing in 41 young, healthy subjects using functional magnetic resonance imaging (fMRI). Participants performed a novelty/familiarity task with complex scene stimuli, which was followed by a delayed recognition memory test 24 hours later. Compared to His homozygotes, Tyr carriers exhibited a diminished hippocampal response to novel stimuli and a higher tendency to judge novel stimuli as familiar during delayed recognition. Across the cohort, the false alarm rate during delayed recognition correlated negatively with the hippocampal novelty response. Our results suggest that previously reported effects of 5-HTR2a on explicit memory performance may, at least in part, be mediated by alterations of hippocampal novelty processing.

  4. The role of serotonin and its receptors in activation of immune responses and inflammation.

    Science.gov (United States)

    Shajib, M S; Khan, W I

    2015-03-01

    Serotonin or 5-hydroxytryptamine (5-HT) is a neurotransmitter and hormone that contributes to the regulation of various physiological functions by its actions in the central nervous system (CNS) and in the respective organ systems. Peripheral 5-HT is predominantly produced by enterochromaffin (EC) cells of the gastrointestinal (GI) tract. These gut-resident cells produce much more 5-HT than all neuronal and other sources combined, establishing EC cells as the main source of this biogenic amine in the human body. Peripheral 5-HT is also a potent immune modulator and affects various immune cells through its receptors and via the recently identified process of serotonylation. Alterations in 5-HT signalling have been described in inflammatory conditions of the gut, such as inflammatory bowel disease. The association between 5-HT and inflammation, however, is not limited to the gut, as changes in 5-HT levels have also been reported in patients with allergic airway inflammation and rheumatoid arthritis. Based on searches for terms such as '5-HT', 'EC cell', 'immune cells' and 'inflammation' in pubmed.gov as well as by utilizing pertinent reviews, the current review aims to provide an update on the role of 5-HT in biological functions with a particular focus on immune activation and inflammation.

  5. Role of acetylcholine and muscarinic receptors in serotonin-induced bronchoconstriction in the mouse.

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    Kummer, Wolfgang; Wiegand, Silke; Akinci, Sibel; Schinkel, Alfred H; Wess, Jürgen; Koepsell, Hermann; Haberberger, Rainer Viktor; Lips, Katrin Susanne

    2006-01-01

    For the murine trachea, it has been reported that constriction evoked by serotonin (5-HT) is largely dependent on acetylcholine (ACh) released from the epithelium, owing to the sensitivity of the 5-HT response to epithelium removal, sensitivity to atropine, and insensitivity to tetrodotoxin (Moffatt et al., 2003). Consistent with this assumption, the respiratory epithelium contains ACh, its synthesizing enzyme, and the high-affinity choline transporter CHT1 (Reinheimer et al., 1996; Pfeil et al., 2003; Proskocil et al., 2004). Recently, we demonstrated that ACh can be released from non-neuronal cells by corticosteroid-sensitive polyspecific organic cation transporters (OCTs), which are also expressed by airway epithelial cells (Lips et al., 2005). Hence, we proposed that 5-HT evokes release of ACh from epithelial cells via OCTs and that this epithelial-derived ACh induces bronchoconstriction. We tested this hypothesis in a well-established model of videomorphometric analysis of bronchial diameter in precision-cut murine lung slices utilizing epithelium removal to assess the role of the epithelium, OCT mouse knockout (KO) strains to assess the role of OCT isoforms, and muscarinic receptor M2/M3 double-KO mice to assess the cholinergic component of 5-HT induced bronchoconstriction, as bronchi of this strain are entirely unresponsive to cholinergic stimulation(Struckmann et al., 2003).

  6. Dopamine D4 receptor and serotonin transporter gene effects on the longitudinal development of infant temperament.

    Science.gov (United States)

    Holmboe, K; Nemoda, Z; Fearon, R M P; Sasvari-Szekely, M; Johnson, M H

    2011-07-01

    Existing studies of the effect on infant temperament of the 48 base pair variable number of tandem repeats polymorphism in exon 3 of the dopamine D4 receptor gene, DRD4 VNTR, and the serotonin transporter-linked polymorphic region, 5-HTTLPR, have provided contradictory results, and age seems to be an important factor. The present study investigated the effect of these two polymorphisms on the stability of infant temperament between 4 and 9 months of age. Furthermore, the effect of a recently discovered single nucleotide polymorphism which modulates the 5-HTTLPR (rs25531) was investigated in relation to infant temperament. The study sample consisted of 90 infants, who were assessed by parental report at the two ages under consideration using the Revised Infant Behavior Questionnaire. It was found that infants carrying the 7-repeat allele of the DRD4 VNTR had higher levels of Negative Affect. Furthermore, there was an interaction between DRD4 VNTR and 5-HTTLPR genotype such that infants with the DRD4 VNTR 7-repeat allele and the highest expressing 5-HTTLPR genotype (L(A) L(A) ) had the highest level of Negative Affect. These effects were largely driven by scores on the Falling Reactivity scale. Genetic effects were stable across age. The results emphasize the need for developmental studies of genetic effects on temperament.

  7. Serotonin and Its Receptor as a New Antioxidant Therapeutic Target for Diabetic Kidney Disease

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    Yu Yang

    2017-01-01

    Full Text Available Diabetic kidney disease (DKD is a widespread chronic microvascular complication of diabetes mellitus (DM, affects almost 30–50% of patients, and represents a leading cause of death of DM. Serotonin or 5-hydroxytryptamine (5-HT is a multifunctional bioamine that has crucial roles in many physiological pathways. Recently, emerging evidence from experimental and clinical studies has demonstrated that 5-HT is involved in the pathogenesis of diabetic vascular complications. The 5-HT receptor (5-HTR antagonists exert renoprotective effects by suppressing oxidative stress, suggesting that 5-HTR can be used as a potential target for treating DKD. In this review, therefore, we summarize the published information available for the involvement of 5-HT and 5-HTR antagonists in the pathogenesis of various diabetic complications with a particular focus of DKD. We conclude that 5-HTR is a potential therapeutic target for treating DKD, as it has been successfully applied in animal models and has currently being investigated in randomized and controlled clinical trials.

  8. Serotonin increases ERK1/2 phosphorylation in astrocytes by stimulation of 5-HT2B and 5-HT2C receptors.

    Science.gov (United States)

    Li, Baoman; Zhang, Shiquen; Li, Min; Hertz, Leif; Peng, Liang

    2010-11-01

    We have previously shown that fluoxetine causes ERK(1/2) phosphorylation in cultured mouse astrocytes mediated exclusively by stimulation of 5-HT(2B) receptors (Li et al., 2008b). This raises the question whether this is also the case for serotonin (5-HT) itself. In the present study serotonin was found to induce ERK(1/2) phosphorylation by stimulation of 5-HT(2B) receptors with high affinity (EC(50): 20-30 pM), and by stimulation of 5-HT(2C) receptor with low affinity (EC(50): 1 microM or higher). ERK(1/2) phosphorylation induced by stimulation of either 5-HT(2B) or 5-HT(2C) receptors was mediated by epidermal growth factor (EGF) receptor transactivation (Peng et al., this issue), shown by the inhibitory effect of AG1478, an inhibitor of the EGF receptor tyrosine kinase, and GM6001, an inhibitor of Zn-dependent metalloproteinases, and thus of 5-HT(2B) receptor-mediated EGF receptor agonist release. It is discussed that the high potency of the 5-HT(2B)-mediated effect is consistent with literature data for binding affinity of serotonin to cloned human 5-HT(2B) receptors and with observations of low extracellular concentrations of serotonin in brain, which would allow a demonstrated moderate and modality-dependent increase in specific brain areas to activate 5-HT(2B) receptors. In contrast the relevance of the observed 5-HT(2C) receptors on astrocytes is questioned.

  9. Effects of serotonin-2A receptor binding and gender on personality traits and suicidal behavior in borderline personality disorder.

    Science.gov (United States)

    Soloff, Paul H; Chiappetta, Laurel; Mason, Neale Scott; Becker, Carl; Price, Julie C

    2014-06-30

    Impulsivity and aggressiveness are personality traits associated with a vulnerability to suicidal behavior. Behavioral expression of these traits differs by gender and has been related to central serotonergic function. We assessed the relationships between serotonin-2A receptor function, gender, and personality traits in borderline personality disorder (BPD), a disorder characterized by impulsive-aggression and recurrent suicidal behavior. Participants, who included 33 BPD patients and 27 healthy controls (HC), were assessed for Axis I and II disorders with the Structured Clinical Interview for DSM-IV and the International Personality Disorders Examination, and with the Diagnostic Interview for Borderline Patients-Revised for BPD. Depressed mood, impulsivity, aggression, and temperament were assessed with standardized measures. Positron emission tomography with [(18)F]altanserin as ligand and arterial blood sampling was used to determine the binding potentials (BPND) of serotonin-2A receptors in 11 regions of interest. Data were analyzed using Logan graphical analysis, controlling for age and non-specific binding. Among BPD subjects, aggression, Cluster B co-morbidity, antisocial PD, and childhood abuse were each related to altanserin binding. BPND values predicted impulsivity and aggression in BPD females (but not BPD males), and in HC males (but not HC females.) Altanserin binding was greater in BPD females than males in every contrast, but it did not discriminate suicide attempters from non-attempters. Region-specific differences in serotonin-2A receptor binding related to diagnosis and gender predicted clinical expression of aggression and impulsivity. Vulnerability to suicidal behavior in BPD may be related to serotonin-2A binding through expression of personality risk factors.

  10. The 5-HT1A serotonin receptor is located on calbindin- and parvalbumin-containing neurons in the rat brain.

    Science.gov (United States)

    Aznar, Susana; Qian, Zhaoxia; Shah, Reshma; Rahbek, Birgitte; Knudsen, Gitte M

    2003-01-03

    The 5-HT(1A) receptor is a well-characterized serotonin receptor playing a role in many central nervous functions and known to be involved in depression and other mental disorders. In situ hybridization, immunocytochemical, and binding studies have shown that the 5-HT(1A) receptor is widely distributed in the rat brain, with a particularly high density in the limbic system. The receptor's localization in the different neuronal subtypes, which may be of importance for understanding its role in neuronal circuitries, is, however, unknown. In this study we show by immunocytochemical double-labeling techniques, that the 5-HT(1A) receptor is present on both pyramidal and principal cells, and calbindin- and parvalbumin-containing neurons, which generally define two different subtypes of interneurons. Moreover, semiquantitative analysis showed that the receptor's distribution in the different neuronal types varies between brain areas. In cortex, hippocampus, hypothalamus, and amygdala the receptor was located on both principal cells and calbindin- and parvalbumin-containing neurons. In septum and thalamus, the receptor was mostly present on calbindin- and parvalbumin-containing cells. Especially in the medial septum and thalamic reticular nucleus, the receptor highly colocalized with parvalbumin-positive neurons. These results suggest a diverse function of the 5-HT(1A) receptor in modulating neuronal circuitry in different brain areas, that may depend on the type of neuron the receptor is predominantly located on.

  11. The effect of chronic selective serotonin reuptake inhibitor treatment on serotonin(1B) receptor sensitivity and HPA axis activity

    NARCIS (Netherlands)

    Jongsma, M.E.; Bosker, F.J; Cremers, T.I.F.H.; Westerink, B.H.C.; Den Boer, J.A.

    2005-01-01

    The authors have investigated 5-HT1B receptor function in prefrontal cortex and dorsal hippocampus as well as the HPA axis response after subchronic (24 h) and chronic (15 days) treatment with the SSRI citalopram. All experiments were carried out in presence of citalopram to prevent rapid resensitiz

  12. Serotonin mediation of early memory formation via 5HT2B receptor-induced glycogenolysis in the day-old chick

    Directory of Open Access Journals (Sweden)

    Marie Elizabeth Gibbs

    2014-04-01

    Full Text Available Investigation of the effects of serotonin on memory formation in the chick revealed an action on at least two 5HT receptors. Serotonin injected intracerebrally produced a biphasic effect on memory consolidation with enhancement at low doses and inhibition at higher doses. The non-selective 5HT receptor antagonist methiothepin and the selective 5HT2B/C receptor antagonist SB221284 both inhibited memory, suggesting actions of serotonin on at least 2 different receptor subtypes. The 5HT2B/C and astrocyte-specific 5-HT receptor agonists, fluoxetine and paroxetine, enhanced memory and the effect was attributed to glycogenolysis. Inhibition of glycogenolysis with a low dose of DAB prevented both serotonin and fluoxetine from enhancing memory during short-term memory but not during intermediate memory. The role of serotonin on the 5HT2B/C receptor appears to involve glycogen breakdown in astrocytes during short-term memory, whereas other published evidence attributes the second period of glycogenolysis to noradrenaline.

  13. Serotonin mediation of early memory formation via 5-HT2B receptor-induced glycogenolysis in the day-old chick.

    Science.gov (United States)

    Gibbs, Marie E; Hertz, Leif

    2014-01-01

    Investigation of the effects of serotonin on memory formation in the chick revealed an action on at least two 5-HT receptors. Serotonin injected intracerebrally produced a biphasic effect on memory consolidation with enhancement at low doses and inhibition at higher doses. The non-selective 5-HT receptor antagonist methiothepin and the selective 5-HT2B/C receptor antagonist SB221284 both inhibited memory, suggesting actions of serotonin on at least two different receptor subtypes. The 5-HT2B/C and astrocyte-specific 5-HT receptor agonist, fluoxetine and paroxetine, enhanced memory and the effect was attributed to glycogenolysis. Inhibition of glycogenolysis with a low dose of DAB (1,4-dideoxy-1,4-imino-D-arabinitol) prevented both serotonin and fluoxetine from enhancing memory during short-term memory but not during intermediate memory. The role of serotonin on the 5-HT2B/C receptor appears to involve glycogen breakdown in astrocytes during short-term memory, whereas other published evidence attributes the second period of glycogenolysis to noradrenaline.

  14. Role of prenatal undernutrition in the expression of serotonin, dopamine and leptin receptors in adult mice: implications of food intake.

    Science.gov (United States)

    Manuel-Apolinar, Leticia; Rocha, Luisa; Damasio, Leticia; Tesoro-Cruz, Emiliano; Zarate, Arturo

    2014-02-01

    Perturbations in the levels of serotonin expression have a significant impact on behavior and have been implicated in the pathogenesis of several neuropsychiatric disorders including anxiety, mood and appetite. Fetal programming is a risk factor for the development of metabolic diseases during adulthood. Moreover, previous studies have shown that serotonin (5‑HT), dopamine and leptin are important in energy balance. In the present study, the impact of maternal malnutrition‑induced prenatal undernutrition (UN) was investigated in mice and the expression of 5‑HT1A, dopamine (D)1, D2 and Ob‑Rb receptors was analyzed in the hypothalamus during adulthood. The UN group showed a low birth weight compared with the control group. With regard to receptor expression, 5‑HT1A in the UN group was increased in the hypothalamus and D1 was reduced, whereas D2 showed an increase from postnatal day (P)14 in the arcuate nucleus. Ob‑Rb receptor expression was increased in the hypothalamus at P14 and P90. These observations indicated that maternal caloric restriction programs a postnatal body weight gain in offspring with an increased food intake in early postnatal life which continues into adulthood. In addition, UN in mice was found to be affected by Ob‑Rb, 5‑HT1A and D1/2 receptor expression, indicating that these observations may be associated with hyperphagia and obesity.

  15. 5-HT7 receptor modulates GABAergic transmission in the rat dorsal raphe nucleus and controls cortical release of serotonin

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    Magdalena eKusek

    2015-08-01

    Full Text Available The 5-HT7 receptor is one of the several serotonin (5-HT receptor subtypes that are expressed in the dorsal raphe nucleus (DRN. Some earlier findings suggested that 5-HT7 receptors in the DRN were localized on GABAergic interneurons modulating the activity of 5-HT projection neurons. The aim of the present study was to find out how the 5-HT7 receptor modulates the GABAergic synaptic input to putative 5-HT DRN neurons, and whether blockade of the 5-HT7 receptor would affect the release of 5-HT in the target structure. Male Wistar rats with microdialysis probes implanted in the prefrontal cortex (PFC received injections of the 5-HT7 receptor antagonist (2R-1-[(3-hydroxyphenylsulfonyl]-2-[2-(4-methyl-1 piperidinylethyl]pyrrolidine hydrochloride (SB 269970, which induced an increase in the levels of 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA in the PFC. In another set of experiments whole-cell recordings from presumed projection neurons were carried out using DRN slices. SB 269970 application resulted in depolarization and in an increase in the firing frequency of the cells. In order to activate 5-HT7 receptors, 5-carboxamidotryptamine (5-CT was applied in the presence of N-[2-[4-(2-methoxyphenyl-1piperazinyl]ethyl]-N-2- pyridinylcyclohexanecarboxamide (WAY100635. Hyperpolarization of cells and a decrease in the firing frequency were observed after activation of the 5-HT7 receptor. Blockade of 5-HT7 receptors caused

  16. Visualisation of serotonin-1A (5-HT{sub 1A}) receptors in the central nervous system

    Energy Technology Data Exchange (ETDEWEB)

    Passchier, J.; Waarde, A. van [PET Center, University Hospital Groningen (Netherlands)

    2001-01-01

    The 5-HT{sub 1A} subtype of receptors for the neurotransmitter serotonin is predominantly located in the limbic forebrain and is involved in the modulation of emotion and the function of the hypothalamus. Since 5-HT{sub 1A} receptors are implicated in the pathogenesis of anxiety, depression, hallucinogenic behaviour, motion sickness and eating disorders, they are an important target for drug therapy. Here, we review the radioligands which are available for visualisation and quantification of this important neuroreceptor in the human brain, using positron emission tomography (PET) or single-photon emission tomography (SPET). More than 20 compounds have been labelled with carbon-11 (half-life 20 min), fluorine-18 (half-life 109.8 min) or iodine-123 (half-life 13.2 h): structural analogues of the agonist, 8-OH-DPAT, structural analogues of the antagonist, WAY 100635, and apomorphines. The most successful radioligands thus far are [carbonyl-{sup 11}C] WAY-100635 (WAY), [carbonyl-{sup 11}C]desmethyl-WAY-100635 (DWAY), p-[{sup 18}F]MPPF and [{sup 11}C]robalzotan (NAD-299). The high-affinity ligands WAY and DWAY produce excellent images of 5-HT{sub 1A} receptor distribution in the brain (even the raphe nuclei are visualised), but they cannot be distributed to remote facilities and they probably cannot be used to measure changes in endogenous serotonin. Binding of the moderate-affinity ligands MPPF and NAD-299 may be more sensitive to serotonin competition and MPPF can be distributed to PET centres within a flying distance of a few hours. Future research should be directed towards: (a) improvement of the metabolic stability in primates; (b) development of a fluorinated radioligand which can be produced in large quantities and (c) production of a radioiodinated or technetium-labelled ligand for SPET. (orig.)

  17. Freud-2/CC2D1B mediates dual repression of the serotonin-1A receptor gene.

    Science.gov (United States)

    Hadjighassem, Mahmoud R; Galaraga, Kimberly; Albert, Paul R

    2011-01-01

    The serotonin-1A (5-HT1A) receptor functions as a pre-synaptic autoreceptor in serotonin neurons that regulates their activity, and is also widely expressed on non-serotonergic neurons as a post-synaptic heteroreceptor to mediate serotonin action. The 5-HT1A receptor gene is strongly repressed by a dual repressor element (DRE), which is recognized by two proteins: Freud-1/CC2D1A and another unknown protein. Here we identify mouse Freud-2/CC2D1B as the second repressor of the 5-HT1A-DRE. Freud-2 shares 50% amino acid identity with Freud-1, and contains conserved structural domains. Mouse Freud-2 bound specifically to the rat 5-HT1A-DRE adjacent to, and partially overlapping, the Freud-1 binding site. By supershift assay using nuclear extracts from L6 myoblasts, Freud-2-DRE complexes were distinguished from Freud-1-DRE complexes. Freud-2 mRNA and protein were detected throughout mouse brain and peripheral tissues. Freud-2 repressed 5-HT1A promoter-reporter constructs in a DRE-dependent manner in non-neuronal (L6) or 5-HT1A-expressing neuronal (NG108-15, RN46A) cell models. In NG108-15 cells, knockdown of Freud-2 using a specific short-interfering RNA reduced endogenous Freud-2 protein levels and decreased Freud-2 bound to the 5-HT1A-DRE as detected by chromatin immunoprecipitation assay, but increased 5-HT1A promoter activity and 5-HT1A protein levels. Taken together, these data show that Freud-2 is the second component that, with Freud-1, mediates dual repression of the 5-HT1A receptor gene at the DRE. © 2010 The Authors. European Journal of Neuroscience © 2010 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

  18. Antidepressant, Antipsychotic, and Hallucinogen Drugs for the Treatment of Psychiatric Disorders: A Convergence at the Serotonin-2A Receptor.

    Science.gov (United States)

    Howland, Robert H

    2016-07-01

    Antidepressant, atypical antipsychotic, and hallucinogen drugs mediate their actions in part by interactions with the serotonin-2A (5HT2A) receptor. Serotonergic hallucinogen drugs, such as psilocybin, bind most potently as agonists at the 5HT2A receptor, producing profound changes in perception, mood, and cognition. Some of these drugs have been or are currently being investigated in small Phase 2 studies for depression, alcoholism, smoking cessation, anxiety, and posttraumatic stress disorder. However, unlike the synergistic effects of combining antidepressant and atypical antipsychotic drugs, the potential therapeutic effects of hallucinogen drugs may be attenuated by the concurrent use of these medications because antidepressant and atypical antipsychotic drugs desensitize and/or down-regulate 5HT2A receptors. This finding has important implications for optimizing the potential therapeutic use of hallucinogen drugs in psychiatry. [Journal of Psychosocial Nursing and Mental Health Services, 54(7), 21-24.]. Copyright 2016, SLACK Incorporated.

  19. (+)Lysergic acid diethylamide, but not its nonhallucinogenic congeners, is a potent serotonin 5HT1C receptor agonist

    Energy Technology Data Exchange (ETDEWEB)

    Burris, K.D.; Breeding, M.; Sanders-Bush, E. (Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN (United States))

    1991-09-01

    Activation of central serotonin 5HT2 receptors is believed to be the primary mechanism whereby lysergic acid diethylamide (LSD) and other hallucinogens induce psychoactive effects. This hypothesis is based on extensive radioligand binding and electrophysiological and behavioral studies in laboratory animals. However, the pharmacological profiles of 5HT2 and 5HT1C receptors are similar, making it difficult to distinguish between effects due to activation of one or the other receptor. For this reason, it was of interest to investigate the interaction of LSD with 5HT1C receptors. Agonist-stimulated phosphoinositide hydrolysis in rat choroid plexus was used as a direct measure of 5HT1C receptor activation. (+)LSD potently stimulated phosphoinositide hydrolysis in intact choroid plexus and in cultures of choroid plexus epithelial cells, with EC50 values of 9 and 26 nM, respectively. The effect of (+)LSD in both systems was blocked by 5HT receptor antagonists with an order of activity consistent with interaction at 5HT1C receptors. Neither (+)-2-bromo-LSD nor lisuride, two nonhallucinogenic congeners of LSD, were able to stimulate 5HT1C receptors in cultured cells or intact choroid plexus. In contrast, lisuride, like (+)LSD, is a partial agonist at 5HT2 receptors in cerebral cortex slices and in NIH 3T3 cells transfected with 5HT2 receptor cDNA. The present finding that (+)LSD, but not its nonhallucinogenic congeners, is a 5HT1C receptor agonist suggests a possible role for these receptors in mediating the psychoactive effects of LSD.

  20. Possible involvement of serotonin 5-HT2 receptor in the regulation of feeding behavior through the histaminergic system.

    Science.gov (United States)

    Murotani, Tomotaka; Ishizuka, Tomoko; Isogawa, Yuka; Karashima, Michitaka; Yamatodani, Atsushi

    2011-01-01

    The central histaminergic system has been proven to be involved in several physiological functions including feeding behavior. Some atypical antipsychotics like risperidone and aripiprazole are known to affect feeding behavior and to antagonize the serotonin (5-HT) receptor subtypes. To examine the possible neural relationship between the serotonergic and histaminergic systems in the anorectic effect of the antipsychotics, we studied the effect of a single administration of these drugs on food intake and hypothalamic histamine release in mice using in vivo microdialysis. Single injection of risperidone (0.5mg/kg, i.p.) or aripiprazole (1mg/kg, i.p.), which have binding affinities to 5-HT(1A, 2A, 2B) and (2C) receptors decreased food intake in C57BL/6N mice with concomitant increase of hypothalamic histamine release. However, a selective D(2)-antagonist, haloperidol (0.5mg/kg, i.p.), did not have effects on food intake or histamine release. Furthermore, in histamine H(1) receptor-deficient mice, there was no reduction of food intake induced by atypical antipsychotics, although histamine release was increased. Moreover, selective 5-HT(2A)-antagonists, volinanserin (0.5, 1mg/kg, i.p.) and ketanserin (5, 10mg/kg, i.p.), significantly increased histamine release and 5-HT(2B/2C) -antagonist, SB206553 (2.5, 5mg/kg, i.p.), slightly increased it. On the contrary, 5-HT(1A) -selective antagonist, WAY100635 (1, 2mg/kg), did not affect the histaminergic tone. These findings suggest that serotonin tonically inhibits histamine release via 5-HT(2) receptors and that antipsychotics enhance the release of hypothalamic histamine by blockade of 5-HT(2) receptors resulting in anorexia via the H(1) receptor.

  1. The extracellular entrance provides selectivity to serotonin 5-HT7 receptor antagonists with antidepressant-like behavior in vivo.

    Science.gov (United States)

    Medina, Rocío A; Vázquez-Villa, Henar; Gómez-Tamayo, José C; Benhamú, Bellinda; Martín-Fontecha, Mar; de la Fuente, Tania; Caltabiano, Gianluigi; Hedlund, Peter B; Pardo, Leonardo; López-Rodríguez, María L

    2014-08-14

    The finding that ergotamine binds serotonin receptors in a less conserved extended binding pocket close to the extracellular entrance, in addition to the orthosteric site, allowed us to obtain 5-HT7R antagonist 6 endowed with high affinity (Ki=0.7 nM) and significant 5-HT1AR selectivity (ratio>1428). Compound 6 exhibits in vivo antidepressant-like effect (1 mg/kg, ip) mediated by the 5-HT7R, which reveals its interest as a putative research tool or pharmaceutical in depression disorders.

  2. Selective serotonin receptor stimulation of the medial nucleus accumbens causes differential effects on food intake and locomotion.

    Science.gov (United States)

    Pratt, Wayne E; Blackstone, Kaitlin; Connolly, Megan E; Skelly, Mary Jane

    2009-10-01

    Substantial evidence suggests that pharmacological manipulations of neural serotonin pathways influence ingestive behaviors. Despite the known role of the nucleus accumbens in directing appetitive and consummatory behavior, there has been little examination of the influences that serotonin receptors may play in modulating feeding within nucleus accumbens circuitry. In these experiments, the authors examined the effects of bilateral nucleus accumbens infusions of the 5-HT1/7 receptor agonist 5-CT (at 0.0, 0.5, 1.0, or 4.0 microg/0.5 microl/side), the 5-HT receptor agonist EMD 386088 (at 0.0, 1.0, and 4.0 microg/0.5 microl/side), or the 5-HT2C preferential agonist RO 60-0175 (at 0.0, 2.0, or 5.0 microg/0.5 microl/side) on food intake and locomotor activity in the rat. Intra-accumbens infusions of 5-CT caused a dose-dependent reduction of food intake and rearing behavior, both in food-restricted animals given 2-hr free access to Purina Protab RMH 3000 Chow, as well as in nondeprived rats offered 2-hr access to a highly palatable fat/sucrose diet. In contrast, stimulation of 5-HT receptors with EMD 386088 caused a dose-dependent increase of intake under both feeding conditions, without affecting measures of locomotion. Infusions of the moderately selective 5-HT2C receptor agonist RO 60-0175 had no effects on feeding or locomotor measures in food-restricted animals, but did reduce intake of the fat/sucrose in nonrestricted animals at the 2.0 microg, but not the 5.0 microg dose. Intra-accumbens infusions of selective antagonists for the 5-HT (SB 269970), 5-HT (SB 252585), and 5-HT2C (RS 102221) receptors did not affect locomotion, and demonstrated no lasting changes in feeding for any of the groups tested. These data are the first to suggest that the activation of different serotonin receptor subtypes within the feeding circuitry of the medial nucleus accumbens differentially influence consummatory behavior.

  3. [CROSS-TALK BETWEEN 5-HT1A AND 5-HT7 RECEPTORS: ROLE IN THE AUTOREGULATION OF THE BRAIN SEROTONIN SYSTEM AND IN MECHANISM OF ANTIDEPRESSANTS ACTION].

    Science.gov (United States)

    Popova, N K; Ponimaskin, E G; Naumenko, V S

    2015-11-01

    Recent studies considerably extended our knowledge of the mechanisms and physiological role of the interaction between different receptors in the brain. Current review summarizes data on the formation of receptor complexes and the role of such complexes in the autoregulation of the brain serotonin system, behavioral abnormalities and mechanism of antidepressants action. Particular attention is paid to 5-HT1A and 5-HT7 receptor heterodimers. The results described in the present review indicate that: i) dimerization and formation of mobile receptor complexes is a common feature for the members of G-protein coupled receptor superfamily; ii) 5-HT7 receptor appears to be a modulator for 5-HT1A receptor - the key autoregulator of the brain serotonin system; iii) 5-HT1A/5-HT7 receptor complexes formation is one of the mechanisms for inactivation and desensitization of the 5-HTIA receptors in the brain; iv) differences in the 5-HT7 receptor and 5-HTIA/5-HT7 heterodimers density define different sensitivity of pre- and postsynaptic 5-HTlA receptors to chronic treatment with selective serotonin reuptake inhibitors.

  4. Differential dynamics of the serotonin1A receptor in membrane bilayers of varying cholesterol content revealed by all atom molecular dynamics simulation.

    Science.gov (United States)

    Patra, Swarna M; Chakraborty, Sudip; Shahane, Ganesh; Prasanna, Xavier; Sengupta, Durba; Maiti, Prabal K; Chattopadhyay, Amitabha

    2015-01-01

    The serotonin1A receptor belongs to the superfamily of G protein-coupled receptors (GPCRs) and is a potential drug target in neuropsychiatric disorders. The receptor has been shown to require membrane cholesterol for its organization, dynamics and function. Although recent work suggests a close interaction of cholesterol with the receptor, the structural integrity of the serotonin1A receptor in the presence of cholesterol has not been explored. In this work, we have carried out all atom molecular dynamics simulations, totaling to 3 μs, to analyze the effect of cholesterol on the structure and dynamics of the serotonin1A receptor. Our results show that the presence of physiologically relevant concentration of membrane cholesterol alters conformational dynamics of the serotonin1A receptor and, on an average lowers conformational fluctuations. Our results show that, in general, transmembrane helix VII is most affected by the absence of membrane cholesterol. These results are in overall agreement with experimental data showing enhancement of GPCR stability in the presence of membrane cholesterol. Our results constitute a molecular level understanding of GPCR-cholesterol interaction, and represent an important step in our overall understanding of GPCR function in health and disease.

  5. Quantitative Phosphoproteomics Unravels Biased Phosphorylation of Serotonin 2A Receptor at Ser280 by Hallucinogenic versus Nonhallucinogenic Agonists*

    Science.gov (United States)

    Karaki, Samah; Becamel, Carine; Murat, Samy; Mannoury la Cour, Clotilde; Millan, Mark J.; Prézeau, Laurent; Bockaert, Joël; Marin, Philippe; Vandermoere, Franck

    2014-01-01

    The serotonin 5-HT2A receptor is a primary target of psychedelic hallucinogens such as lysergic acid diethylamine, mescaline, and psilocybin, which reproduce some of the core symptoms of schizophrenia. An incompletely resolved paradox is that only some 5-HT2A receptor agonists exhibit hallucinogenic activity, whereas structurally related agonists with comparable affinity and activity lack such a psychoactive activity. Using a strategy combining stable isotope labeling by amino acids in cell culture with enrichment in phosphorylated peptides by means of hydrophilic interaction liquid chromatography followed by immobilized metal affinity chromatography, we compared the phosphoproteome in HEK-293 cells transiently expressing the 5-HT2A receptor and exposed to either vehicle or the synthetic hallucinogen 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI) or the nonhallucinogenic 5-HT2A agonist lisuride. Among the 5995 identified phosphorylated peptides, 16 sites were differentially phosphorylated upon exposure of cells to DOI versus lisuride. These include a serine (Ser280) located in the third intracellular loop of the 5-HT2A receptor, a region important for its desensitization. The specific phosphorylation of Ser280 by hallucinogens was further validated by quantitative mass spectrometry analysis of immunopurified receptor digests and by Western blotting using a phosphosite specific antibody. The administration of DOI, but not of lisuride, to mice, enhanced the phosphorylation of 5-HT2A receptors at Ser280 in the prefrontal cortex. Moreover, hallucinogens induced a less pronounced desensitization of receptor-operated signaling in HEK-293 cells and neurons than did nonhallucinogenic agonists. The mutation of Ser280 to aspartic acid (to mimic phosphorylation) reduced receptor desensitization by nonhallucinogenic agonists, whereas its mutation to alanine increased the ability of hallucinogens to desensitize the receptor. This study reveals a biased phosphorylation of

  6. Lack of the specific influence of histamine and histamine H1, H2 and H3 receptor ligands on the serotonin uptake and release in rat blood platelets.

    Science.gov (United States)

    Pawlak, D; Malinowska, B; Wollny, T; Godlewski, G; Buczko, W

    1996-01-01

    This work was designed to investigate the influence of histamine, and H1 receptor agonist 2-(2-thiazolyl)ethylamine, H2 receptor agonist dimaprit and H3 receptor agonist R-(-)-alpha-methylhistamine on the serotonin uptake and release in rat blood platelets. Histamine and R-(-)-alpha-methylhistamine (up to 1 mmol/l), 2-(2-thiazolyl)ethylamine (up to 10 mumol/l) and dimaprit (up to 1 mumol/l) failed to affect the serotonin uptake. The concentration-dependent inhibitory effects of higher concentrations of 2-(2-thiazolyl)ethylamine and dimaprit (up to 1 mmol/l) were not diminished by the H1 receptor antagonist dimetindene and the H2 receptor antagonist ranitidine (1 and 100 mumol/l each), respectively. Histamine, 2-(2-thiazolyl)ethylamine, dimaprit and R-(-)-alpha-methylhistamine (up to 10 mumol/l) did not change the serotonin release from rat blood platelets. Our results demonstrate that histamine and histamine H1, H2 and H3 receptor agonists do not affect in a specific manner the serotonin uptake and release in rat blood platelets.

  7. The diversity of abnormal hormone receptors in adrenal Cushing's syndrome allows novel pharmacological therapies

    Directory of Open Access Journals (Sweden)

    Lacroix A.

    2000-01-01

    Full Text Available Recent studies from several groups have indicated that abnormal or ectopic expression and function of adrenal receptors for various hormones may regulate cortisol production in ACTH-independent hypercortisolism. Gastric inhibitory polypeptide (GIP-dependent Cushing's syndrome has been described in patients with either unilateral adenoma or bilateral macronodular adrenal hyperplasia; this syndrome results from the large adrenal overexpression of the GIP receptor without any activating mutation. We have conducted a systematic in vivo evaluation of patients with adrenal Cushing's syndrome in order to identify the presence of abnormal hormone receptors. In macronodular adrenal hyperplasia, we have identified, in addition to GIP-dependent Cushing's syndrome, other patients in whom cortisol production was regulated abnormally by vasopressin, ß-adrenergic receptor agonists, hCG/LH, or serotonin 5HT-4 receptor agonists. In patients with unilateral adrenal adenoma, the abnormal expression or function of GIP or vasopressin receptor has been found, but the presence of ectopic or abnormal hormone receptors appears to be less prevalent than in macronodular adrenal hyperplasia. The identification of the presence of an abnormal adrenal receptor offers the possibility of a new pharmacological approach to control hypercortisolism by suppressing the endogenous ligands or by using specific antagonists for the abnormal receptors.

  8. Differentiated effects of the multimodal antidepressant vortioxetine on sleep architecture: Part 2, pharmacological interactions in rodents suggest a role of serotonin-3 receptor antagonism

    OpenAIRE

    Steven C Leiser; Iglesias-Bregna, Deborah; Westrich, Ligia; Pehrson, Alan L.; Sanchez, Connie

    2015-01-01

    Antidepressants often disrupt sleep. Vortioxetine, a multimodal antidepressant acting through serotonin (5-HT) transporter (SERT) inhibition, 5-HT3, 5-HT7 and 5-HT1D receptor antagonism, 5-HT1B receptor partial agonism, and 5-HT1A receptor agonism, had fewer incidences of sleep-related adverse events reported in depressed patients. In the accompanying paper a polysomnographic electroencephalography (sleep-EEG) study of vortioxetine and paroxetine in healthy subjects indicated that at low/inte...

  9. 5-HT7 receptor modulates GABAergic transmission in the rat dorsal raphe nucleus and controls cortical release of serotonin.

    Science.gov (United States)

    Kusek, Magdalena; Sowa, Joanna; Kamińska, Katarzyna; Gołembiowska, Krystyna; Tokarski, Krzysztof; Hess, Grzegorz

    2015-01-01

    The 5-HT7 receptor is one of the several serotonin (5-HT) receptor subtypes that are expressed in the dorsal raphe nucleus (DRN). Some earlier findings suggested that 5-HT7 receptors in the DRN were localized on GABAergic interneurons modulating the activity of 5-HT projection neurons. The aim of the present study was to find out how the 5-HT7 receptor modulates the GABAergic synaptic input to putative 5-HT DRN neurons, and whether blockade of the 5-HT7 receptor would affect the release of 5-HT in the target structure. Male Wistar rats with microdialysis probes implanted in the prefrontal cortex (PFC) received injections of the 5-HT7 receptor antagonist (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine hydrochloride (SB 269970), which induced an increase in the levels of 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA) in the PFC. In another set of experiments whole-cell recordings from presumed projection neurons were carried out using DRN slices. SB 269970 application resulted in depolarization and in an increase in the firing frequency of the cells. In order to activate 5-HT7 receptors, 5-carboxamidotryptamine (5-CT) was applied in the presence of N-[2-[4-(2-methoxyphenyl)-1piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY100635). Hyperpolarization of cells and a decrease in the firing frequency were observed after activation of the 5-HT7 receptor. Blockade of 5-HT7 receptors caused a decrease in the mean frequency of spontaneous inhibitory postsynaptic currents (sIPSCs), while its activation induced an increase. The mechanism of these effects appears to involve tonically-active 5-HT7 receptors modulating firing and/or GABA release from inhibitory interneurons which regulate the activity of DRN serotonergic projection neurons.

  10. Gene structure and expression of serotonin receptor HTR2C in hypothalamic samples from infanticidal and control sows

    Directory of Open Access Journals (Sweden)

    Quilter Claire R

    2012-04-01

    Full Text Available Abstract Background The serotonin pathways have been implicated in behavioural phenotypes in a number of species, including human, rat, mouse, dog and chicken. Components of the pathways, including the receptors, are major targets for drugs used to treat a variety of physiological and psychiatric conditions in humans. In our previous studies we have identified genetic loci potentially contributing to maternal infanticide in pigs, which includes a locus on the porcine X chromosome long arm. The serotonin receptor HTR2C maps to this region, and is therefore an attractive candidate for further study based on its function and its position in the genome. Results In this paper we describe the structure of the major transcripts produced from the porcine HTR2C locus using cDNA prepared from porcine hypothalamic and pooled total brain samples. We have confirmed conservation of sites altered by RNA editing in other mammalian species, and identified polymorphisms in the gene sequence. Finally, we have analysed expression and editing of HTR2C in hypothalamus samples from infanticidal and control animals. Conclusions The results confirm that although the expression of the long transcriptional variant of HTR2C is raised in infanticidal animals, the overall patterns of editing in the hypothalamus are similar between the two states. Sequences associated with the cDNA and genomic structures of HTR2C reported in this paper are deposited in GenBank under accession numbers FR720593, FR720594 and FR744452.

  11. Individual differences in positivity offset and negativity bias: Gender-specific associations with two serotonin receptor genes.

    Science.gov (United States)

    Ashare, Rebecca L; Norris, Catherine J; Wileyto, E Paul; Cacioppo, John T; Strasser, Andrew A

    2013-09-01

    Individual differences in the evaluation of affective stimuli, such as the positivity offset and negativity bias may have a biological basis. We tested whether two SNPs (HTR2A; 102T>C and HTR1A; 1019C>G) related to serotonin receptor function, a biological pathway associated with affective regulation, were differentially related to positivity offset and negativity bias for males and females. Participants were 109 cigarette smokers who rated a series of affective stimuli to assess reactions to positive and negative pictures. Gender × genotype interactions were found for both SNPs. Males with the 102T allele showed a greater positivity offset than males with the 102C allele. For females, in contrast, the 1019C allele was associated with a greater positivity offset than the 1019G allele, whereas the 102T allele was associated with a greater negativity bias than the 102C allele. Identifying how gender differences may moderate the effect of serotonin receptor genes on affective information processing may provide insight into their role in guiding behavior and regulating affect.

  12. Robust upregulation of serotonin 2A receptors after chronic spinal transection of rats: An immunohistochemical study

    DEFF Research Database (Denmark)

    Kong, Xiang-Yu; Wienecke, Jacob; Hultborn, Hans;

    2010-01-01

    It is well known that spinal motoneurons below a spinal transection become supersensitive to a systemic administration of serotonin (5-HT) precursors, such as 5-hydroxytryptophan. This supersensitivity has been implicated in both the process of functional recovery following chronic lesions, and a...

  13. 5-HT1B receptors and serotonin function : microdialysis studies in rats and knockout mice

    NARCIS (Netherlands)

    Groote, Lotte de

    2002-01-01

    The serotonergic system is an important target in the treatment of psychiatric disorders. Selective serotonin reuptake inhibitors (SSRIs) are widely used in the treatment of depression and anxiety disorders, but a clinical problem is the delayed therapeutic effect. This delayed onset of action sugge

  14. Serotonin 1A receptors and sexual behavior in a genetic model of depression

    NARCIS (Netherlands)

    Schijven, D.; Sousa, V. C.; Roelofs, J.; Olivier, B.; Olivier, J. D. A.

    2014-01-01

    The Flinder Sensitive Line (FSL) is a rat strain that displays distinct behavioral and neurochemical features of major depression. Chronic selective serotonin reuptake inhibitors (SSRls) are able to reverse these symptoms in FSL rats. It is well known that several abnormalities in the serotonergic s

  15. Decreased Incentive Motivation Following Knockout or Acute Blockade of the Serotonin Transporter: Role of the 5-HT2C Receptor.

    Science.gov (United States)

    Browne, Caleb J; Fletcher, Paul J

    2016-09-01

    Acute pharmacological elevation of serotonin (5-hydroxytryptamine; 5-HT) activity decreases operant responding for primary reinforcers, suggesting that 5-HT reduces incentive motivation. The mechanism by which 5-HT alters incentive motivation is unknown, but parallel evidence that 5-HT2C receptor agonists also reduce responding for primary reinforcers implicates this receptor as a potential candidate. These experiments examined whether chronic and acute disruptions of serotonin transporter (SERT) activity altered incentive motivation, and whether the 5-HT2C receptor mediated the effects of elevated 5-HT on behavior. To assess incentive motivation, we measured responding for three different reinforcers: a primary reinforcer (saccharin), a conditioned reinforcer (CRf), and an unconditioned sensory reinforcer (USRf). In the chronic condition, responding was compared between SERT knockout (SERT-KO) mice and their wild-type littermates. In the acute condition, responding was examined in wild-type mice following treatment with 10 or 20 mg/kg citalopram, or its vehicle. The ability of the selective 5-HT2C antagonist SB 242084 to prevent the effects of SERT-KO and citalopram on responding was subsequently examined. Both SERT-KO and citalopram reduced responding for saccharin, a CRf, and a USRf. Treatment with SB 242084 enhanced responding for a CRf and a USRf in SERT-KO mice and blocked the effects of citalopram on CRf and USRf responding. However, SB 242084 was unable to prevent the effects of SERT-KO or citalopram on responding for saccharin. These results support a powerful inhibitory function for 5-HT in the control of incentive motivation, and indicate that the 5-HT2C receptor mediates these effects of 5-HT in a reinforcer-dependent manner.

  16. Striatal dopamine D1 and D2 receptors: widespread influences on methamphetamine-induced dopamine and serotonin neurotoxicity.

    Science.gov (United States)

    Gross, Noah B; Duncker, Patrick C; Marshall, John F

    2011-11-01

    Methamphetamine (mAMPH) is an addictive psychostimulant drug that releases monoamines through nonexocytotic mechanisms. In animals, binge mAMPH dosing regimens deplete markers for monoamine nerve terminals, for example, dopamine and serotonin transporters (DAT and SERT), in striatum and cerebral cortex. Although the precise mechanism of mAMPH-induced damage to monoaminergic nerve terminals is uncertain, both dopamine D1 and D2 receptors are known to be important. Systemic administration of dopamine D1 or D2 receptor antagonists to rodents prevents mAMPH-induced damage to striatal dopamine nerve terminals. Because these studies employed systemic antagonist administration, the specific brain regions involved remain to be elucidated. The present study examined the contribution of dopamine D1 and D2 receptors in striatum to mAMPH-induced DAT and SERT neurotoxicities. In this experiment, either the dopamine D1 antagonist, SCH23390, or the dopamine D2 receptor antagonist, sulpiride, was intrastriatally infused during a binge mAMPH regimen. Striatal DAT and cortical, hippocampal, and amygdalar SERT were assessed as markers of mAMPH-induced neurotoxicity 1 week following binge mAMPH administration. Blockade of striatal dopamine D1 or D2 receptors during an otherwise neurotoxic binge mAMPH regimen produced widespread protection against mAMPH-induced striatal DAT loss and cortical, hippocampal, and amygdalar SERT loss. This study demonstrates that (1) dopamine D1 and D2 receptors in striatum, like nigral D1 receptors, are needed for mAMPH-induced striatal DAT reductions, (2) these same receptors are needed for mAMPH-induced SERT loss, and (3) these widespread influences of striatal dopamine receptor antagonists are likely attributable to circuits connecting basal ganglia to thalamus and cortex.

  17. Normalization of hypothalamic serotonin (5-HT 1B) receptor and NPY in cancer anorexia after tumor resection: an immunocytochemical study.

    Science.gov (United States)

    Makarenko, Irina G; Meguid, Michael M; Gatto, Louis; Chen, Chung; Ramos, Eduardo J B; Goncalves, Carolina G; Ugrumov, Michael V

    2005-08-05

    Tumor growth leads to anorexia and decreased food intake, the regulation of which is via the integrated hypothalamic peptidergic and monoaminergic system. Serotonin (5-HT), an anorectic monoamine acts primarily via 5-HT 1B-receptors in hypothalamic nuclei while neuropeptide Y (NPY) acts an orexigenic peptide. We previously reported that 5-HT 1B-receptors are up regulated while NPY is down regulated in tumor-bearing (TB)-related anorexia, contributing to food intake reduction. In anorectic TB rats we hypothesize that after tumor resection when food intake has reverted to normal, normalization of 5-HT 1B-receptor and NPY will occur. The aim of this study was to demonstrate normalization of these hypothalamic changes compared to Controls. In anorectic tumor-bearing rats after tumor resection (TB-R) and in sham-operated (Control) rats, distribution of 5-HT 1B-receptors and NPY in hypothalamic nuclei was analyzed using peroxidase antiperoxidase immunocytochemical methods. Image analysis of immunostaining was performed and the data were statistically analyzed. Immunostaining specificity was controlled by omission of primary or secondary antibodies and pre-absorption test. Our results show that after TB-R versus Controls a normalization of food intake, 5-H-1B-receptor and NPY expression in the hypothalamus occurs. These data, discussed in context with our previous studies, support the hypothesis that tumor resection results not only in normalization of food intake but also in reversible changes of anorectic and orexigenic hypothalamic modulators.

  18. Associations of the 5-hydroxytryptamine (serotonin) receptor 1B gene (HTR1B) with alcohol, cocaine, and heroin abuse.

    Science.gov (United States)

    Cao, Jian; LaRocque, Emily; Li, Dawei

    2013-03-01

    Abnormal serotonergic pathways are implicated in numerous neuropsychiatric disorders including alcohol and drug dependence (abuse). The human 5-hydroxytryptamine (serotonin) receptor 1B, encoded by the HTR1B (5-HT1B) gene, is a presynaptic serotonin autoreceptor that plays an important role in regulating serotonin synthesis and release. Although there was evidence of associations of the HTR1B gene variants in the etiologies of substance use disorders, negative findings were also reported. To clarify the roles of commonly reported single nucleotide polymorphisms (SNPs) of the HTR1B gene underlying alcohol and drug dependence (abuse), we performed a meta-analysis based on the available genotype data from individual candidate gene-based association studies. Evidence of association was found between the functional SNP -161A>T (rs130058) and alcohol, cocaine, and heroin dependence (e.g., P = 0.03 and odds ratio (OR) = 1.2 (1.02, 1.42) in the combined European, Asian, African, and Hispanic populations). SNP -261T>G (rs11568817) also showed evidence of association but with different directions in Europeans and non-Europeans (e.g., P = 0.0018 with OR = 1.42 (1.14, 1.76) and P = 0.01 with ORs = 0.5 (0.3, 0.85), respectively). This meta-analysis supports the associations of HTR1B -261T>G and -161A>T with alcohol and drug abuse and further investigations are warranted in larger samples.

  19. Discovery of a new class of potential multifunctional atypical antipsychotic agents targeting dopamine D3 and serotonin 5-HT1A and 5-HT2A receptors: design, synthesis, and effects on behavior

    DEFF Research Database (Denmark)

    Butini, Stefania; Gemma, Sandra; Campiani, Giuseppe;

    2009-01-01

    Dopamine D(3) antagonism combined with serotonin 5-HT(1A) and 5-HT(2A) receptor occupancy may represent a novel paradigm for developing innovative antipsychotics. The unique pharmacological features of 5i are a high affinity for dopamine D(3), serotonin 5-HT(1A) and 5-HT(2A) receptors, together...... with a low affinity for dopamine D(2) receptors (to minimize extrapyramidal side effects), serotonin 5-HT(2C) receptors (to reduce the risk of obesity under chronic treatment), and for hERG channels (to reduce incidence of torsade des pointes). Pharmacological and biochemical data, including specific c...

  20. Serotonin effects in the crab Neohelice granulata: Possible involvement of two types of receptors in peripheral tissues.

    Science.gov (United States)

    Inohara, Elen Thegla Sander; Pinto, Charles Budazewsky; Model, Jorge Felipe Argenta; Trapp, Márcia; Kucharski, Luiz Carlos; Da Silva, Roselis Silveira Martins; Vinagre, Anapaula Sommer

    2015-07-01

    In crustaceans, serotonin (5-HT) controls various physiological processes, such as hormonal secretion, color changes, reproduction, and metabolism. Since 5-HT injections cause hyperglycemia, this study was designed to further investigate this action of 5-HT in the crab Neohelice granulate, fed with a high-carbohydrate (HC) or a high-protein (HP) diet. The effects of pre-treatment with mammalian 5-HT receptor antagonists, cyproheptadine and methiothepin, were also investigated. A series of in vivo experiments with (3)H-5-HT was carried out in order to investigate the presence of putative receptors in peripheral tissues. Since gills were the tissue with the highest labeling in in vivo experiments, in vitro studies with isolated anterior and posterior gills were also conducted. Cyproheptadine blocked the hyperglycemic effect of 5-HT in HP-fed crabs. Methiothepin reduced glycogen levels in the anterior gills of HP crabs and partially blocked the 5-HT-like posture. The injection of (3)H-5-HT identified specific binding sites in all the tissues studied and revealed that the binding can be influenced by the type of diet administered to the crabs. Incubation of the anterior and posterior gills with (3)H-5-HT and 5-HT confirmed the specificity of the binding sites. Both antagonists inhibited (3)H-5-HT binding. In conclusion, this study highlights the importance of serotonin in the control of glucose homeostasis in crustaceans and provides evidences of at least two types of 5-HT binding sites in peripheral tissues. Further studies are necessary to identify the structure of these receptors and their signaling pathways.

  1. 5-HT1B receptor modulation of the serotonin transporter in vivo: Studies using KO mice

    OpenAIRE

    Montañez, Sylvia; Munn, Jaclyn L.; Owens, W. Anthony; Horton, Rebecca E.; Daws, Lynette C.

    2013-01-01

    The serotonin transporter (SERT) controls the strength and duration of serotonergic neurotransmission by the high-affinity uptake of ser otonin (5-HT) from extracellular fluid. SERT is a key target for many psychotherapeutic and abused drugs, therefore understanding how SERT activity and expression are regulated is of fundamental importance. A growing literature suggests that SERT activity is under regulatory control of the 5-HT1B autoreceptor. The present studies made use of mice with a cons...

  2. Agonist properties of N,N-dimethyltryptamine at serotonin 5-HT2A and 5-HT2C receptors.

    Science.gov (United States)

    Smith, R L; Canton, H; Barrett, R J; Sanders-Bush, E

    1998-11-01

    Extensive behavioral and biochemical evidence suggests an agonist role at the 5-HT2A receptor, and perhaps the 5-HT2C receptor, in the mechanism of action of hallucinogenic drugs. However the published in vitro pharmacological properties of N,N-dimethyltryptamine (DMT), an hallucinogenic tryptamine analog, are not consistent with this hypothesis. We, therefore, undertook an extensive investigation into the properties of DMT at 5-HT2A and 5-HT2C receptors. In fibroblasts transfected with the 5-HT2A receptor or the 5-HT2C receptor, DMT activated the major intracellular signaling pathway (phosphoinositide hydrolysis) to an extent comparable to that produced by serotonin. Because drug efficacy changes with receptor density and cellular microenvironment, we also examined the properties of DMT in native preparations using a behavioral and biochemical approach. Rats were trained to discriminate an antagonist ketanserin from an agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) in a two-lever choice paradigm. Pharmacological studies showed that responding on the DOI and ketanserin lever reflected agonist and antagonist activity at 5-HT2A receptors, and hence, was a suitable model for evaluating the in vivo functional properties of DMT. Like other 5-HT2A receptor agonists, DMT substituted fully for DOI. Intact choroid plexus was used to evaluate the agonist properties at endogenous 5-HT2C receptors; DMT was a partial agonist at 5-HT2C receptors in this native preparation. Thus, we conclude that DMT behaves as an agonist at both 5-HT2A and 5-HT2A receptors. One difference was evident in that the 5-HT2C, but not the 5-HT2A, receptor showed a profound desensitization to DMT over time. This difference is interesting in light of the recent report that the hallucinogenic activity of DMT does not tolerate in humans and suggests the 5-HT2C receptor plays a less prominent role in the action of DMT.

  3. Novelty-induced activity-regulated cytoskeletal-associated protein (Arc) expression in frontal cortex requires serotonin 2A receptor activation

    DEFF Research Database (Denmark)

    Santini, Martin; Klein, A B; El-Sayed, M

    2011-01-01

    Many psychiatric disorders are characterized by cognitive and emotional alterations that are related to abnormal function of the frontal cortex (FC). FC is involved in working memory and decision making and is activated following exposure to a novel environment. The serotonin 2A receptor (5-HT(2A...

  4. Drosophila insulin-producing cells are differentially modulated by serotonin and octopamine receptors and affect social behavior.

    Directory of Open Access Journals (Sweden)

    Jiangnan Luo

    Full Text Available A set of 14 insulin-producing cells (IPCs in the Drosophila brain produces three insulin-like peptides (DILP2, 3 and 5. Activity in IPCs and release of DILPs is nutrient dependent and controlled by multiple factors such as fat body-derived proteins, neurotransmitters, and neuropeptides. Two monoamine receptors, the octopamine receptor OAMB and the serotonin receptor 5-HT1A, are expressed by the IPCs. These receptors may act antagonistically on adenylate cyclase. Here we investigate the action of the two receptors on activity in and output from the IPCs. Knockdown of OAMB by targeted RNAi led to elevated Dilp3 transcript levels in the brain, whereas 5-HT1A knockdown resulted in increases of Dilp2 and 5. OAMB-RNAi in IPCs leads to extended survival of starved flies and increased food intake, whereas 5-HT1A-RNAi produces the opposite phenotypes. However, knockdown of either OAMB or 5-HT1A in IPCs both lead to increased resistance to oxidative stress. In assays of carbohydrate levels we found that 5-HT1A knockdown in IPCs resulted in elevated hemolymph glucose, body glycogen and body trehalose levels, while no effects were seen after OAMB knockdown. We also found that manipulations of the two receptors in IPCs affected male aggressive behavior in different ways and 5-HT1A-RNAi reduced courtship latency. Our observations suggest that activation of 5-HT1A and OAMB signaling in IPCs generates differential effects on Dilp transcription, fly physiology, metabolism and social interactions. However the findings do not support an antagonistic action of the two monoamines and their receptors in this particular system.

  5. Theophylline-induced respiratory recovery following cervical spinal cord hemisection is augmented by serotonin 2 receptor stimulation.

    Science.gov (United States)

    Basura, Gregory J; Nantwi, Kwaku D; Goshgarian, Harry G

    2002-11-22

    Cervical spinal cord hemisection leads to a disruption of bulbospinal innervation of phrenic motoneurons resulting in paralysis of the ipsilateral hemidiaphragm. We have previously demonstrated separate therapeutic roles for theophylline, and more recently serotonin (5-HT) as modulators to phrenic nerve motor recovery; mechanisms that likely occur via adenosine A1 and 5-HT2 receptors, respectively. The present study was designed to specifically determine if concurrent stimulation of 5-HT2 receptors may enhance motor recovery induced by theophylline alone. Adult female rats (250-350 g; n=7 per group) received a left cervical (C2) hemisection that resulted in paralysis of the ipsilateral hemidiaphragm. Twenty-four hours later rats were given systemic theophylline (15 mg/kg, i.v.), resulting in burst recovery in the ipsilateral phrenic nerve. Theophylline-induced recovery was enhanced with the 5-HT2A/2C receptor agonist, (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI; 1.0 mg/kg). DOI-evoked augmentation of theophylline-induced recovery was attenuated following subsequent injection of the 5-HT2 receptor antagonist, ketanserin (2.0 mg/kg). In a separate group, rats were pretreated with ketanserin, which did not prevent subsequent theophylline-induced respiratory recovery. However, pretreatment with ketanserin did prevent DOI-induced augmentation of the theophylline-evoked phrenic nerve burst recovery. Lastly, using immunocytochemistry and in situ hybridization, we showed for the first time a positive co-localization of adenosine A1 receptor mRNA and immunoreactivity with phrenic motoneurons of the cervical ventral horns. Taken together, the results of the present study suggest that theophylline may induce motor recovery likely at adenosine A1 receptors located at the level of the spinal cord, and the concurrent stimulation of converging 5-HT2 receptors may augment the response.

  6. Impact of serotonin 2C receptor null mutation on physiology and behavior associated with nigrostriatal dopamine pathway function.

    Science.gov (United States)

    Abdallah, Luna; Bonasera, Stephen J; Hopf, F Woodward; O'Dell, Laura; Giorgetti, Marco; Jongsma, Minke; Carra, Scott; Pierucci, Massimo; Di Giovanni, Giuseppe; Esposito, Ennio; Parsons, Loren H; Bonci, Antonello; Tecott, Laurence H

    2009-06-24

    The impact of serotonergic neurotransmission on brain dopaminergic pathways has substantial relevance to many neuropsychiatric disorders. A particularly prominent role has been ascribed to the inhibitory effects of serotonin 2C receptor (5-HT(2C)R) activation on physiology and behavior mediated by the mesolimbic dopaminergic pathway, particularly in the terminal region of the nucleus accumbens. The influence of this receptor subtype on functions mediated by the nigrostriatal dopaminergic pathway is less clear. Here we report that a null mutation eliminating expression of 5-HT(2C)Rs produces marked alterations in the activity and functional output of this pathway. 5-HT(2C)R mutant mice displayed increased activity of substantia nigra pars compacta (SNc) dopaminergic neurons, elevated baseline extracellular dopamine concentrations in the dorsal striatum (DSt), alterations in grooming behavior, and enhanced sensitivity to the stereotypic behavioral effects of d-amphetamine and GBR 12909. These psychostimulant responses occurred in the absence of phenotypic differences in drug-induced extracellular dopamine concentration, suggesting a phenotypic alteration in behavioral responses to released dopamine. This was further suggested by enhanced behavioral responses of mutant mice to the D(1) receptor agonist SKF 81297. Differences in DSt D(1) or D(2) receptor expression were not found, nor were differences in medium spiny neuron firing patterns or intrinsic membrane properties following dopamine stimulation. We conclude that 5-HT(2C)Rs regulate nigrostriatal dopaminergic activity and function both at SNc dopaminergic neurons and at a locus downstream of the DSt.

  7. Differential effects of selective lesions of cholinergic and dopaminergic neurons on serotonin-type 1 receptors in rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Quirion, R.; Richard, J.

    1987-01-01

    Serotonin (5-HT)-type1 receptor binding sites are discretely distributed in rat brain. High densities of (3H)5-HT1 binding sites are especially located in areas enriched with cholinergic and dopaminergic innervation, such as the substantia innominata/ventral pallidum, striatum, septal nuclei, hippocampus and substantia nigra. The possible association of (3H)5-HT1 binding sites with cholinergic or dopaminergic cell bodies and/or nerve fiber terminals was investigated by selective lesions of the substantia innominata/ventral pallidum-cortical and septohippocampal cholinergic pathways and the nigrostriatal dopaminergic projection. (3H)5-HT1 receptor binding sites are possibly located on cholinergic cell bodies in the ventral pallidum-cortical pathway since (3H)5-HT1 binding in the substantia innominata/ventral pallidal area was markedly decreased following kainic acid lesions. Fimbriaectomies markedly decreased (3H)5-HT1 binding in the hippocampus, suggesting the presence of 5-HT1 binding sites on cholinergic nerve fiber terminals in the septohippocampal pathway. Lesions of the nigrostriatal dopaminergic projection did not modify (3H)5-HT1 binding in the substantia nigra and the striatum, suggesting that 5-HT1 receptors are not closely associated with dopaminergic cell bodies and nerve terminals in this pathway. These results demonstrate differential association between 5-HT1 receptors and cholinergic and dopaminergic innervation in rat brain.

  8. Inhibition of serotonin transporters by cocaine and meprylcaine through 5-TH2C receptor stimulation facilitates their seizure activities.

    Science.gov (United States)

    Morita, Katsuya; Hamamoto, Masahiro; Arai, Shigeaki; Kitayama, Shigeo; Irifune, Masahiro; Kawahara, Michio; Kihira, Kenji; Dohi, Toshihiro

    2005-09-28

    The present study examined whether the inhibition of serotonin transporters (SERT) contributes to cocaine- and other local anesthetics-induced convulsions, and which subtypes of 5-HT receptor are involved in the convulsions. For this purpose, cocaine, meprylcaine and lidocaine, all of which have different effects on SERT, were used as convulsants and the effects of serotonin reuptake inhibitors (SSRIs), specific agonists and antagonists for 5-HT receptor subtypes were evaluated in mice. Administration of SSRI, zimelidine, citalopram and fluoxetine, 5-HT(2A,2C) receptor agonist, R(-)-DOI and the 5-HT2C receptor agonists, mCPP, and MK212 resulted in a marked increase in incidence of convulsions and a reduction in the threshold of lidocaine-induced convulsions, while the 5-HT2B receptor agonist, BW723C86, had little influence. On the other hand, SSRI did not affect the measured parameters in meprylcaine- and cocaine-induced convulsions. R(-)-DOI, mCPP, and MK212 reduced the threshold of meprylcaine or cocaine with less extent than the reduction of lidocaine threshold. Incidence of cocaine- and meprylcaine-induced convulsions was significantly reduced by 5-HT(2A,2B,2C) antagonist, LY-53857, and 5-HT2C antagonist, RS 102221. The threshold of cocaine and meprylcaine was significantly increased by both antagonists. 5-HT2A antagonists MDL 11,939 and ketanserin, and 5-HT2B antagonist SB 204741 except at high doses had little effect on cocaine- and meprylcaine-induced convulsions. None of these antagonists altered the parameters of lidocaine-induced convulsions. Pretreatment with fluoxetine but not citalopram increased the plasma concentration of lidocaine. These results suggest that the increase of serotonergic neuronal activity through 5-HT2C receptor stimulation was responsible for increased activity of local anesthetics-induced convulsions and support the involvement of this mechanism in cocaine- and meprylcaine- but not in lidocaine-induced convulsions through their

  9. Effect of acute and chronic treatment with risperidone on the serotonin and dopamine receptors in the rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Yun Young; Moon, Dae Hyuk; Son, Hye Kyung; Kim, Chang Yoon; Lee, Chul; Lee, Hee Kyung [College of Medicine, Ulsan Univ., Seoul (Korea, Republic of)

    1997-03-01

    The therapeutic efficacy of antipsychotic drugs is generally attributed to their ability to block dopamine D{sub 2} receptors. Classical D{sub 2} antagonists are not effective to treat negative symptoms and produce extrapyramidal side effects. On the other hand, atypical antipsychotic agents ameliorate negative symptoms without producing extrapyramidal side effects, and it is reported to be associated with blockade of serotonin 5-HT{sub 2} receptors. The purpose of this study was to evaluate the effect of risperidone on neuroreceptors in the rat brain by quantitative autoradiography method. In acute treatment group, risperidone was injected into peritoneal cavity of male Wistar rats with dose of 0, 0.1, 0.25, 0.5, 1.0 and 2.0mg/kg in each group (5/group), and they were decapitated after 2 hours. In chronic treatment group, risperidone was injected with dose of 0, 0.1, and 1m/kg (I.P.) for 21 ays and decapitated after 24 hours following last treatment. The effect of risperodone on the binding of [{sup 3}H) spiperone to 5-HT{sub 2} and D{sub 2} receptors were analysed in 4 discrete regions of the striatum, nucleus accumbens, and frontal cortex by quantitative autoradiography. Acute treatment with risperidone reduced cortical 5-HT{sub 2} specific [{sup 3}H]spiperone binding to 32% of vehicle-treated control. Subcortical 5-HR{sub 2} specific [{sup 3}H]spiperone binding was not affected at all dose groups whereas a significant reduction (57%) in D{sub 2} specific [{sup 3}H]spiperone binding was observed in risperidone treated group at doses of 1-2mg/kg. Chronic treatment with risperidone produced a decrease in the maximal number of cortical 5-HT{sub 2} receptors to 51% and 46% of control in 0.1mg/kg and 1mg/kg treated group respectively. In conclusion, risperidone is a cortical serotonin receptor antagonist with relatively weak antagonistic action on dopamine receptors. These effects on neuroreceptors may explain the therapeutic effect of risperidone as a atypical

  10. Serotonin in human skin

    Institute of Scientific and Technical Information of China (English)

    Jianguo Huang; Qiying Gong; Guiming Li

    2005-01-01

    In this review the authors summarize data of a potential role for serotonin in human skin physiology and pathology. The uncovering of endogenous serotonin synthesis and its transformation to melatonin underlines a putative important role of this pathway in melanocyte physiology and pathology. Pathways of the biosynthesis and biodegradation of serotonin have been characterized in human beings and its major cellular populations. Moreover, receptors of serotonin are expressed on keratinocytes, melanocytes, and fibroblasts and these mediate phenotypic actions on cellular proliferation and differentiation. And the widespread expression of a cutaneous seorotoninergic system indicates considerable selectivity of action to facilitate intra-, auto-, or paracrine mechanisms that define and influence skin function in a highly compartmentalized manner. Melatonin, in turn, can also act as a hormone, neurotransmitter, cytokine, biological modifier and immunomodulator. Thus, Serotonin local synthesis and cellular localization could thus become of great importance in the diagnosis and management of cutaneous pathology.

  11. Adaptations in pre- and postsynaptic 5-HT(1A) receptor function and cocaine supersensitivity in serotonin transporter knockout rats

    NARCIS (Netherlands)

    Homberg, Judith R; De Boer, Sietse F; Raasø, Halfdan S; Olivier, Jocelien D A; Verheul, Mark; Ronken, Eric; Cools, Alexander R; Ellenbroek, Bart A; Schoffelmeer, Anton N M; Vanderschuren, Louk J M J; De Vries, Taco J; Cuppen, Edwin

    2008-01-01

    RATIONALE: While individual differences in vulnerability to psychostimulants have been largely attributed to dopaminergic neurotransmission, the role of serotonin is not fully understood. OBJECTIVES: To study the rewarding and motivational properties of cocaine in the serotonin transporter knockout

  12. Adaptations in pre- and postsynaptic 5-HT1A receptor function and cocaine supersensitivity in serotonin transporter knockout rats.

    NARCIS (Netherlands)

    Homberg, J.R.; Boer, SF De; Raaso, H.S.; Olivier, J.D.A.; Verheul, M.; Ronken, E.; Cools, A.R.; Ellenbroek, B.A.; Schoffelmeer, A.N.; Schuren, L.J. van der; Vries, TJ De; Cuppen, E.

    2008-01-01

    RATIONALE: While individual differences in vulnerability to psychostimulants have been largely attributed to dopaminergic neurotransmission, the role of serotonin is not fully understood. OBJECTIVES: To study the rewarding and motivational properties of cocaine in the serotonin transporter knockout

  13. Hippocampal serotonin-2A receptor-immunoreactive neurons density increases after testosterone therapy in the gonadectomized male mice

    Science.gov (United States)

    Nikmahzar, Emsehgol; Ghaemi, Amir; Naseri, Gholam Reza; Moharreri, Ali Reza; Lotfinia, Ahmad Ali

    2016-01-01

    The change of steroid levels may also exert different modulatory effects on the number and class of serotonin receptors present in the plasma membrane. The effects of chronic treatment of testosterone for anxiety were examined and expression of 5-HT2A serotonergic receptor, neuron, astrocyte, and dark neuron density in the hippocampus of gonadectomized male mice was determined. Thirty-six adult male NMRI mice were randomly divided into six groups: intact-no testosterone treatment (No T), gonadectomy (GDX)-No T, GDX-Vehicle, GDX-6.25 mg/kg testosterone (T), GDX-12.5 mg/kg T, and GDX-25 mg/kg T. Anxiety-related behavior was evaluated using elevated plus maze apparatus. The animals were anesthetized after 48 hours after behavioral testing, and decapitated and micron slices were prepared for immunohistochemical as well as histopathological assessment. Subcutaneous injection of testosterone (25 mg/kg) may induce anxiogenic-like behavior in male mice. In addition, immunohistochemical data reveal reduced expression of 5-HT2A serotonergic receptor after gonadectomy in all areas of the hippocampus. However, treatment with testosterone could increase the mean number of dark neurons as well as immunoreactive neurons in CA1 and CA3 area, dose dependently. The density of 5-HT2A receptor-immunoreactive neurons may play a crucial role in the induction of anxiety like behavior. As reduction in such receptor expression have shown to significantly enhance anxiety behaviors. However, replacement of testosterone dose dependently enhances the number of 5-HT2A receptor-immunoreactive neurons and interestingly also reduced anxiety like behaviors. PMID:28127501

  14. Global decrease of serotonin-1A receptor binding after electroconvulsive therapy in major depression measured by PET

    Science.gov (United States)

    Lanzenberger, R; Baldinger, P; Hahn, A; Ungersboeck, J; Mitterhauser, M; Winkler, D; Micskei, Z; Stein, P; Karanikas, G; Wadsak, W; Kasper, S; Frey, R

    2013-01-01

    Electroconvulsive therapy (ECT) is a potent therapy in severe treatment-refractory depression. Although commonly applied in psychiatric clinical routine since decades, the exact neurobiological mechanism regarding its efficacy remains unclear. Results from preclinical and clinical studies emphasize a crucial involvement of the serotonin-1A receptor (5-HT1A) in the mode of action of antidepressant treatment. This includes associations between treatment response and changes in 5-HT1A function and density by antidepressants. Further, alterations of the 5-HT1A receptor are consistently reported in depression. To elucidate the effect of ECT on 5-HT1A receptor binding, 12 subjects with severe treatment-resistant major depression underwent three positron emission tomography (PET) measurements using the highly selective radioligand [carbonyl-11C]WAY100635, twice before (test–retest variability) and once after 10.08±2.35 ECT sessions. Ten patients (∼83%) were responders to ECT. The voxel-wise comparison of the 5-HT1A receptor binding (BPND) before and after ECT revealed a widespread reduction in cortical and subcortical regions (P<0.05 corrected), except for the occipital cortex and the cerebellum. Strongest reductions were found in regions consistently reported to be altered in major depression and involved in emotion regulation, such as the subgenual part of the anterior cingulate cortex (−27.5%), the orbitofrontal cortex (−30.1%), the amygdala (−31.8%), the hippocampus (−30.6%) and the insula (−28.9%). No significant change was found in the raphe nuclei. There was no significant difference in receptor binding in any region comparing the first two PET scans conducted before ECT. This PET study proposes a global involvement of the postsynaptic 5-HT1A receptor binding in the effect of ECT. PMID:22751491

  15. Human Freud-2/CC2D1B: a novel repressor of postsynaptic serotonin-1A receptor expression.

    Science.gov (United States)

    Hadjighassem, Mahmoud R; Austin, Mark C; Szewczyk, Bernadeta; Daigle, Mireille; Stockmeier, Craig A; Albert, Paul R

    2009-08-01

    Altered expression of serotonin-1A (5-HT1A) receptors, both presynaptic in the raphe nuclei and post-synaptic in limbic and cortical target areas, has been implicated in mood disorders such as major depression and anxiety. Within the 5-HT1A receptor gene, a powerful dual repressor element (DRE) is regulated by two protein complexes: Freud-1/CC2D1A and a second, unknown repressor. Here we identify human Freud-2/CC2D1B, a Freud-1 homologue, as the second repressor. Freud-2 distribution was examined with Northern and Western blot, reverse transcriptase polymerase chain reaction, and immunohistochemistry/immunofluorescence; Freud-2 function was examined by electrophoretic mobility shift, reporter assay, and Western blot. Freud-2 RNA was widely distributed in brain and peripheral tissues. Freud-2 protein was enriched in the nuclear fraction of human prefrontal cortex and hippocampus but was weakly expressed in the dorsal raphe nucleus. Freud-2 immunostaining was co-localized with 5-HT1A receptors, neuronal and glial markers. In prefrontal cortex, Freud-2 was expressed at similar levels in control and depressed male subjects. Recombinant hFreud-2 protein bound specifically to 5' or 3' human DRE adjacent to the Freud-1 site. Human Freud-2 showed strong repressor activity at the human 5-HT1A or heterologous promoter in human HEK-293 5-HT1A-negative cells and neuronal SK-N-SH cells, a model of postsynaptic 5-HT1A receptor-positive cells. Furthermore, small interfering RNA knockdown of endogenous hFreud-2 expression de-repressed 5-HT1A promoter activity and increased levels of 5-HT1A receptor protein in SK-N-SH cells. Human Freud-2 binds to the 5-HT1A DRE and represses the human 5-HT1A receptor gene to regulate its expression in non-serotonergic cells and neurons.

  16. Human fear acquisition deficits in relation to genetic variants of the corticotropin releasing hormone receptor 1 and the serotonin transporter.

    Directory of Open Access Journals (Sweden)

    Ivo Heitland

    Full Text Available The ability to identify predictors of aversive events allows organisms to appropriately respond to these events, and failure to acquire these fear contingencies can lead to maladaptive contextual anxiety. Recently, preclinical studies demonstrated that the corticotropin-releasing factor and serotonin systems are interactively involved in adaptive fear acquisition. Here, 150 healthy medication-free human subjects completed a cue and context fear conditioning procedure in a virtual reality environment. Fear potentiation of the eyeblink startle reflex (FPS was measured to assess both uninstructed fear acquisition and instructed fear expression. All participants were genotyped for polymorphisms located within regulatory regions of the corticotropin releasing hormone receptor 1 (CRHR1 - rs878886 and the serotonin transporter (5HTTLPR. These polymorphisms have previously been linked to panic disorder and anxious symptomology and personality, respectively. G-allele carriers of CRHR1 (rs878886 showed no acquisition of fear conditioned responses (FPS to the threat cue in the uninstructed phase, whereas fear acquisition was present in C/C homozygotes. Moreover, carrying the risk alleles of both rs878886 (G-allele and 5HTTLPR (short allele was associated with increased FPS to the threat context during this phase. After explicit instructions regarding the threat contingency were given, the cue FPS and context FPS normalized in all genotype groups. The present results indicate that genetic variability in the corticotropin-releasing hormone receptor 1, especially in interaction with the 5HTTLPR, is involved in the acquisition of fear in humans. This translates prior animal findings to the human realm.

  17. Long-lasting beneficial effects of central serotonin receptor 7 stimulation in female mice modeling Rett syndrome.

    Science.gov (United States)

    De Filippis, Bianca; Chiodi, Valentina; Adriani, Walter; Lacivita, Enza; Mallozzi, Cinzia; Leopoldo, Marcello; Domenici, Maria Rosaria; Fuso, Andrea; Laviola, Giovanni

    2015-01-01

    Rett syndrome (RTT) is a rare neurodevelopmental disorder, characterized by severe behavioral and physiological symptoms. Mutations in the methyl CpG binding protein 2 gene (MECP2) cause more than 95% of classic cases, and currently there is no cure for this devastating disorder. Recently we have demonstrated that specific behavioral and brain molecular alterations can be rescued in MeCP2-308 male mice, a RTT mouse model, by pharmacological stimulation of the brain serotonin receptor 7 (5-HT7R). This member of the serotonin receptor family-crucially involved in the regulation of brain structural plasticity and cognitive processes-can be stimulated by systemic repeated treatment with LP-211, a brain-penetrant selective 5-HT7R agonist. The present study extends previous findings by demonstrating that the LP-211 treatment (0.25 mg/kg, once per day for 7 days) rescues RTT-related phenotypic alterations, motor coordination (Dowel test), spatial reference memory (Barnes maze test) and synaptic plasticity (hippocampal long-term-potentiation) in MeCP2-308 heterozygous female mice, the genetic and hormonal milieu that resembles that of RTT patients. LP-211 also restores the activation of the ribosomal protein (rp) S6, the downstream target of mTOR and S6 kinase, in the hippocampus of RTT female mice. Notably, the beneficial effects on neurobehavioral and molecular parameters of a seven-day long treatment with LP-211 were evident up to 2 months after the last injection, thus suggesting long-lasting effects on RTT-related impairments. Taken together with our previous study, these results provide compelling preclinical evidence of the potential therapeutic value for RTT of a pharmacological approach targeting the brain 5-HT7R.

  18. Serotonergic innervation and serotonin receptor expression of NPY-producing neurons in the rat lateral and basolateral amygdaloid nuclei.

    Science.gov (United States)

    Bonn, M; Schmitt, A; Lesch, K-P; Van Bockstaele, E J; Asan, E

    2013-03-01

    Pharmacobehavioral studies in experimental animals, and imaging studies in humans, indicate that serotonergic transmission in the amygdala plays a key role in emotional processing, especially for anxiety-related stimuli. The lateral and basolateral amygdaloid nuclei receive a dense serotonergic innervation in all species studied to date. We investigated interrelations between serotonergic afferents and neuropeptide Y (NPY)-producing neurons, which are a subpopulation of inhibitory interneurons in the rat lateral and basolateral nuclei with particularly strong anxiolytic properties. Dual light microscopic immunolabeling showed numerous appositions of serotonergic afferents on NPY-immunoreactive somata. Using electron microscopy, direct membrane appositions and synaptic contacts between serotonin-containing axon terminals and NPY-immunoreactive cellular profiles were unequivocally established. Double in situ hybridization documented that more than 50 %, and about 30-40 % of NPY mRNA-producing neurons, co-expressed inhibitory 5-HT1A and excitatory 5-HT2C mRNA receptor subtype mRNA, respectively, in both nuclei with no gender differences. Triple in situ hybridization showed that individual NPY mRNA-producing interneurons co-express both 5-HT1A and 5-HT2C mRNAs. Co-expression of NPY and 5-HT3 mRNA was not observed. The results demonstrate that serotonergic afferents provide substantial innervation of NPY-producing neurons in the rat lateral and basolateral amygdaloid nuclei. Studies of serotonin receptor subtype co-expression indicate a differential impact of the serotonergic innervation on this small, but important, population of anxiolytic interneurons, and provide the basis for future studies of the circuitry underlying serotonergic modulation of emotional stimulus processing in the amygdala.

  19. Lifelong disturbance of serotonin transporter functioning results in fear learning deficits: Reversal by blockade of CRF1 receptors.

    Science.gov (United States)

    Bijlsma, Elisabeth Y; Hendriksen, Hendrikus; Baas, Johanna M P; Millan, Mark J; Groenink, Lucianne

    2015-10-01

    The inability to associate aversive events with relevant cues (i.e. fear learning) may lead to maladaptive anxiety. To further study the role of the serotonin transporter (SERT) in fear learning, classical fear conditioning was studied in SERT knockout rats (SERT(-/-)) using fear potentiation of the startle reflex. Next, fear acquisition and concomitant development of contextual conditioned fear were monitored during training. To differentiate between developmental and direct effects of reduced SERT functioning, effects of acute and chronic SSRI treatment were studied in adult rats. Considering the known interactions between serotonin and corticotropin-releasing factor (CRF), we studied the effect of the CRFR1 antagonist CP154,526 on behavioral changes observed and determined CRF1 receptor levels in SERT(-/-) rats. SERT(-/-) showed blunted fear potentiation and enhanced contextual fear, which resulted from a deficit in fear acquisition. Paroxetine treatment did not affect acquisition or expression of fear-potentiated startle, suggesting that disturbed fear learning in SERT(-/-) results from developmental changes and not from reduced SERT functioning. Although CRF1 receptor levels did not differ significantly between genotypes, CP154,526 treatment normalized both cue- and contextual fear in SERT(-/-) during acquisition, but not expression of fear-potentiated startle. The disrupted fear acquisition and concomitant increase in contextual conditioned fear-potentiated startle fear in SERT(-/-) resembles the associative learning deficit seen in patients with panic disorder and suggests that normal SERT functioning is crucial for the development of an adequate fear neuro-circuitry. Moreover, the normalization of fear acquisition by CP154,526 suggests a role for central CRF signaling in the generalization of fear.

  20. Long-lasting beneficial effects of central serotonin receptor 7 stimulation in female mice modeling Rett syndrome

    Directory of Open Access Journals (Sweden)

    Bianca eDe Filippis

    2015-04-01

    Full Text Available Rett syndrome (RTT is a rare neurodevelopmental disorder, characterized by severe behavioral and physiological symptoms. Mutations in the methyl CpG binding protein 2 gene (MECP2 cause more than 95% of classic cases, and currently there is no cure for this devastating disorder. Recently we have demonstrated that specific behavioral and brain molecular alterations can be rescued in MeCP2-308 male mice, a RTT mouse model, by pharmacological stimulation of the brain serotonin receptor 7 (5-HT7R. This member of the serotonin receptor family – crucially involved in the regulation of brain structural plasticity and cognitive processes – can be stimulated by systemic repeated treatment with LP-211, a brain-penetrant selective 5-HT7R agonist. The present study extends previous findings by demonstrating that the LP-211 treatment (0.25 mg/kg, once per day for 7 days rescues RTT-related phenotypic alterations, motor coordination (Dowel test, spatial reference memory (Barnes maze test and synaptic plasticity (hippocampal long-term-potentiation in MeCP2-308 heterozygous female mice, the genetic and hormonal milieu that resembles that of RTT patients. LP-211 also restores the activation of the ribosomal protein S6, the downstream target of mTOR and S6 kinase, in the hippocampus of RTT female mice. Notably, the beneficial effects on neurobehavioral and molecular parameters of a seven-day long treatment with LP-211 were evident up to two months after the last injection, thus suggesting long-lasting effects on RTT-related impairments. Taken together with our previous study, these results provide compelling preclinical evidence of the potential therapeutic value for RTT of a pharmacological approach targeting the brain 5-HT7R.

  1. Stimulation of glutamate receptors in the ventral tegmental area is necessary for serotonin-2 receptor-induced increases in mesocortical dopamine release

    Science.gov (United States)

    Pehek, E.A.; Hernan, A.E.

    2017-01-01

    Modulation of dopamine (DA) released by serotonin-2 (5-HT2) receptors has been implicated in the mechanism of action of antipsychotic drugs. The mesocortical DA system has been implicated particularly in the cognitive deficits observed in schizophrenia. Agonism at 5-HT2A receptors in the prefrontal cortex is associated with increases in cortical DA release. Evidence indicates that 5-HT2A receptors in the cortex regulate mesocortical DA release through stimulation of a “long-loop” feedback system from the PFC to the VTA and back. However, a causal role for VTA glutamate in the 5-HT2-induced increases in PFC DA has not been established. The present study does so by measuring 5-HT2 agonist-induced DA release in the cortex after infusions of glutamate antagonists into the VTA. Infusions of a combination of a NMDA (AP-5: 2-amino-5-phosphopentanoic acid) and an AMPA/kainate (CNQX: 6-cyano-7-nitroquinoxaline-2,3-dione) receptor antagonist into the VTA blocked the increases in cortical DA produced by administration of the 5-HT2 agonist DOI [(±)-2,5-Dimethoxy-4-iodoamphetamine] (2.5 mg/kg s.c.). These results demonstrate that stimulation of glutamate receptors in the VTA is necessary for 5-HT2 agonist-induced increases in cortical DA. PMID:25637799

  2. Endocannabinoids blunt the augmentation of synaptic transmission by serotonin 2A receptors in the nucleus tractus solitarii (nTS).

    Science.gov (United States)

    Austgen, James R; Kline, David D

    2013-11-06

    Serotonin (5-Hydroxytryptamine, 5-HT) and the 5-HT2 receptor modulate cardiovascular and autonomic function in part through actions in the nTS, the primary termination and integration point for cardiorespiratory afferents in the brainstem. In other brain regions, 5-HT2 receptors (5-HT2R) modify synaptic transmission directly, as well as through 5-HT2AR-induced endocannabinoid release. This study examined the role of 5-HT2AR as well as their interaction with endocannabinoids on neurotransmission in the nucleus tractus solitarii (nTS). Excitatory postsynaptic currents (EPSCs) in monosynaptic nTS neurons were recorded in the horizontal brainstem slice during activation and blockade of 5-HT2ARs. 5-HT2AR activation augmented solitary tract (TS) evoked EPSC amplitude whereas 5-HT2AR blockade depressed TS-EPSC amplitude at low and high TS stimulation rates. The 5-HT2AR-induced increase in neurotransmission was reduced by endocannabinoid receptor block and increased endogenous endocannabinoids in the synaptic cleft during high frequency, but not low, TS stimulation. Endocannabinoids did not tonically modify EPSCs. These data suggest 5-HT acting through the 5-HT2AR is an excitatory neuromodulator in the nTS and its effects are modulated by the endocannabinoid system.

  3. No hypothermic response to serotonin in 5-HT7 receptor knockout mice

    OpenAIRE

    Hedlund, P. B.; Danielson, P. E.; Thomas, E. A.; Slanina, K.; Carson, M.J.; Sutcliffe, J G

    2003-01-01

    With data from recently available selective antagonists for the 5-HT7 receptor, it has been hypothesized that 5-hydroxytryptamine (5-HT)-induced hypothermia is mediated by the 5-HT7 receptor, an effect previously attributed to other receptor subtypes. It has been established that the biologically active lipid oleamide allosterically interacts with the 5-HT7 receptor to regulate its transmission. The most well characterized effects of oleamide administration are induction of sleep and hypother...

  4. Serotonin-induced blood flow changes in the rat hindlegs after unilateral ligation of the femoral artery. Inhibition by the S2 receptor antagonist ketanserin.

    Science.gov (United States)

    Verheyen, A; Vlaminckx, E; Lauwers, F; Van Den Broeck, C; Wouters, L

    1984-08-01

    Collateral arteries can clearly be visualized in corrosion cast material after ligation of the femoral artery in rats. To characterize the influence of serotonin on the blood circulation under the experimental condition of unilateral ligation, we performed intermuscular thermoflow measurements. The data showed that intraperitoneal serotonin (8.7 and 20 mg.kg-1) injection markedly reduced the muscle temperature in both hindlegs. However, the effect was significantly more pronounced on the ligated side, where the blood was supplied through a collateral circulation, than on the non-ligated side with its normal arterial vasculature. Almost identical changes were obtained in rats with an early as well as in animals with a more advanced stage of collateral development (challenge with 8.7 mg.kg-1 serotonin). Evans blue dye experiments and angiographic data further revealed that, after challenge with 20 mg.kg-1 serotonin, the severe temperature decrease at the ligated side probably reflected a nearly complete blockage of blood supply. Pretreatment with the S2 receptor antagonist ketanserin (2.5 mg.kg-1) resulted in a significant reduction in the extent and duration of the serotonin-induced temperature decrease as revealed by the temperature measurements; such a treatment inhibited also the blockage in blood flow as seen with the other techniques. This study shows that serotonin, through its vasoconstrictive properties, can restrict the blood flow to the lower extremities of the rat, particularly when the blood is supplied through collateral circulation. This probably results in moderate to severe skeletal muscle ischaemia. It also suggests that the vasoconstriction is not only important in the inhibition of collateral blood flow in recently established collaterals but also in collateral vessels in a more advanced stage of development. The in vivo vasoconstriction and subsequent reduction of the blood supply caused by serotonin can be effectively counteracted by

  5. Effect of 5-hydroxytryptamine (serotonin) receptor inhibitors on the radiation-induced bystander effect.

    Science.gov (United States)

    Fazzari, Jennifer; Mersov, Anna; Smith, Richard; Seymour, Colin; Mothersill, Carmel

    2012-10-01

    To test the importance of serotonin as a signaling molecule involved in the production and response of radiation-induced bystander effects. HPV-G human keratinocyte cultures were spiked with various concentrations of Granisetron or Ketanserin and subject to either 0 Gy or 0.5 Gy X-irradiation to observe the inhibitor's effects on bystander signal production. Medium from these cultures was harvested and introduced to non- irradiated cultures of the same cell line to determine the clonogenic bystander response. Separate HPV-G cultures were set up for subsequent calcium measurements in response to irradiated cell conditioned medium (ICCM) in the presence or absence of Granisetron in an attempt to block bystander signal response. Granisetron and Ketanserin produced a dose-dependent propagation of the bystander effect in recipient cultures. Granisetron completely abolished the characteristic calcium pulse observed when non-irradiated cultures are exposed to irradiated cell medium in the presence of this drug. Serotonin-dependent mechanisms appear to be involved in bystander signal production and response to radiation in this system.

  6. CB-1 receptors modulate the effect of the selective serotonin reuptake inhibitor, citalopram on extracellular serotonin levels in the rat prefrontal cortex

    NARCIS (Netherlands)

    Kleijn, Jelle; Cremers, Thomas I. F. H.; Hofland, Corry M.; Westerink, Ben H. C.

    2011-01-01

    A large percentage of depressed individuals use drugs of abuse, like cannabis. This study investigates the impact of cannabis on the pharmacological effects of the antidepressant citalopram. Using microdialysis in the prefrontal cortex of rats we monitored serotonin levels before and after cannabino

  7. CB-1 receptors modulate the effect of the selective serotonin reuptake inhibitor, citalopram on extracellular serotonin levels in the rat prefrontal cortex

    NARCIS (Netherlands)

    Kleijn, Jelle; Cremers, Thomas I. F. H.; Hofland, Corry M.; Westerink, Ben H. C.

    2011-01-01

    A large percentage of depressed individuals use drugs of abuse, like cannabis. This study investigates the impact of cannabis on the pharmacological effects of the antidepressant citalopram. Using microdialysis in the prefrontal cortex of rats we monitored serotonin levels before and after cannabino

  8. Serotonin-3 Receptors in the Posterior Ventral Tegmental Area Regulate Ethanol Self-Administration of Alcohol-Preferring (P) Rats

    Science.gov (United States)

    Rodd, Zachary A.; Bell, Richard L.; Oster, Scott M.; Toalston, Jamie E.; Pommer, Tylene J.; McBride, William J.; Murphy, James M.

    2015-01-01

    Several studies indicated the involvement of serotonin-3 (5-HT3) receptors in regulating alcohol-drinking behavior. The objective of this study was to determine the involvement of 5-HT3 receptors within the ventral tegmental area (VTA) in regulating ethanol self-administration by alcohol-preferring (P) rats. Standard two-lever operant chambers were used to examine the effects of 7 consecutive bilateral micro-infusions of ICS205-930 (ICS), a 5-HT3 receptor antagonist, directly into the posterior VTA on the acquisition and maintenance of 15% (v/v) ethanol self-administration. P rats readily acquired ethanol self-administration by the 4th session. The three highest doses (0.125, 0.25 and 1.25 ug) of ICS prevented acquisition of ethanol self-administration. During the acquisition post-injection period, all rats treated with ICS demonstrated higher responding on the ethanol lever, with the highest dose producing the greatest effect. In contrast, during the maintenance phase, the 3 highest doses (0.75, 1.0 and 1.25 ug) of ICS significantly increased responding on the ethanol lever; following the 7-day dosing regimen, responding on the ethanol lever returned to control levels. Micro-infusion of ICS into the posterior VTA did not alter the low responding on the water lever, and did not alter saccharin (0.0125% w/v) self-administration.. Micro-infusion of ICS into the anterior VTA did not alter ethanol self-administration. Overall, the results of this study suggest that 5-HT3 receptors in the posterior VTA of the P rat may be involved in regulating ethanol self-administration. In addition, chronic operant ethanol self-administration, and/or repeated treatments with a 5-HT3 receptor antagonist may alter neuronal circuitry within the posterior VTA. PMID:20682192

  9. Control of sensory neuron excitability by serotonin involves 5HT2C receptors and Ca(2+)-activated chloride channels.

    Science.gov (United States)

    Salzer, Isabella; Gantumur, Enkhbileg; Yousuf, Arsalan; Boehm, Stefan

    2016-11-01

    Serotonin (5HT) is a constituent of the so-called "inflammatory soup" that sensitizes nociceptors during inflammation. Nevertheless, receptors and signaling mechanisms that mediate an excitation of dorsal root ganglion (DRG) neurons by 5HT remained controversial. Therefore, capsaicin-sensitive nociceptive neurons dissociated from rat DRGs were used to investigate effects of 5HT on membrane excitability and currents through ligand- as well as voltage-gated ion channels. In 58% of the neurons tested, 5HT increased action potential firing, an effect that was abolished by the 5HT2 receptor antagonist ritanserin, but not by the 5HT3 antagonist tropisetron. Unlike other algogenic mediators, such as PGE2 and bradykinin, 5HT did not affect currents through TTX-resistant Na(+) channels or Kv7 K(+) channels. In all neurons investigated, 5HT potentiated capsaicin-evoked currents through TRPV1 channels, an effect that was attenuated by antagonists at 5HT2A (4 F 4 PP), 5HT2B (SB 204741), as well as 5HT2C (RS 102221) receptors. 5HT triggered slowly arising inward Cl(-) currents in 53% of the neurons. This effect was antagonized by the 5HT2C receptor blocker only, and the current was prevented by an inhibitor of Ca(2+)-activated chloride channels (CaCC). The 5HT-induced increase in action potential firing was also abolished by this CaCC blocker and by the TRPV1 inhibitor capsazepine. Amongst the subtype selective 5HT2 antagonists, only RS 102221 (5HT2C-selectively) counteracted the rise in action potential firing elicited by 5HT. These results show that 5HT excites DRG neurons mainly via 5HT2C receptors which concomitantly mediate a sensitization of TRPV1 channels and an opening of CaCCs.

  10. Serotonin and the 5-HT7 receptor: the link between hepatocytes, IGF-1 and small intestinal neuroendocrine tumors.

    Science.gov (United States)

    Svejda, Bernhard; Kidd, Mark; Timberlake, Andrew; Harry, Kathy; Kazberouk, Alexander; Schimmack, Simon; Lawrence, Ben; Pfragner, Roswitha; Modlin, Irvin M

    2013-07-01

    Platelet-derived serotonin (5-HT) is involved in liver regeneration. The liver is also the metastatic site for malignant enterochromaffin (EC) cell "carcinoid" (neuroendocrine) neoplasms, the principal cellular source of 5-HT. We hypothesized that 5-HT produced by metastatic EC cells played a role in the hepatic tumor-microenvironment principally via 5-HT₇ receptor-mediated activation of hepatocyte IGF-1 synthesis and secretion. Using isolated rat hepatocytes, we evaluated 5-HT₇ receptor expression (using PCR, sequencing and western blot). ELISA, cell transfection and western blots delineated 5-HT-mediated signaling pathways (pCREB, AKT and ERK). IGF-1 synthesis/secretion was evaluated using QPCR and ELISA. IGF-1 was tested on small intestinal neuroendocrine neoplasm proliferation, while IGF-1 production and 5-HT₇ expression were examined in an in vivo SCID metastasis model. Our results demonstrated evidence for a functional 5-HT₇ receptor. 5-HT activated cAMP/PKA activity, pCREB (130-205%, P < 0.05) and pERK/pAKT (1.2-1.75, P < 0.05). Signaling was reversed by the 5-HT₇ receptor antagonist SB269970. IGF-1 significantly stimulated proliferation of two small intestinal neuroendocrine neoplasm cell lines (EC₅₀: 7-70 pg/mL) and could be reversed by the small molecule inhibitor BMS-754807. IGF-1 and 5-HT were elevated (40-300×) in peri-tumoral hepatic tissue in nude mice, while 5-HT₇ was increased fourfold compared to sham-operated animals. We conclude that hepatocytes express a cAMP-coupled 5-HT₇ receptor, which, at elevated 5-HT concentrations that occur in liver metastases, signals via CREB/AKT and is linked to IGF-1 synthesis and secretion. Because IGF-1 regulates NEN proliferation, identification of a role for 5-HT₇ in the hepatic metastatic tumor microenvironment suggests the potential for novel therapeutic strategies for amine-producing mid-gut tumors.

  11. Cerebral 5-HT2A receptor and serotonin transporter binding in humans are not affected by the val66met BDNF polymorphism status or blood BDNF levels

    DEFF Research Database (Denmark)

    Klein, Anders Bue; Trajkovska, Viktorija; Erritzoe, David;

    2010-01-01

    Recent studies have proposed an interrelation between the brain-derived neurotrophic factor (BDNF) val66met polymorphism and the serotonin system. In this study, we investigated whether the BDNF val66met polymorphism or blood BDNF levels are associated with cerebral 5-hydroxytryptamine 2A (5-HT(2A......)) receptor or serotonin transporter (SERT) binding in healthy subjects. No statistically significant differences in 5-HT(2A) receptor or SERT binding were found between the val/val and met carriers, nor were blood BDNF values associated with SERT binding or 5-HT(2A) receptor binding. In conclusion, val66met...... BDNF polymorphism status is not associated with changes in the serotonergic system. Moreover, BDNF levels in blood do not correlate with either 5-HT(2A) or SERT binding....

  12. Antinociceptive interactions between Mu-opioid receptor agonists and the serotonin uptake inhibitor clomipramine in rhesus monkeys: role of Mu agonist efficacy.

    Science.gov (United States)

    Banks, Matthew L; Rice, Kenner C; Negus, S Stevens

    2010-11-01

    Mu-opioid agonists are effective analgesics but have undesirable effects such as sedation and abuse liability that limit their clinical effectiveness. Serotonergic systems also modulate nociception, and serotonin uptake inhibitors may be useful as adjuncts to enhance analgesic effects and/or attenuate undesirable effects of mu agonists. This study examined the effects of the serotonin uptake inhibitor clomipramine on behavioral effects produced in rhesus monkeys by mu agonists with varying efficacy at mu receptors (nalbuphine morphine > methadone. In the assay of capsaicin-induced allodynia, nalbuphine produced dose-dependent antiallodynia. Clomipramine alone was inactive, but as in the assay of thermal nociception, it produced a proportion-dependent enhancement in the effects of nalbuphine. These findings suggest that serotonin uptake inhibitors can selectively enhance the antinociceptive effects of mu agonists in nonhuman primates. These effects of serotonin uptake inhibitors may depend on the proportion of the serotonin uptake inhibitor and the efficacy of the mu agonist. The greatest enhancement was observed with intermediate proportions of clomipramine in combination with the low-efficacy mu agonist nalbuphine.

  13. Impact of RNA editing on functions of the serotonin 2C receptor in vivo

    Directory of Open Access Journals (Sweden)

    Uade B Olaghere Da Silva

    2010-03-01

    Full Text Available Transcripts encoding 5-HT2C receptors are modified posttranscriptionally by RNA editing, generating up to 24 protein isoforms. In recombinant cells, the fully edited isoform, 5-HT2C-VGV, exhibits blunted G-protein coupling and reduced constitutive activity. The present studies examine the signal transduction properties of 5-HT2C-VGV receptors in brain to determine the in vivo consequences of altered editing. Using mice solely expressing the 5-HT2C-VGV receptor (VGV/Y, we demonstrate reduced G-protein coupling efficiency and high-affinity agonist binding of brain 5-HT2C-VGV receptors. However, enhanced behavioral sensitivity to a 5-HT2C receptor agonist was also seen in mice expressing 5-HT2C-VGV receptors, an unexpected finding given the blunted G-protein coupling. In addition, mice expressing 5-HT2C-VGV receptors had greater sensitivity to a 5-HT2C inverse agonist/antagonist enhancement of dopamine turnover relative to wild-type mice. These behavioral and biochemical results are most likely explained by increases in 5-HT2C receptor binding sites in the brains of mice solely expressing -5HT2C-VGV receptors. We conclude that 5-HT2C-VGV receptor signaling in brain is blunted, but this deficiency is masked by a marked increase in 5HT2C receptor binding site density in mice solely expressing the VGV isoform. These findings suggest that RNA editing may regulate the density of 5-HT2C receptor binding sites in brain. We further caution that the pattern of 5-HT2C receptor RNA isoforms may not reflect the pattern of protein isoforms, and hence the inferred overall function of the receptor.

  14. The inhibitory effect of combination treatment with leptin and cannabinoid CB1 receptor agonist on food intake and body weight gain is mediated by serotonin 1B and 2C receptors.

    Science.gov (United States)

    Wierucka-Rybak, M; Wolak, M; Juszczak, M; Drobnik, J; Bojanowska, E

    2016-06-01

    Previous studies reported that the co-injection of leptin and cannabinoid CB1 receptor antagonists reduces food intake and body weight in rats, and this effect is more profound than that induced by these compounds individually. Additionally, serotonin mediates the effects of numerous anorectic drugs. To investigate whether serotonin interacts with leptin and endocannabinoids to affect food intake and body weight, we administered 5-hydroxytryptamine(HT)1B and 5-hydroxytryptamine(HT)2C serotonin receptor antagonists (3 mg/kg GR 127935 and 0.5 mg/kg SB 242084, respectively) to male Wistar rats treated simultaneously with leptin (100 μg/kg) and the CB1 receptor inverse agonist AM 251 (1 mg/kg) for 3 days. In accordance with previous findings, the co-injection of leptin and AM 251, but not the individual injection of each drug, resulted in a significant decrease in food intake and body weight gain. Blockade of the 5-HT1B and 5-HT2C receptors completely abolished the leptin- and AM 251-induced anorectic and body-weight-reducing effects. These results suggest that serotonin mediates the leptin- and AM 251-dependent regulation of feeding behavior in rats via the 5-HT1B and 5-HT2C receptors.

  15. Suppression of piriform cortex activity in rat by corticotropin-releasing factor 1 and serotonin 2A/C receptors

    Directory of Open Access Journals (Sweden)

    Chakravarthi eNarla

    2015-05-01

    Full Text Available The piriform cortex (PC is richly innervated by Corticotropin-releasing factor (CRF and Serotonin (5-HT containing axons arising from central amygdala and Raphe nucleus. CRFR1 and 5-HT2A/2CRs have been shown to interact in manner where CRFR activation subsequently potentiates the activity of 5-HT2A/2CRs. The purpose of this study was to determine how the activation of CRFR1 and/or 5-HT2Rs modulates PC activity at both the circuit and cellular level. Voltage sensitive dye imaging showed that CRF acting through CRFR1 dampened activation of the layer II of PC and interneurons of endopiriform nucleus. Application of the selective 5-HT2A/CR agonist 2,5-dimethoxy-4-iodoamphetamine (DOI following CRFR1 activation potentiated this effect. Blocking the interaction between CRFR1 and 5-HT2R with a Tat-CRFR1-CT peptide abolished this potentiation. Application of forskolin did not mimic CRFR1 activity but instead blocked it, while a protein kinase A antagonist had no effect. However, activation and antagonism of protein kinase C (PKC either mimicked or blocked CRF modulation respectively. DOI had no effect when applied alone indicating that the prior activation of CRFR1 receptors was critical for DOI to show significant effects similar to CRF. Patch clamp recordings showed that both CRF and DOI reduced the synaptic responsiveness of layer II pyramidal neurons. CRF had highly variable effects on interneurons within layer III, both increasing and decreasing their excitability, but DOI had no effect on the excitability of this group of neurons. These data show that CRF and serotonin, acting through both CRFR1 and 5-HT2A/CRs, reduce the activation of the PC. This modulation may be an important blunting mechanism of stressor behaviours mediated through the olfactory cortex.

  16. Pharmacological characterization of dopamine, norepinephrine and serotonin release in the rat prefrontal cortex by neuronal nicotinic acetylcholine receptor agonists.

    Science.gov (United States)

    Rao, Tadimeti S; Correa, Lucia D; Adams, Pamala; Santori, Emily M; Sacaan, Aida I

    2003-11-14

    Neuronal nicotinic acetylcholine receptors (nAChRs) modulate synaptic transmission by regulating neurotransmitter release, an action that involves multiple nAChRs. The effects of four nAChR agonists, nicotine (NIC), 1,1-dimethyl-4-phenylpiperzinium iodide (DMPP), cytisine (CYT) and epibatidine (EPI) were investigated on [3H]-norepinephrine (NE), [3H]-dopamine (DA) and [3H]-serotonin (5-HT) release from rat prefrontal cortical (PFC) slices. All four agonists evoked [3H]-DA release to a similar magnitude but with a differing rank order of potency of EPI>DMPP approximately NIC approximately CYT. Similarly, all four agonists also increased [3H]-NE release, but with a differing rank order of potency of EPI>CYT approximately DMPP>NIC. NIC-induced [3H]-NE and [3H]-DA release responses were both calcium-dependent and attenuated by the sodium channel antagonist, tetrodotoxin (TTX) and by the nAChR antagonists mecamylamine (MEC) and dihydro-beta-erythroidine (DHbetaE), but not by D-tubocurare (D-TC). The modulation of [3H]-5-HT release by nAChR agonists was distinct from that seen for catecholamines. DMPP produced robust increases with minimal release observed with other agonists. DMPP-induced [3H]-5-HT release was neither sensitive to known nAChR antagonists nor dependent on external calcium. The differences between nicotinic agonist induced catecholamine and serotonin release suggest involvement of distinct nAChRs.

  17. Photoperiod regulates genes encoding melanocortin 3 and serotonin receptors and secretogranins in the dorsomedial posterior arcuate of the Siberian hamster.

    Science.gov (United States)

    Nilaweera, K N; Archer, Z A; Campbell, G; Mayer, C-D; Balik, A; Ross, A W; Mercer, J G; Ebling, F J P; Morgan, P J; Barrett, P

    2009-02-01

    The mechanism(s) involved in the regulation of the seasonal-appropriate body weight of the Siberian hamster are currently unknown. We have identified photoperiodically regulated genes including VGF in a sub-region of the arcuate nucleus termed the dorsomedial posterior arcuate (dmpARC). Gene expression changes in this nucleus so far account for a significant number of those reported as photoperiodically regulated and are therefore likely to contribute to seasonal physiological responses of the hamsters. The present study aimed to identify additional genes expressed in the dmpARC regulated by photoperiod that could be involved in regulating the activity of this nucleus with respect to seasonal physiology of the Siberian hamster. Using laser capture microdissection coupled with a microarray analysis and a candidate gene approach, we have identified several photoperiodically regulated genes in the dmpARC that are known to have roles in secretory and intracellular signalling pathways. These include secretogranin (sg) III and SgVI (secretory pathway), melanocortin 3 receptor (MC3-R) and serotonin (5-HT) receptors 2A and 7 (signalling pathway), all of which increase in expression under a short photoperiod. The spatial relationship between receptor signalling and potential secretory pathways was investigated by dual in situ hybridisation, which revealed that 5-HT2A and 5-HT7 receptors are expressed in neurones expressing VGF mRNA and that a sub-population (approximately 40%) of these neurones express MC3-R. These gene expression changes in dmpARC neurones may reflect the functional requirement of these neurones for seasonal physiological responses of the hamster.

  18. Expression of hippocampal serotonin receptors 5-HT2C and 5-HT5A in a rat model of diet-induced obesity supplemented with tryptophan.

    Science.gov (United States)

    Lopez-Esparza, Sarahi; Berumen, Laura C; Padilla, Karla; Miledi, Ricardo; García-Alcocer, Guadalupe

    2015-05-01

    Food intake regulation is a complex mechanism that involves endogenous substances and central nervous system structures like hypothalamus or even hippocampus. The neurotransmitter serotonin is distinguished as food intake mediator; within its multiples receptors, the 5-HT2C type is characterized by its inhibitory appetite action but there is no information about 5-HT5A receptors involvement in obesity disease. It is also unknown if there are any changes in the receptors expression in rats hippocampus with induced obesity during development through a high energy diet (HED) supplemented with tryptophan (W). To appreciate the receptors expression pattern in the hippocampus, obesity was induced to young Sprague Dawley rats through a HED and supplemented with W. Immunocytochemical and western blot techniques were used to study the receptor distribution and quantify the protein expression. The rats with HED diet developed obesity until week 13 of treatment. The 5-HT2C receptor expression decreased in CA1, CA2, CA3 and DG of HED group; and also in CA2, CA3 and DG for HEDW group. The 5-HT5A receptor expression only decreased in DG for HED group. Variations of the two serotonin receptors subtypes support their potential role in obesity.

  19. A PrP(C)-caveolin-Lyn complex negatively controls neuronal GSK3β and serotonin 1B receptor.

    Science.gov (United States)

    Hernandez-Rapp, Julia; Martin-Lannerée, Séverine; Hirsch, Théo Z; Pradines, Elodie; Alleaume-Butaux, Aurélie; Schneider, Benoît; Baudry, Anne; Launay, Jean-Marie; Mouillet-Richard, Sophie

    2014-05-08

    The cellular prion protein, PrP(C), is a glycosylphosphatidylinositol-anchored protein, abundant in lipid rafts and highly expressed in the brain. While PrP(C) is much studied for its involvement under its abnormal PrP(Sc) isoform in Transmissible Spongiform Encephalopathies, its physiological role remains unclear. Here, we report that GSK3β, a multifunctional kinase whose inhibition is neuroprotective, is a downstream target of PrP(C) signalling in serotonergic neuronal cells. We show that the PrP(C)-dependent inactivation of GSK3β is relayed by a caveolin-Lyn platform located on neuronal cell bodies. Furthermore, the coupling of PrP(C) to GSK3β potentiates serotonergic signalling by altering the distribution and activity of the serotonin 1B receptor (5-HT1BR), a receptor that limits neurotransmitter release. In vivo, our data reveal an increased GSK3β kinase activity in PrP-deficient mouse brain, as well as sustained 5-HT1BR activity, whose inhibition promotes an anxiogenic behavioural response. Collectively, our data unveil a new facet of PrP(C) signalling that strengthens neurotransmission.

  20. S100B interacts with the serotonin 5-HT7 receptor to regulate a depressive-like behavior.

    Science.gov (United States)

    Stroth, Nikolas; Svenningsson, Per

    2015-12-01

    The serotonin 5-HT7 receptor (5-HT7) is an emerging target for psychiatric pharmacotherapy. Recent observations in rodent models and humans suggest that its blockade mediates antidepressant efficacy. In the present study, we identify the Ca(2+)-binding protein S100B as an interacting partner of 5-HT7 and show that S100B negatively regulates inducible cyclic AMP (cAMP) accumulation in transfected HeLa cells and mouse cortical astrocytes. Overexpression of S100B causes brain region-specific dysregulation of the cAMP pathway in vivo, such that concentrations of cAMP in the frontal cortex are higher in S100B transgenic female mice compared to wild-types. Finally, S100B transgenic female mice show depressive-like behavior in the forced swim test (FST) and pharmacological blockade of 5-HT7 with SB269970 normalizes FST behavior. Taken together, our results show that S100B affects behavioral despair in female mice through functional interaction with the 5-HT7 receptor. Furthermore, we identify S100B as a cAMP-regulatory protein in cultured astrocytes and the murine frontal cortex. Future experiments will clarify whether there is a direct link between the 5-HT7-associated and cAMP-regulatory actions of S100B.

  1. Using psilocybin to investigate the relationship between attention, working memory, and the serotonin 1A and 2A receptors.

    Science.gov (United States)

    Carter, Olivia L; Burr, David C; Pettigrew, John D; Wallis, Guy M; Hasler, Felix; Vollenweider, Franz X

    2005-10-01

    Increasing evidence suggests a link between attention, working memory, serotonin (5-HT), and prefrontal cortex activity. In an attempt to tease out the relationship between these elements, this study tested the effects of the hallucinogenic mixed 5-HT1A/2A receptor agonist psilocybin alone and after pretreatment with the 5-HT2A antagonist ketanserin. Eight healthy human volunteers were tested on a multiple-object tracking task and spatial working memory task under the four conditions: placebo, psilocybin (215 microg/kg), ketanserin (50 mg), and psilocybin and ketanserin. Psilocybin significantly reduced attentional tracking ability, but had no significant effect on spatial working memory, suggesting a functional dissociation between the two tasks. Pretreatment with ketanserin did not attenuate the effect of psilocybin on attentional performance, suggesting a primary involvement of the 5-HT1A receptor in the observed deficit. Based on physiological and pharmacological data, we speculate that this impaired attentional performance may reflect a reduced ability to suppress or ignore distracting stimuli rather than reduced attentional capacity. The clinical relevance of these results is also discussed.

  2. PRX-00023, a selective serotonin 1A receptor agonist, reduces ultrasonic vocalizations in infant rats bred for high infantile anxiety.

    Science.gov (United States)

    Brunelli, Susan A; Aviles, Jessica A; Gannon, Kimberly S; Branscomb, Aron; Shacham, Sharon

    2009-11-01

    To address the development of early anxiety disorders across the lifespan, the High USV line of rats was bred based on rates of infant ultrasonic vocalization in the 40-50 kHz range of predominant frequencies (USV) to maternal separation at postnatal day (P) 10. In this study, rates of USV in High line infants (pups: Postnatal Day 11+/-1) were compared to those of randomly-bred controls in response to EPIX compound PRX-00023, a unique serotonin (5-HT) agonist, acting exclusively at the 5-HT1A receptor, or buspirone, a nonspecific 5HT1A agonist. After testing, pups were examined for sedation and other drug-related effects. The results indicated that all doses of buspirone reduced USV rates in isolation, consistent with other reports. PRX-00023 significantly reduced USV rates at the lowest doses (0.01-0.05 mg/kg). None of the PRX-00023 doses produced sedation, whereas all but the lowest dose of buspirone (0.1 mg/kg) produced sedation effects. The results suggest that this compound alleviates infantile anxiety-like behavior with great specificity in rats bred for high anxiety/depressive phenotypes by selectively targeting 5-HT1A receptors, possibly by both pre- and post-synaptic mechanisms.

  3. DREADD Modulation of Transplanted DA Neurons Reveals a Novel Parkinsonian Dyskinesia Mechanism Mediated by the Serotonin 5-HT6 Receptor.

    Science.gov (United States)

    Aldrin-Kirk, Patrick; Heuer, Andreas; Wang, Gang; Mattsson, Bengt; Lundblad, Martin; Parmar, Malin; Björklund, Tomas

    2016-06-01

    Transplantation of DA neurons is actively pursued as a restorative therapy in Parkinson's disease (PD). Pioneering clinical trials using transplants of fetal DA neuroblasts have given promising results, although a number of patients have developed graft-induced dyskinesias (GIDs), and the mechanism underlying this troublesome side effect is still unknown. Here we have used a new model where the activity of the transplanted DA neurons can be selectively modulated using a bimodal chemogenetic (DREADD) approach, allowing either enhancement or reduction of the therapeutic effect. We show that exclusive activation of a cAMP-linked (Gs-coupled) DREADD or serotonin 5-HT6 receptor, located on the grafted DA neurons, is sufficient to induce GIDs. These findings establish a mechanistic link between the 5-HT6 receptor, intracellular cAMP, and GIDs in transplanted PD patients. This effect is thought to be mediated through counteraction of the D2 autoreceptor feedback inhibition, resulting in a dysplastic DA release from the transplant.

  4. Drug: D06396 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D06396 Drug Renzapride (INN) C16H22ClN3O2 323.1401 323.8178 D06396.gif 5-HT4-recept...r08310] G Protein-coupled receptors Rhodopsin family Serotonin 5-HT4-receptor [HSA:3360] [KO:K04160] Renzapride D06396 Renzapride

  5. Expresion of 5 - Hydroxytryptamine 4 Receptor in Congenital Hirschsprung's Disease and Hirschsprung's Allied Disease%5-羟色胺4受体在先天性巨结肠和同源病中的表达

    Institute of Scientific and Technical Information of China (English)

    朱旭; 魏明发; 卞红强; 段栩飞

    2012-01-01

    目的 探讨5-羟色胺4(5-HT4)受体在先天性巨结肠(HD)和先天性巨结肠同源病(HAD)中的表达,并研究能否将此检测应用于HD和HAD的术前鉴别诊断.方法 共收集HD标本25例(HD组)、HAD标本20例(HAD组)和正常结肠标本15例(正常对照组).应用免疫组织化学SP法染色,分析5-HT4受体表达的部位及肠管不同部位5-HT4受体表达水平强度的差异.采用t检验比较其表达是否存在差异性.结果 HD组5-HT4受体阳性指数在远端黏膜层较近端表达下降,肌间神经丛无表达;HAD组远端5 -HT4受体阳性指数在黏膜层和肌间神经丛中均显著低于近端.与正常对照组比较,HD组和HAD组5-HT4受体阳性指数在黏膜及肌间神经从表达均下降.结论 5 -HT4受体在HD及HAD中的表达水平可作为术前鉴别诊断的参考指标之一,也为临床治疗提供新的参考指标.%Objective To explore the role of 5 - hydroxytryptamine 4(5 - HT4) receptor in the pathogenesis of Hirschsprung disease (HD)and Hirschsprung's allied disorder (HAD) .and to research whether the study could be used for preoperative diagnosis of HD and HAD. Methods Twenty -five cases of HD specimens( HD group) .20 cases of HAD specimens( HAD group) and 15 normal colon specimens (normal control group) were collected. SP irnmunorustochemical staining was used to analyze 5 - HT4 receptor sites and the differences of 5 - HT4 receptor sites expression levels in different parts of intestines. T - test was adopted to compare the expression differences. Results In HD group, 5 - HT4 receptors in the distal end of mucosa decreased compared with the proximal end, while 5 - HT4 receptors were not expressed in the mye-nteric plexus of the proximal end. In HAD group, the number of 5 - HT4 receptors also decreased in the distal mucosa and myenteric plexus. Compared with the normal control group ,5 - HT4 receptor expression decreased in HD group and HAD group. Conclusion 5 - HT4 receptors in HD/HAD can

  6. Downregulation of 5-HT7 Serotonin Receptors by the Atypical Antipsychotics Clozapine and Olanzapine. Role of Motifs in the C-Terminal Domain and Interaction with GASP-1.

    Science.gov (United States)

    Manfra, Ornella; Van Craenenbroeck, Kathleen; Skieterska, Kamila; Frimurer, Thomas; Schwartz, Thue W; Levy, Finn Olav; Andressen, Kjetil Wessel

    2015-07-15

    The human 5-HT7 serotonin receptor, a G-protein-coupled receptor (GPCR), activates adenylyl cyclase constitutively and upon agonist activation. Biased ligands differentially activate 5-HT7 serotonin receptor desensitization, internalization and degradation in addition to G protein activation. We have previously found that the atypical antipsychotics clozapine and olanzapine inhibited G protein activation and, surprisingly, induced both internalization and lysosomal degradation of 5-HT7 receptors. Here, we aimed to determine the mechanism of clozapine- and olanzapine-mediated degradation of 5-HT7 receptors. In the C-terminus of the 5-HT7 receptor, we identified two YXXΦ motifs, LR residues, and a palmitoylated cysteine anchor as potential sites involved in receptor trafficking to lysosomes followed by receptor degradation. Mutating either of these sites inhibited clozapine- and olanzapine-mediated degradation of 5-HT7 receptors and also interfered with G protein activation. In addition, we tested whether receptor degradation was mediated by the GPCR-associated sorting protein-1 (GASP-1). We show that GASP-1 binds the 5-HT7 receptor and regulates the clozapine-mediated degradation. Mutations of the identified motifs and residues, located in or close to Helix-VIII of the 5-HT7 receptor, modified antipsychotic-stimulated binding of proteins (such as GASP-1), possibly by altering the flexibility of Helix-VIII, and also interfered with G protein activation. Taken together, our data demonstrate that binding of clozapine or olanzapine to the 5-HT7 receptor leads to antagonist-mediated lysosomal degradation by exposing key residues in the C-terminal tail that interact with GASP-1.

  7. Alterations in serotonin, transient receptor potential channels and protease-activated receptors in rats with irritable bowel syndrome attenuated by Shugan decoction.

    Science.gov (United States)

    Shi, Hai-Lian; Liu, Chu-Hsuan; Ding, Li-Li; Zheng, Yu; Fei, Xiao-Yan; Lu, Lu; Zhou, Xue-Ming; Yuan, Jian-Ye; Xie, Jian-Qun

    2015-04-28

    To determine the molecular mechanisms of Shugan decoction (SGD) in the regulation of colonic motility and visceral hyperalgesia (VHL) in irritable bowel syndrome (IBS). The chemical compounds contained in SGD were measured by high-performance liquid chromatography. A rat model of IBS was induced by chronic water avoidance stress (WAS). The number of fecal pellets was counted after WAS and the pain pressure threshold was measured by colorectal distension. Morphological changes in colonic mucosa were detected by hematoxylin-eosin staining. The contents of tumor necrosis factor (TNF)-α in colonic tissue and calcitonin-gene-related peptide (CGRP) in serum were measured by ELISA. The protein expression of serotonin [5-hydroxytryptamide (5-HT)], serotonin transporter (SERT), chromogranin A (CgA) and CGRP in colon tissue was measured by immunohistochemistry. SGD inhibited colonic motility dysfunction and VHL in rats with IBS. Blockers of transient receptor potential (TRP) vanilloid 1 (TRPV1) (Ruthenium Red) and TRP ankyrin-1 (TRPA1) (HC-030031) and activator of protease-activated receptor (PAR)4 increased the pain pressure threshold, whereas activators of PAR2 and TRPV4 decreased the pain pressure threshold in rats with IBS. The effect of SGD on pain pressure threshold in these rats was abolished by activators of TRPV1 (capsaicin), TRPV4 (RN1747), TRPA1 (Polygodial) and PAR2 (AC55541). In addition, CGRP levels in serum and colonic tissue were both increased in these rats. TNF-α level in colonic tissue was also significantly upregulated. However, the levels of 5-HT, SERT and CgA in colonic tissue were decreased. All these pathological changes in rats with IBS were attenuated by SGD. SGD alleviated VHL and attenuated colon motility in IBS, partly by regulating TRPV1, TRPV4, TRPA1, PAR2, 5-HT, CgA and SERT, and reducing CGRP and TNF-α level.

  8. Serotonin (5-HT) regulates neurite outgrowth through 5-HT1A and 5-HT7 receptors in cultured hippocampal neurons.

    Science.gov (United States)

    Rojas, Paulina S; Neira, David; Muñoz, Mauricio; Lavandero, Sergio; Fiedler, Jenny L

    2014-08-01

    Serotonin (5-HT) production and expression of 5-HT receptors (5-HTRs) occur early during prenatal development. Recent evidence suggests that, in addition to its classical role as a neurotransmitter, 5-HT regulates neuronal connectivity during mammalian development by modulating cell migration and neuronal cytoarchitecture. Given the variety of 5-HTRs, researchers have had difficulty clarifying the specific role of each receptor subtype in brain development. Signalling mediated by the G-protein-coupled 5-HT1A R and 5-HT7 R, however, has been associated with neuronal plasticity. Thus, we hypothesized that 5-HT promotes neurite outgrowth through 5-HT1A R and 5-HT7 R. The involvement of 5-HT1A R and 5-HT7 R in the morphology of rat hippocampal neurons was evaluated by treating primary cultures at 2 days in vitro with 5-HT and specific antagonists for 5-HT1A R and 5-HT7 R (WAY-100635 and SB269970, respectively). The stimulation of hippocampal neurons with 100 nM 5-HT for 24 hr produced no effect on either the number or the length of primary neurites. Nonetheless, after 5HT7 R was blocked, the addition of 5-HT increased the number of primary neurites, suggesting that 5HT7 R could inhibit neuritogenesis. In contrast, 5-HT induced secondary neurite outgrowth, an effect inhibited by 1 μM WAY-100635 or SB269970. These results suggest that both serotonergic receptors participate in secondary neurite outgrowth. We conclude that 5-HT1A R and 5-HT7 R regulate neuronal morphology in primary hippocampal cultures by promoting secondary neurite outgrowth.

  9. Urocortin1-induced anorexia is regulated by activation of the serotonin 2C receptor in the brain.

    Science.gov (United States)

    Harada, Yumi; Takayama, Kiyoshige; Ro, Shoki; Ochiai, Mitsuko; Noguchi, Masamichi; Iizuka, Seiichi; Hattori, Tomohisa; Yakabi, Koji

    2014-01-01

    This study was conducted to determine the mechanisms by which serotonin (5-hydroxytryptamine, 5-HT) receptors are involved in the suppression of food intake in a rat stress model and to observe the degree of activation in the areas of the brain involved in feeding. In the stress model, male Sprague-Dawley rats (8 weeks old) were given intracerebroventricular injections of urocortin (UCN) 1. To determine the role of the 5-HT2c receptor (5-HT2cR) in the decreased food intake in UCN1-treated rats, specific 5-HT2cR or 5-HT2b receptor (5-HT2bR) antagonists were administered. Food intake was markedly reduced in UCN1-injected rats compared with phosphate buffered saline treated control rats. Intraperitoneal administration of a 5-HT2cR antagonist, but not a 5-HT2bR antagonist, significantly inhibited the decreased food intake. To assess the involvement of neural activation, we tracked the expression of c-fos mRNA as a neuronal activation marker. Expression of the c-fos mRNA in the arcuate nucleus, ventromedial hypothalamic nucleus (VMH) and rostral ventrolateral medulla (RVLM) in UNC1-injected rats showed significantly higher expression than in the PBS-injected rats. Increased c-fos mRNA was also observed in the paraventricular nucleus (PVN), the nucleus of the solitary tract (NTS), and the amygdala (AMG) after injection of UCN1. Increased 5-HT2cR protein expression was also observed in several areas. However, increased coexpression of 5-HT2cR and c-fos was observed in the PVN, VMH, NTS, RVLM and AMG. Whereas, pro-opiomelanocortin mRNA expression was not changed. In an UNC1-induced stress model, 5-HT2cR expression and activation was found in brain areas involved in feeding control.

  10. The role of the serotonin receptor subtypes 5-HT1A and 5-HT7 and its interaction in emotional learning and memory

    OpenAIRE

    Stiedl, Oliver; Pappa, Elpiniki; Konradsson-Geuken, Åsa; Ögren, Sven Ove

    2015-01-01

    Serotonin [5-hydroxytryptamine (5-HT)] is a multifunctional neurotransmitter innervating cortical and limbic areas involved in cognition and emotional regulation. Dysregulation of serotonergic transmission is associated with emotional and cognitive deficits in psychiatric patients and animal models. Drugs targeting the 5-HT system are widely used to treat mood disorders and anxiety-like behaviors. Among the fourteen 5-HT receptor (5-HTR) subtypes, the 5-HT1AR and 5-HT7R are associated with th...

  11. The role of the serotonin receptor subtypes 5-HT1A and 5-HT7 and its interaction in emotional learning and memory

    OpenAIRE

    Oliver eStiedl; Elpiniki ePappa; Åsa eKonradsson-Geuken; Sven Ove eÖgren

    2015-01-01

    Serotonin (5-hydroxytryptamine, 5-HT) is a multifunctional neurotransmitter innervating cortical and limbic areas involved in cognition and emotional regulation. Dysregulation of serotonergic transmission is associated with emotional and cognitive deficits in psychiatric patients and animal models. Drugs targeting the 5-HT system are widely used to treat mood disorders and anxiety-like behaviors. Among the fourteen 5-HT receptor (5-HTR) subtypes, the 5-HT1AR and 5-HT7R are associated with the...

  12. Serotonin Transporter (5-HTT) and gamma-Aminobutyric Acid Receptor Subunit beta3 (GABRB3) Gene Polymorphisms are not Associated with Autism in the IMGSA Families

    DEFF Research Database (Denmark)

    Maestrini, E.; Lai, C.; Marlow, A.;

    1999-01-01

    Previous studies have suggested that the serotonin transporter (5-HTT) gene and the gamma-aminobutyric acid receptor subunit beta3 (GABRB3) gene, or other genes in the 15q11-q13 region, are possibly involved in susceptibility to autism. To test this hypothesis we performed an association study...... and the GABRB3 genes are unlikely to play a major role in the aetiology of autism in our family data set....

  13. Brain imaging of serotonin 4 receptors in humans with [11C]SB207145-PET

    DEFF Research Database (Denmark)

    Marner, Lisbeth; Gillings, Nic; Madsen, Karine

    2010-01-01

    subjects (20-45 years, 8 males) using the simplified reference tissue model. We tested within our population the effect of age and other demographic factors on the endpoint. In seven subjects, we tested the vulnerability of radioligand binding to a pharmacolological challenge with citalopram, which...... is expected to increase competition from endogenous serotonin. Given radiotracer administration at a range of specific activities, we were able to use the individual BP(ND) measurements for population-based estimation of the saturation binding parameters; B(max) ranged from 0.3 to 1.6 nM. B......(max) was in accordance with post-mortem brain studies (Spearman's r=0.83, p=0.04), and the regional binding potentials, BP(ND), were on average 2.6 in striatum, 0.42 in prefrontal cortex, and 0.91 in hippocampus. We found no effect of sex but a decreased binding with age (p=0.046). A power analysis showed that, given...

  14. 5-Hydroxytryptamine(1F) receptors do not participate in vasoconstriction: lack of vasoconstriction to LY344864, a selective serotonin(1F) receptor agonist in rabbit saphenous vein.

    Science.gov (United States)

    Cohen, M L; Schenck, K

    1999-09-01

    Recently, several novel approaches to the treatment of migraine have been advanced, including selective 5-hydroxytryptamine (or serotonin) 1B/1D (5-HT(1B/1D)) receptor agonists such as sumatriptan and 5-HT(1F) receptor agonists such as LY344864. Many 5-HT(1B/1D) receptor agonists have been identified based on their ability to produce cerebral vascular contraction, whereas LY344864 was identified as an inhibitor of trigeminal nerve-mediated dural extravasation. In our study, several triptan derivatives were compared with LY344864 for their ability to contract the rabbit saphenous vein, a tissue used in the preclinical identification of sumatriptan-related agonists. Sumatriptan, zolmitriptan, rizatriptan, and naratriptan all contracted the rabbit saphenous vein from baseline tone, whereas LY344864 in concentrations up to 10(-4) M did not contract the rabbit saphenous vein. Furthermore, vascular contractions to sumatriptan were markedly augmented in the presence of prostaglandin F(2alpha) (PGF(2alpha)). However, even in the presence of PGF(2alpha) (3 x 10(-7) M), LY344864 did not contract the rabbit saphenous vein in concentrations well in excess of its 5-HT(1F) receptor affinity (pK(i) = 8.2). Only when concentrations exceeded those likely to activate 5-HT(1B) and 5-HT(1D) receptors (>10(-5) M) did modest contractile responses occur in the presence of PGF(2alpha). Use of these serotonergic agonists revealed a significant correlation between the contractile potency in the rabbit saphenous vein and the affinities of these agonists at 5-HT(1B) and 5-HT(1D) receptors, although contractile agonist potencies were not quantitatively similar to 5-HT(1B) or 5-HT(1D) receptor affinities. In contrast, no significant correlation existed between the contractile potencies of these serotonergic agonists in the rabbit saphenous vein and their affinity at 5-HT(1F) receptors. These data support the contention that activation of 5-HT(1F) receptors will not result in vascular

  15. Comparison of P2X and TRPV1 receptors in ganglia or primary culture of trigeminal neurons and their modulation by NGF or serotonin

    Directory of Open Access Journals (Sweden)

    Giniatullin Rashid

    2006-03-01

    Full Text Available Abstract Background Cultured sensory neurons are a common experimental model to elucidate the molecular mechanisms of pain transduction typically involving activation of ATP-sensitive P2X or capsaicin-sensitive TRPV1 receptors. This applies also to trigeminal ganglion neurons that convey pain inputs from head tissues. Little is, however, known about the plasticity of these receptors on trigeminal neurons in culture, grown without adding the neurotrophin NGF which per se is a powerful algogen. The characteristics of such receptors after short-term culture were compared with those of ganglia. Furthermore, their modulation by chronically-applied serotonin or NGF was investigated. Results Rat or mouse neurons in culture mainly belonged to small and medium diameter neurons as observed in sections of trigeminal ganglia. Real time RT-PCR, Western blot analysis and immunocytochemistry showed upregulation of P2X3 and TRPV1 receptors after 1–4 days in culture (together with their more frequent co-localization, while P2X2 ones were unchanged. TRPV1 immunoreactivity was, however, lower in mouse ganglia and cultures. Intracellular Ca2+ imaging and whole-cell patch clamping showed functional P2X and TRPV1 receptors. Neurons exhibited a range of responses to the P2X agonist α, β-methylene-adenosine-5'-triphosphate indicating the presence of homomeric P2X3 receptors (selectively antagonized by A-317491 and heteromeric P2X2/3 receptors. The latter were observed in 16 % mouse neurons only. Despite upregulation of receptors in culture, neurons retained the potential for further enhancement of P2X3 receptors by 24 h NGF treatment. At this time point TRPV1 receptors had lost the facilitation observed after acute NGF application. Conversely, chronically-applied serotonin selectively upregulated TRPV1 receptors rather than P2X3 receptors. Conclusion Comparing ganglia and cultures offered the advantage of understanding early adaptive changes of nociception

  16. Regulating prefrontal cortex activation: an emerging role for the 5-HT₂A serotonin receptor in the modulation of emotion-based actions?

    Science.gov (United States)

    Aznar, Susana; Klein, Anders B

    2013-12-01

    The prefrontal cortex (PFC) is involved in mediating important higher-order cognitive processes such as decision making, prompting thereby our actions. At the same time, PFC activation is strongly influenced by emotional reactions through its functional interaction with the amygdala and the striatal circuitry, areas involved in emotion and reward processing. The PFC, however, is able to modulate amygdala reactivity via a feedback loop to this area. A role for serotonin in adjusting for this circuitry of cognitive regulation of emotion has long been suggested based primarily on the positive pharmacological effect of elevating serotonin levels in anxiety regulation. Recent animal and human functional magnetic resonance studies have pointed to a specific involvement of the 5-hydroxytryptamine (5-HT)2A serotonin receptor in the PFC feedback regulatory projection onto the amygdala. This receptor is highly expressed in the prefrontal cortex areas, playing an important role in modulating cortical activity and neural oscillations (brain waves). This makes it an interesting potential pharmacological target for the treatment of neuropsychiatric modes characterized by lack of inhibitory control of emotion-based actions, such as addiction and other impulse-related behaviors. In this review, we give an overview of the 5-HT2A receptor distribution (neuronal, intracellular, and anatomical) along with its functional and physiological effect on PFC activation, and how that relates to more recent findings of a regulatory effect of the PFC on the emotional control of our actions.

  17. Serotonin 1A, 1B, and 7 receptors of the rat medial nucleus accumbens differentially regulate feeding, water intake, and locomotor activity.

    Science.gov (United States)

    Clissold, Kara A; Choi, Eugene; Pratt, Wayne E

    2013-11-01

    Serotonin (5-HT) signaling has been widely implicated in the regulation of feeding behaviors in both humans and animal models. Recently, we reported that co-stimulation of 5-HT1&7 receptors of the anterior medial nucleus accumbens with the drug 5-CT caused a dose-dependent decrease in food intake, water intake, and locomotion in rats (Pratt et al., 2009). The current experiments sought to determine which of three serotonin receptor subtypes (5-HT1A, 5-HT1B, or 5-HT7) might be responsible for these consummatory and locomotor effects. Food-deprived rats were given 2-h access to rat chow after stimulation of nucleus accumbens 5-HT1A, 5-HT1B, or 5-HT7 receptors, or blockade of the 5-HT1A or 5-HT1B receptors. Stimulation of 5-HT1A receptors with 8-OH-DPAT (at 0.0, 2.0, 4.0, and 8.0 μg/0.5 μl/side) caused a dose-dependent decrease in food and water intake, and reduced rearing behavior but not ambulation. In contrast, rats that received the 5-HT1B agonist CP 93129 (at 0.0, 1.0, 2.0 and 4.0 μg/0.5 μl/side) showed a significant dose-dependent decrease in water intake only; stimulation of 5-HT7 receptors (AS 19; at 0.0, 1.0, and 5.0 μg/0.5 μl/side) decreased ambulatory activity but did not affect food or water consumption. Blockade of 5-HT1A or 5-HT1B receptors had no lasting effects on measures of food consumption. These data suggest that the food intake, water intake, and locomotor effects seen after medial nucleus accumbens injections of 5-CT are due to actions on separate serotonin receptor subtypes, and contribute to growing evidence for selective roles of individual serotonin receptors within the nucleus accumbens on motivated behavior. © 2013.

  18. Effect of the 5-HT{sub 4} receptor and serotonin transporter on visceral hypersensitivity in rats

    Energy Technology Data Exchange (ETDEWEB)

    Chi, Yan; Liu, Xin-Guang; Wang, Hua-Hong; Li, Jun-Xia; Li, Yi-Xuan [Department of Gastroenterology, Peking University First Hospital, Beijing (China)

    2012-07-27

    Visceral hypersensitivity plays an important role in motor and sensory abnormalities associated with irritable bowel syndrome, but the underlying mechanisms are not fully understood. The present study was designed to evaluate the expression of the 5-HT{sub 4} receptor and the serotonin transporter (SERT) as well as their roles in chronic visceral hypersensitivity using a rat model. Neonatal male Sprague-Dawley rats received intracolonic injections of 0.5% acetic acid (0.3-0.5 mL at different times) between postnatal days 8 and 21 to establish an animal model of visceral hypersensitivity. On day 43, the threshold intensity for a visually identifiable contraction of the abdominal wall and body arching were recorded during rectal distention. Histological evaluation and the myeloperoxidase activity assay were performed to determine the severity of inflammation. The 5-HT{sub 4} receptor and SERT expression of the ascending colon were monitored using immunohistochemistry and Western blot analyses; the plasma 5-HT levels were measured using an ELISA method. As expected, transient colonic irritation at the neonatal stage led to visceral hypersensitivity, but no mucosal inflammation was later detected during adulthood. Using this model, we found reduced SERT expression (0.298 ± 0.038 vs 0.634 ± 0.200, P < 0.05) and increased 5-HT{sub 4} receptor expression (0.308 ± 0.017 vs 0.298 ± 0.021, P < 0.05). Treatment with fluoxetine (10 mg·kg{sup −1}·day{sup −1}, days 36-42), tegaserod (1 mg·kg{sup −1}·day{sup −1}, day 43), or the combination of both, reduced visceral hypersensitivity and plasma 5-HT levels. Fluoxetine treatment increased 5-HT{sub 4} receptor expression (0.322 ± 0.020 vs 0.308 ± 0.017, P < 0.01) but not SERT expression (0.219 ± 0.039 vs 0.298 ± 0.038, P = 0.654). These results indicate that both the 5-HT{sub 4} receptor and SERT play a role in the pathogenesis of visceral hypersensitivity, and its mechanism may be involved in the local 5-HT

  19. Differential regulation of serotonin-1A receptor-stimulated [35S]GTP gamma S binding in the dorsal raphe nucleus by citalopram and escitalopram.

    Science.gov (United States)

    Rossi, Dania V; Burke, Teresa F; Hensler, Julie G

    2008-03-31

    The effect of chronic citalopram or escitalopram administration on 5-HT1A receptor function in the dorsal raphe nucleus was determined by measuring [35S]GTP gamma S binding stimulated by the 5-HT1A receptor agonist (R)-(+)-8-OH-DPAT (1nM-10 microM). Although chronic administration of citalopram or escitalopram has been shown to desensitize somatodendritic 5-HT1A autoreceptors, we found that escitalopram treatment decreased the efficacy of 5-HT1A receptors to activate G proteins, whereas citalopram treatment did not. The binding of [3H]8-OH-DPAT to the coupled, high affinity agonist state of the receptor was not altered by either treatment. Interestingly, escitalopram administration resulted in greater occupancy of serotonin transporter sites as measured by the inhibition of [3H]cyanoimipramine binding. As the binding and action of escitalopram is limited by the inactive enantiomer R-citalopram present in racemic citalopram, we propose that the regulation of 5-HT1A receptor function in the dorsal raphe nucleus at the level of receptor-G protein interaction may be a result of greater inhibition of the serotonin transporter by escitalopram.

  20. Serotonin receptor binding affinities of several hallucinogenic phenylalkylamine and N,N-dimethyltryptamine analogues.

    Science.gov (United States)

    Glennon, R A; Liebowitz, S M; Mack, E C

    1978-08-01

    Hallucinogenic phenylalkylamine and N,N-dimethyltryptamine analogues are known to affect serotonergic systems both in vivo and in vitro. Using a rat stomach fundus model, the 5-HT receptor binding affinities of several of these analogues were determined and compared. The most behaviorally potent analogues examined, DOB, DOM, and 5-methoxy-N,N-dimethyltryptamine, were found to possess rather high affirmities (pA2 = 7.35, 7.12, and 7.08, respectively) for the 5-HT receptors of the model system.

  1. Familial risk for mood disorder and the personality risk factor, neuroticism, interact in their association with frontolimbic serotonin 2A receptor binding

    DEFF Research Database (Denmark)

    Frøkjær, Vibe; Vinberg, Maj; Erritzøe, David

    2010-01-01

    .026) in an analysis adjusting for age and body mass index. Within the high-risk group only, neuroticism and frontolimbic 5-HT(2A) receptor binding was positively associated (p=0.0037). In conclusion, our data indicate that familial risk and neuroticism interact in their relation to frontolimbic 5-HT(2A) receptor...... and is positively correlated to frontolimbic serotonin 2A (5-HT(2A)) receptor binding. Here, we investigate whether neuroticism interacts with familial risk in relation to frontolimbic 5-HT(2A) receptor binding. Twenty-one healthy twins with a co-twin history of mood disorder and 16 healthy twins without a co......-twin history of mood disorder were included. They answered self-report personality questionnaires and underwent [(18)F]altanserin positron emission tomography. We found a significant interaction between neuroticism and familial risk in predicting the frontolimbic 5-HT(2A) receptor binding (p=0...

  2. Statistical distribution of blood serotonin as a predictor of early autistic brain abnormalities

    Directory of Open Access Journals (Sweden)

    Janušonis Skirmantas

    2005-07-01

    Full Text Available Abstract Background A wide range of abnormalities has been reported in autistic brains, but these abnormalities may be the result of an earlier underlying developmental alteration that may no longer be evident by the time autism is diagnosed. The most consistent biological finding in autistic individuals has been their statistically elevated levels of 5-hydroxytryptamine (5-HT, serotonin in blood platelets (platelet hyperserotonemia. The early developmental alteration of the autistic brain and the autistic platelet hyperserotonemia may be caused by the same biological factor expressed in the brain and outside the brain, respectively. Unlike the brain, blood platelets are short-lived and continue to be produced throughout the life span, suggesting that this factor may continue to operate outside the brain years after the brain is formed. The statistical distributions of the platelet 5-HT levels in normal and autistic groups have characteristic features and may contain information about the nature of this yet unidentified factor. Results The identity of this factor was studied by using a novel, quantitative approach that was applied to published distributions of the platelet 5-HT levels in normal and autistic groups. It was shown that the published data are consistent with the hypothesis that a factor that interferes with brain development in autism may also regulate the release of 5-HT from gut enterochromaffin cells. Numerical analysis revealed that this factor may be non-functional in autistic individuals. Conclusion At least some biological factors, the abnormal function of which leads to the development of the autistic brain, may regulate the release of 5-HT from the gut years after birth. If the present model is correct, it will allow future efforts to be focused on a limited number of gene candidates, some of which have not been suspected to be involved in autism (such as the 5-HT4 receptor gene based on currently available clinical and

  3. 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.

  4. The Fabric of Meaning and Subjective Effects in LSD-Induced States Depend on Serotonin 2A Receptor Activation.

    Science.gov (United States)

    Preller, Katrin H; Herdener, Marcus; Pokorny, Thomas; Planzer, Amanda; Kraehenmann, Rainer; Stämpfli, Philipp; Liechti, Matthias E; Seifritz, Erich; Vollenweider, Franz X

    2017-02-06

    A core aspect of the human self is the attribution of personal relevance to everyday stimuli enabling us to experience our environment as meaningful [1]. However, abnormalities in the attribution of personal relevance to sensory experiences are also critical features of many psychiatric disorders [2, 3]. Despite their clinical relevance, the neurochemical and anatomical substrates enabling meaningful experiences are largely unknown. Therefore, we investigated the neuropharmacology of personal relevance processing in humans by combining fMRI and the administration of the mixed serotonin (5-HT) and dopamine receptor (R) agonist lysergic acid diethylamide (LSD), well known to alter the subjective meaning of percepts, with and without pretreatment with the 5-HT2AR antagonist ketanserin. General subjective LSD effects were fully blocked by ketanserin. In addition, ketanserin inhibited the LSD-induced attribution of personal relevance to previously meaningless stimuli and modulated the processing of meaningful stimuli in cortical midline structures. These findings point to the crucial role of the 5-HT2AR subtype and cortical midline regions in the generation and attribution of personal relevance. Our results thus increase our mechanistic understanding of personal relevance processing and reveal potential targets for the treatment of psychiatric illnesses characterized by alterations in personal relevance attribution. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. [Association between serotonin receptor 2C gene Cys23Ser polymorphism and social behavior in schizophrenia patients and healthy individuals].

    Science.gov (United States)

    Alfimova, M V; Golimbet, V E; Korovaitseva, G I; Abramova, L I; Kaleda, V G

    2015-02-01

    The purpose of this work was to search for associations between the serotonin receptor 2C gene (HTR2C) and the peculiarities of social behavior and social cognition in schizophrenia. To do this, patients with schizophrenia spectrum disorders and healthy control subjects were genotyped for the Cys23Ser HTR2C marker and underwent psychological examination, including assessment of Machiavellianism, recognition of emotions in facial expression, and theory of mind. In addition, we estimated the trait anxiety level as a potential factor affecting the relationship between the gene HTR2C and social behavior. We found a significant association between the Ser allele and a reduction of estimates on the Mach-LV Machiavellianism scale in the total sample of patients (n = 182) and control subjects (n = 189), which did not reach the confidence level in either of the groups. A tendency towards a HTR2C gene influence on the trait anxiety level was also revealed. The association between HTR2C and Machiavellianism was retained if the anxiety level was taken into account. The results suggest a pleiotropic effect of HTR2Con anxiety and Machiavellianism.

  6. The serotonin receptor 2A gene moderates the influence of parental socioeconomic status on adulthood harm avoidance.

    Science.gov (United States)

    Jokela, Markus; Lehtimäki, Terho; Keltikangas-Järvinen, Liisa

    2007-07-01

    We examined whether the T102C polymorphism of the serotonin receptor 2A gene (HTR2A) moderated the influence of childhood or adolescence parental socioeconomic status (SES) on adulthood temperament trait harm avoidance (HA) in a population-based sample of 1246 healthy Finnish men and women, who were 24-39 years of age in the last follow-up phase. High parental SES predicted low adulthood HA. In addition, the C allele of the T102C polymorphism was associated with high HA in one of the two test settings, and with the mean of the two measurements. Most importantly, we found that the T102C polymorphism moderated the influence of parental SES, such that high parental SES predicted low adulthood HA in subjects with the T/T or T/C genotypes, while this was not true for those carrying the C/C genotype. The role of the T102C polymorphism was most pronounced among those with high parental SES. We conclude that the T102C polymorphism of the HTR2A gene may be involved in the development of temperament by moderating the influence of environmental conditions.

  7. Enhanced food anticipatory activity associated with enhanced activation of extrahypothalamic neural pathways in serotonin2C receptor null mutant mice.

    Directory of Open Access Journals (Sweden)

    Jennifer L Hsu

    Full Text Available The ability to entrain circadian rhythms to food availability is important for survival. Food-entrained circadian rhythms are characterized by increased locomotor activity in anticipation of food availability (food anticipatory activity. However, the molecular components and neural circuitry underlying the regulation of food anticipatory activity remain unclear. Here we show that serotonin(2C receptor (5-HT2CR null mutant mice subjected to a daytime restricted feeding schedule exhibit enhanced food anticipatory activity compared to wild-type littermates, without phenotypic differences in the impact of restricted feeding on food consumption, body weight loss, or blood glucose levels. Moreover, we show that the enhanced food anticipatory activity in 5-HT2CR null mutant mice develops independent of external light cues and persists during two days of total food deprivation, indicating that food anticipatory activity in 5-HT2CR null mutant mice reflects the locomotor output of a food-entrainable oscillator. Whereas restricted feeding induces c-fos expression to a similar extent in hypothalamic nuclei of wild-type and null mutant animals, it produces enhanced expression in the nucleus accumbens and other extrahypothalamic regions of null mutant mice relative to wild-type subjects. These data suggest that 5-HT2CRs gate food anticipatory activity through mechanisms involving extrahypothalamic neural pathways.

  8. Spatiotemporal brain dynamics of emotional face processing modulations induced by the serotonin 1A/2A receptor agonist psilocybin.

    Science.gov (United States)

    Bernasconi, Fosco; Schmidt, André; Pokorny, Thomas; Kometer, Michael; Seifritz, Erich; Vollenweider, Franz X

    2014-12-01

    Emotional face processing is critically modulated by the serotonergic system. For instance, emotional face processing is impaired by acute psilocybin administration, a serotonin (5-HT) 1A and 2A receptor agonist. However, the spatiotemporal brain mechanisms underlying these modulations are poorly understood. Here, we investigated the spatiotemporal brain dynamics underlying psilocybin-induced modulations during emotional face processing. Electrical neuroimaging analyses were applied to visual evoked potentials in response to emotional faces, following psilocybin and placebo administration. Our results indicate a first time period of strength (i.e., Global Field Power) modulation over the 168-189 ms poststimulus interval, induced by psilocybin. A second time period of strength modulation was identified over the 211-242 ms poststimulus interval. Source estimations over these 2 time periods further revealed decreased activity in response to both neutral and fearful faces within limbic areas, including amygdala and parahippocampal gyrus, and the right temporal cortex over the 168-189 ms interval, and reduced activity in response to happy faces within limbic and right temporo-occipital brain areas over the 211-242 ms interval. Our results indicate a selective and temporally dissociable effect of psilocybin on the neuronal correlates of emotional face processing, consistent with a modulation of the top-down control.

  9. Bioinformatic analysis of insect serotonin receptor proteins%昆虫血清素受体蛋白的生物信息学分析

    Institute of Scientific and Technical Information of China (English)

    常菊花; 何月平

    2015-01-01

    Objectives] There are five subtypes of serotonin receptor proteins of insects. The relationship between protein structure and the evolution of serotonin receptors in insects was comprehensively studied. [Methods] First, the bioinformatics of 23 protein sequences of serotonin receptors in seven insects reported in the literature were analyzed;Second, the protein sequences of serotonin receptors in the NCBI database were verified by multiple sequence alignment and constructing a phylogenetic tree. [Results] The results show that 40 of 47 putative protein sequences were those of insect serotonin receptors, whereas the other 7 protein sequences, which had 7 transmembrane regions, belong to the G protein-coupled receptor superfamily. It is uncertain if these 7 proteins are insect serotonin receptors. [Conclusion] This study provides a basis for analyzing the function of insect serotonin receptors.%【目的】昆虫血清素(5-羟色胺)受体已知有5个亚型。本文旨在系统分析昆虫5-羟色胺受体亚型蛋白的结构和进化关系。【方法】首先对文献报道已明确亚型7种昆虫的5-羟色胺受体(23个亚型序列)进行生物信息学分析,然后采用多序列比对和进化树构建的方法对NCBI数据库中推测可能为昆虫5-羟色胺受体蛋白序列进行分析。【结果】发现47个推测是昆虫5-羟色胺受体的蛋白序列中,有40个蛋白序列属于昆虫5-羟色胺受体,其余7个未能确认的昆虫5-羟色胺受体的蛋白序列都具有7个跨膜区域,属于G蛋白偶联受体家族,但不一定为5-羟色胺受体。【结论】本文对昆虫5-羟色胺受体蛋白的系统进化树分析,间接地证明了本文确认的昆虫5-羟色胺受体亚型注释信息的准确性,发现分类上同属一个目的昆虫5-HT受体序列的亲缘性较近。本研究为昆虫5-羟色胺受体的结构和功能分析提供基础。

  10. X-ray structure of the mouse serotonin 5-HT3 receptor

    NARCIS (Netherlands)

    Hassaine, Gherici; Deluz, Cedric; Grasso, Luigino; Wyss, Romain; Tol, Menno B.; Hovius, Ruud; Graff, Alexandra; Stahlberg, Henning; Tomizaki, Takashi; Desmyter, Aline; Moreau, Christophe; Li, Xiao-Dan; Poitevin, Frederic; Vogel, Horst; Nury, Hugues

    2014-01-01

    Neurotransmitter-gated ion channels of the Cys-loop receptor family mediate fast neurotransmission throughout the nervous system. The molecular processes of neurotransmitter binding, subsequent opening of the ion channel and ion permeation remain poorly understood. Here we present the X-ray structur

  11. Activation of serotonin 2C receptors in dopamine neurons inhibits binge-like eating in mice

    Science.gov (United States)

    Neural networks that regulate binge eating remain to be identified, and effective treatments for binge eating are limited. We combined neuroanatomic, pharmacologic, electrophysiological, Cre-lox, and chemogenetic approaches to investigate the functions of 5-hydroxytryptamine (5-HT) 2C receptor (5-HT...

  12. Effect of selective and non-selective serotonin receptor activation on L-DOPA-induced therapeutic efficacy and dyskinesia in parkinsonian rats.

    Science.gov (United States)

    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.

  13. Tyramine and octopamine independently inhibit serotonin-stimulated aversive behaviors in Caenorhabditis elegans through two novel amine receptors.

    Science.gov (United States)

    Wragg, Rachel T; Hapiak, Vera; Miller, Sarah B; Harris, Gareth P; Gray, John; Komuniecki, Patricia R; Komuniecki, Richard W

    2007-12-05

    Biogenic amines modulate key behaviors in both vertebrates and invertebrates. In Caenorhabditis elegans, tyramine (TA) and octopamine (OA) inhibit aversive responses to 100%, but not dilute (30%) octanol. TA and OA also abolish food- and serotonin-dependent increases in responses to dilute octanol in wild-type but not tyra-3(ok325) and f14d12.6(ok371) null animals, respectively, suggesting that TA and OA modulated responses to dilute octanol are mediated by separate, previously uncharacterized, G-protein-coupled receptors. TA and OA are high-affinity ligands for TYRA-3 and F14D12.6, respectively, based on their pharmacological characterization after heterologous expression. f14d12.6::gfp is expressed in the ASHs, the neurons responsible for sensitivity to dilute octanol, and the sra-6-dependent expression of F14D12.6 in the ASHs is sufficient to rescue OA sensitivity in f14d12.6(ok371) null animals. In contrast, tyra-3::gfp appears not to be expressed in the ASHs, but instead in other neurons, including the dopaminergic CEP/ADEs. However, although dopamine (DA) also inhibits 5-HT-dependent responses to dilute octanol, TA still inhibits in dop-2; dop-1; dop-3 animals that do not respond to DA and cat-2(tm346) and Pdat-1::ICE animals that lack significant dopaminergic signaling, suggesting that DA is not an intermediate in TA inhibition. Finally, responses to TA and OA selectively desensitize after preexposure to the amines. Our data suggest that although tyraminergic and octopaminergic signaling yield identical phenotypes in these olfactory assays, they act independently through distinct receptors to modulate the ASH-mediated locomotory circuit and that C. elegans is a useful model to study the aminergic modulation of sensory-mediated locomotory behaviors.

  14. Weight Loss After RYGB Is Independent of and Complementary to Serotonin 2C Receptor Signaling in Male Mice

    Science.gov (United States)

    Carmody, Jill S.; Ahmad, Nadia N.; Machineni, Sriram; Lajoie, Scott

    2015-01-01

    Roux-en-Y gastric bypass (RYGB) typically leads to substantial, long-term weight loss (WL) and diabetes remission, although there is a wide variation in response to RYGB among individual patients. Defining the pathways through which RYGB works should aid in the development of less invasive anti-obesity treatments, whereas identifying weight-regulatory pathways unengaged by RYGB could facilitate the development of therapies that complement the beneficial effects of surgery. Activation of serotonin 2C receptors (5-HT2CR) by serotonergic drugs causes WL in humans and animal models. 5-HT2CR are located on neurons that activate the melanocortin-4 receptors, which are essential for WL after RYGB. We therefore sought to determine whether 5-HT2CR signaling is also essential for metabolic effects of RYGB or whether it is a potentially complementary pathway, the activation of which could extend the benefits of RYGB. Diet-induced obese male mice deficient for the 5-HT2CR and their wild-type littermates underwent RYGB or sham operation. Both groups lost similar amounts of weight after RYGB, demonstrating that the improved metabolic phenotype after RYGB is 5-HT2CR independent. Consistent with this hypothesis, wild-type RYGB-treated mice lost additional weight after the administration of the serotonergic drugs fenfluramine and meta-chlorophenylpiperazine but not the nonserotonergic agent topiramate. The fact that RYGB does not depend on 5-HT2CR signaling suggests that there are important WL mechanisms not fully engaged by surgery that could potentially be harnessed for medical treatment. These results suggest a rational basis for designing medical-surgical combination therapies to optimize clinical outcomes by exploiting complementary physiological mechanisms of action. PMID:26066076

  15. Lower cortical serotonin 2A receptors in major depressive disorder, suicide and in rats after administration of imipramine.

    Science.gov (United States)

    Dean, Brian; Tawadros, Nahed; Seo, Myoung Suk; Jeon, Won Je; Everall, Ian; Scarr, Elizabeth; Gibbons, Andrew

    2014-06-01

    We have attempted to replicate studies showing higher levels of serotonin 2A receptors (HTR2A) in the cortex of people with mood disorders and to determine the effects of treating rats with antidepressant drugs on levels of that receptor. In situ [3H]ketanserin binding and autoradiography was used to measure levels of HTR2A in Brodmann's area (BA) 46 and 24 from people with major depressive disorders (MDD, n = 16), bipolar disorders (BD, n = 14) and healthy controls (n = 14) as well as the central nervous system (CNS) of rats (20 per treatment arm) treated for 10 or 28 d with fluoxetine (10 mg/kg/d) or imipramine (20 mg/kg/d). Compared with controls, HTR2A were lower in BA 24, but not BA 46, from people with MDD (p = 0.005); HTR2A were not changed in BD. Levels of HTR2A were lower in BA 24 (p = 0.007), but not BA 46, from people who had died by suicide. Finally, levels of HTR2A were lower in the CNS of rats treated with imipramine, but not fluoxetine, for 28 d, but not 10 d. From our current and previous data we conclude cortical HTR2A are lower in schizophrenia, MDD, people with mood disorders who died by suicide, rats treated with some antipsychotic or some antidepressant drugs. As levels of cortical HTR2A can be affected by the aetiologies of different disorders and mechanisms of action of different drugs, a better understanding of how such changes can occur needs to be elucidated.

  16. Weight Loss After RYGB Is Independent of and Complementary to Serotonin 2C Receptor Signaling in Male Mice.

    Science.gov (United States)

    Carmody, Jill S; Ahmad, Nadia N; Machineni, Sriram; Lajoie, Scott; Kaplan, Lee M

    2015-09-01

    Roux-en-Y gastric bypass (RYGB) typically leads to substantial, long-term weight loss (WL) and diabetes remission, although there is a wide variation in response to RYGB among individual patients. Defining the pathways through which RYGB works should aid in the development of less invasive anti-obesity treatments, whereas identifying weight-regulatory pathways unengaged by RYGB could facilitate the development of therapies that complement the beneficial effects of surgery. Activation of serotonin 2C receptors (5-HT2CR) by serotonergic drugs causes WL in humans and animal models. 5-HT2CR are located on neurons that activate the melanocortin-4 receptors, which are essential for WL after RYGB. We therefore sought to determine whether 5-HT2CR signaling is also essential for metabolic effects of RYGB or whether it is a potentially complementary pathway, the activation of which could extend the benefits of RYGB. Diet-induced obese male mice deficient for the 5-HT2CR and their wild-type littermates underwent RYGB or sham operation. Both groups lost similar amounts of weight after RYGB, demonstrating that the improved metabolic phenotype after RYGB is 5-HT2CR independent. Consistent with this hypothesis, wild-type RYGB-treated mice lost additional weight after the administration of the serotonergic drugs fenfluramine and meta-chlorophenylpiperazine but not the nonserotonergic agent topiramate. The fact that RYGB does not depend on 5-HT2CR signaling suggests that there are important WL mechanisms not fully engaged by surgery that could potentially be harnessed for medical treatment. These results suggest a rational basis for designing medical-surgical combination therapies to optimize clinical outcomes by exploiting complementary physiological mechanisms of action.

  17. Suicide, stress and serotonin receptor 1A promoter polymorphism -1019C>G in Slovenian suicide victims.

    Science.gov (United States)

    Videtic, Alja; Zupanc, Tomaz; Pregelj, Peter; Balazic, Joze; Tomori, Martina; Komel, Radovan

    2009-06-01

    Implication of serotonergic system in suicide and suicide attempts has been discussed for several years. One of the most abundant serotonin receptors in the mammalian brain is the receptor 1A (5-HT1A); studies of its polymorphisms and suicide have provided very inconsistent results so far. The suggestion that the G allele depresses HTR1A autoreceptor expression, and therefore reduces serotonergic neurotransmission that might predispose to depression and suicide, made the promoter polymorphism -1019C>G a very promising candidate gene. In our study we analyzed promoter polymorphism -1019C>G on 323 suicide victims and 190 controls (all of Slovenian origin), taking into account sex, suicide method, and in case of suicide victims also stressful life events. Differences in the distributions of genotype and allele frequencies were not statistically significant between suicide victims and control group, and the same was found for distributions according to sex and suicide method. For 62 suicide victims information about stressful life events in the month prior to the suicide and in childhood was provided. For analysis we combined CG/GG genotypes and compared them to the CC genotype. More stressful life events in the month prior to the suicide were reported for the subgroup with CC genotype (mean number of events = 2.53; SD = 1.50) in comparison to subgroup with CG/GG genotypes (mean number of events = 1.58; SD = 1.32; P suicide victims with CC or CG/GG genotypes did not differ regarding numbers of reported stressful life events in childhood (P > 0.05). Our study provides no evidence for the implication of HTR1A promoter polymorphism in suicide in general, but it suggests further studies that would take into account the interconnected network of suicide completion, genetic background and stress, beside other risk factors.

  18. Serotonin 5-HT7 receptor increases the density of dendritic spines and facilitates synaptogenesis in forebrain neurons.

    Science.gov (United States)

    Speranza, Luisa; Labus, Josephine; Volpicelli, Floriana; Guseva, Daria; Lacivita, Enza; Leopoldo, Marcello; Bellenchi, Gian Carlo; di Porzio, Umberto; Bijata, Monika; Perrone-Capano, Carla; Ponimaskin, Evgeni

    2017-06-01

    Precise control of dendritic spine density and synapse formation is critical for normal and pathological brain functions. Therefore, signaling pathways influencing dendrite outgrowth and remodeling remain a subject of extensive investigations. Here, we report that prolonged activation of the serotonin 5-HT7 receptor (5-HT7R) with selective agonist LP-211 promotes formation of dendritic spines and facilitates synaptogenesis in postnatal cortical and striatal neurons. Critical role of 5-HT7R in neuronal morphogenesis was confirmed by analysis of neurons isolated from 5-HT7R-deficient mice and by pharmacological inactivation of the receptor. Acute activation of 5-HT7R results in pronounced neurite elongation in postnatal striatal and cortical neurons, thus extending previous data on the morphogenic role of 5-HT7R in embryonic and hippocampal neurons. We also observed decreased number of spines in neurons with either genetically (i.e. 5-HT7R-knock-out) or pharmacologically (i.e. antagonist treatment) blocked 5-HT7R, suggesting that constitutive 5-HT7R activity is critically involved in the spinogenesis. Moreover, cyclin-dependent kinase 5 and small GTPase Cdc42 were identified as important downstream effectors mediating morphogenic effects of 5-HT7R in neurons. Altogether, our data suggest that the 5-HT7R-mediated structural reorganization during the postnatal development might have a crucial role for the development and plasticity of forebrain areas such as cortex and striatum, and thereby can be implicated in regulation of the higher cognitive functions. Read the Editorial Highlight for this article on page 644. © 2017 International Society for Neurochemistry.

  19. A serotonin-1A receptor agonist and an N-methyl-D-aspartate receptor antagonist oppose each others effects in a genetic rat epilepsy model.

    Science.gov (United States)

    Filakovszky, J; Gerber, K; Bagdy, G

    1999-02-12

    The WAG/RIJ rats exhibit spontaneously occurring spike-wave discharges (SWD) accompanied by behavioural phenomena, with characteristics similar to the human absence type epilepsy. To study the mechanisms involved in this type of epileptiform activity we investigated the effects of the serotonin-1A (5-HT1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) and the N-methyl-D-aspartate (NMDA) receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d]cyclohepten-5,10-imine maleate (MK-801). Intracerebroventricular (i.c.v.) injection of 8-OH-DPAT caused marked, dose dependent increase, MK-801 a decrease in the cumulative duration and number of spike-wave discharges. Pretreatment with MK-801 (10 microg/rat i.c.v.) abolished the increase caused by 8-OH-DPAT (20 microg/rat i.c.v.), but the decrease in SWD to MK-801 was counterbalanced by 8-OH-DPAT. These data provide evidence for an interaction of glutamatergic and serotonergic mechanisms in the triggering and maintenance of epileptic activity in this genetic model of absence epilepsy.

  20. Synthesis and serotonin receptor activity of the arylpiperazine alkyl/propoxy derivatives of new azatricycloundecanes.

    Science.gov (United States)

    Bojarski, A J; Kuran, B; Kossakowski, J; Kozioł, A; Jagiełło-Wójtowicz, E; Chodkowska, A

    2009-01-01

    A set of 36 arylpiperazine derivatives with two novel complex terminal imide fragments, 8,11-dimethyl-3,5-dioxo-4-azatricyclo[5.2.2.0(2,6)]undec-8-en-1-yl acetate and 1,11-dimethyl-4-azatricyclo[5.2.2.0(2,6)]undecane-3,5,8-trione, were synthesized and tested for their affinity for 5-HT(1A) and 5-HT(2A) receptors. The Fujita-Ban analysis showed that the influence of structural modifications on the affinity for both receptor subtypes is additive and that the activity of similar compounds could be predicted with high accuracy. Compounds 46, 48 and 18 out of 14 screened in a functional model of anxiety and depression demonstrated antidepressant activity in the forced swimming tests in mice, and were devoid of neurotoxic effects (chimney test in mice).

  1. Novel highly potent serotonin 5-HT7 receptor ligands: structural modifications to improve pharmacokinetic properties.

    Science.gov (United States)

    Lacivita, Enza; Di Pilato, Pantaleo; Stama, Madia Letizia; Colabufo, Nicola Antonio; Berardi, Francesco; Perrone, Roberto; De Filippis, Bianca; Laviola, Giovanni; Adriani, Walter; Niso, Mauro; Leopoldo, Marcello

    2013-11-15

    Here we report the synthesis, pharmacological and pharmacokinetic evaluation of a pilot set of compounds structurally related to the potent and selective 5-HT7 ligand LP-211. Among the studied compounds, N-pyridin-3-ylmethyl-3-[4-[2-(4-methoxyphenyl)phenyl]piperazin-1-yl]ethoxy]propanamide (4b) showed high affinity for 5-HT7 receptors (K(i)=23.8 nM), selectivity over 5-HT1A receptors (>50-fold), in vitro metabolic stability (82%) and weak interaction with P-glycoprotein (BA/AB=3.3). Compound 4b was injected ip in mice to preliminarily evaluate its distribution between blood and brain.

  2. The time course of serotonin 2C receptor expression after spinal transection of rats

    DEFF Research Database (Denmark)

    Ren, Li-Qun; Wienecke, Jacob; Chen, Meng

    2013-01-01

    -IR analysis was confined to the ventral horn motoneuron somata (including a proportion of proximal dendrites) a significant increase was not detected until 45 day post-operation. 5-HT2CR upregulation in the spinal gray matter is confirmed with Western blot in the rats 60 days post-operation. The time course......In the spinal cord 5-HT systems modulate the spinal network via various 5-HT receptors. 5-HT2A and 2C receptors are likely the most important 5-HT receptors for enhancing the motoneuron excitability by facilitating the persistent inward current, and thus play an important role for the pathogenesis...... after transection (with an average ~1.3-fold higher than in sham-operated group) but did not reach a significant level until at 21 days (~1.4-fold). The increase sustained thereafter and a plateau level was reached at 45 days (~1.7-fold higher), a value similar as that at 60 days. When 5-HT2CR...

  3. A systematic investigation of the differential roles for ventral tegmentum serotonin 1- and 2-type receptors on food intake in the rat.

    Science.gov (United States)

    Pratt, Wayne E; Clissold, Kara A; Lin, Peagan; Cain, Amanda E; Ciesinski, Alexa F; Hopkins, Thomas R; Ilesanmi, Adeolu O; Kelly, Erin A; Pierce-Messick, Zachary; Powell, Daniel S; Rosner, Ian A

    2016-10-01

    Central serotonin (5-HT) pathways are known to influence feeding and other ingestive behaviors. Although the ventral tegmentum is important for promoting the seeking and consumption of food and drugs of abuse, the roles of 5-HT receptor subtypes in this region on food intake have yet to be comprehensively examined. In these experiments, food restricted rats were given 2-h access to rat chow; separate groups of non-restricted animals had similar access to a sweetened fat diet. Feeding and locomotor activity were monitored following ventral tegmentum stimulation or blockade of 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, or 5-HT2C receptors. 5-HT1A receptor stimulation transiently inhibited rearing behavior and chow intake in food-restricted rats, and had a biphasic effect on non-restricted rats offered the palatable diet. 5-HT1B receptor agonism transiently inhibited feeding in restricted animals, but did not affect intake of non-restricted rats. In contrast, 5-HT1B receptor antagonism decreased palatable feeding. Although stimulation of ventral tegmental 5-HT2B receptors with BW723C86 did not affect hunger-driven food intake, it significantly affected palatable feeding, with a trend for an increasing intake at 2.0µg/side but not at 5.0µg/side. Antagonism of the same receptor modestly but significantly inhibited feeding of the palatable diet at 5.0µg/side ketanserin. Neither stimulation nor blockade of 5-HT2A or 5-HT2C receptors caused prolonged effects on intake or locomotion. These data suggest that serotonin's effects on feeding within the ventral tegmentum depend upon the specific receptor targeted, as well as whether intake is motivated by food restriction or the palatable nature of the offered diet.

  4. The human 5-HT7 serotonin receptor splice variants: constitutive activity and inverse agonist effects

    OpenAIRE

    Krobert, Kurt A; Levy, Finn Olav

    2002-01-01

    Using membranes from stably or transiently transfected HEK293 cells cultured in 5-HT-free medium and expressing the recombinant human 5-HT7 receptor splice variants (h5-HT7(a), h5-HT7(b) and h5-HT7(d)), we compared their abilities to constitutively activate adenylyl cyclase (AC).All h5-HT7 splice variants elevated basal and forskolin-stimulated AC. The basal AC activity was reduced by the 5-HT7 antagonist methiothepin and this effect was blocked by mesulergine (neutral 5-HT7 antagonist) indic...

  5. Modulatory effects of two novel agonists for serotonin receptor 7 on emotion, motivation and circadian rhythm profiles in mice.

    Science.gov (United States)

    Adriani, Walter; Travaglini, Domenica; Lacivita, Enza; Saso, Luciano; Leopoldo, Marcello; Laviola, Giovanni

    2012-02-01

    Serotonin receptor 7, i.e. 5-HT(7) protein coded by Htr7 gene, was discovered in supra-chiasmatic nucleus (SCN) of the hypothalamus but is widespread in the forebrain. Studies have shown that this receptor is involved in learning/memory, regulation of mood and circadian rhythms. The modulatory effects of two novel agonists, LP-211 and LP-378, were assessed in male adult CD-1 mice with a battery of behavioral tests. Exp. 1 (Black/White Boxes, BWB: Adriani et al., 2009) and Exp. 2 (Dark/Light, D/L; Novelty-seeking, N-S) show: a) that LP-211 administration (acutely, at a 0.25 mg/kg dose i.p.) increases locomotion and BWB exploration; b) that the time spent away from an aversive, lit chamber (i.e., stress-induced anxiety) and in a new environment (i.e., novelty-induced curiosity) are both reduced. Sub-chronic LP-211 (at a 2.5 mg/kg dose i.p.) reveals a sensitization of locomotor-stimulant properties over 4-5 days. In Exp. 3 (BWB), a three- to four-fold dosage (acutely, at 0.83 mg/kg i.p.) is needed with LP-378 to increase locomotion and BWB exploration. In Exp. 4, mice under constant-light conditions reveal the expected spontaneous lengthening (1.5 h per day) of circadian rhythms. A significant phase advance is induced by LP-211 (at a 0.25 mg/kg dose i.p., administered around activity offset), with onset of activity taking place 6 h earlier than in controls. In summary, LP-211 is able to act consistently onto exploratory motivation, anxiety-related profiles, and spontaneous circadian rhythm. In the next future, agonist modulation of 5-HT(7) receptors might turn out to be beneficial for sleep and/or anxiety disorders. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.

  6. Anti-pruritic activity of pioglitazone on serotonin-induced scratching in mice: possible involvement of PPAR-gamma receptor and nitric oxide.

    Science.gov (United States)

    Shafizadeh, Milad; Rajaba, Armin; Imran khan, Muhammad; Ostadhadi, Sattar; Rastegar, Hosein; Dehpour, Ahmadreza

    2014-12-05

    Pioglitazone is a member of peroxisome proliferator-activated receptor gamma (PPARγ) agonists, particularly used in management of type II diabetes. However it also has effects in some dermatological disorders. The current study was designed to investigate the effects of oral administration of pioglitazone and the association of nitric oxide, in serotonin-induced scratching in mice. In order to produce the scratching activity, serotonin (141 nm/site) was administered intradermally in the nape of the neck. Pioglitazone in concentrations of 10, 20, 40 and 80 mg/kg, was peroral administered (p.o) as a single dose, 4 h before the serotonin injection. PPAR-γ antagonist, GW9662 (2 mg/kg, i.p); a non-specific nitric oxide synthase (NOS) inhibitor, NG-nitro-L-arginine methyl ester (L-NAME; 1 mg/kg, i.p); or a nitric oxide precursor, L-arginine (100 mg/kg, i.p.); adminstrated 15 min before pioglitazone were analyzed for anti-scratching activity. Results obtained showed that pioglitazone (40 and 80 mg/kg, p.o) reduced the scratching in a dose-dependent manner. GW9662 inverted the anti-scratching effect of pioglitazone (80 mg/kg). Acute dose of L-NAME (1 mg/kg, i.p) also prevented the anti-scratching property of pioglitazone (80 mg/kg, p.o); although L-arginine was used in sub-effective dose (100 mg/kg, i.p), however it potentiated the anti-scratching behavior when co-injected with pioglitazone (20 mg/kg, p.o). The results indicate that acute pioglitazone has an anti-scratching effect on serotonin-induced scratching in mice. It is concluded that anti-scratching outcome of acute pioglitazone is initiated via activation of PPAR-γ receptor and to some extent by the NO pathway.

  7. Systematic Screening of the Serotonin Receptor 1A (5-HT1A) Gene in Chronic Tinnitus

    Institute of Scientific and Technical Information of China (English)

    Kleinjung T; Langguth B; Fischer B; Hajak G; Eichhammer P; Sand PG

    2006-01-01

    Objective Chronic tinnitus is a highly prevalent condition and has been hypothesized to result from an innate disturbance in central nervous serotonergic transmission. Given the frequent comorbidity with major depression and anxiety, we argue that candidate genes for these disorders are likely to overlap. The present study addresses the gene encoding for the 5-HT1A receptor as a putative risk factor for tinnitus. Methods In 88 subjects with a diagnosis of chronic subjective tinnitus who underwent a detailed neurootological examination, the entire 5-HT1A gene was amplified using overlapping PCR products. Amplicons were custom sequenced bidirectionally and were screened for variants in multiple alignments against the human genome reference. Results We identified a synonymous C > T exchange at residue 184 (Pro) in 7/88 subjects, but detected no missense variants in the population under study. Specifically, the following residues were fully conserved: 16 (Pro), 22 (Gly), 28 (Ile), 98 (Val), 220(Arg), 267 (Val), 273 (Gly), and 418 (Asn). Discussion The present data count against the causation of chronic tinnitus by a change in the 5-HT1A receptor's amino acid sequence. However, the allele frequency for the 184Pro minor allele (0.04) reached twice the frequency reported in control cohorts from the same ethnicity.Additional investigations are invited to clarify the role of the 5-HT1A polymorphism in larger samples, and to control for comorbid affective disorders.

  8. Structure-activity relationships of constrained phenylethylamine ligands for the serotonin 5-HT2 receptors.

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    Vignir Isberg

    Full Text Available Serotonergic ligands have proven effective drugs in the treatment of migraine, pain, obesity, and a wide range of psychiatric and neurological disorders. There is a clinical need for more highly 5-HT2 receptor subtype-selective ligands and the most attention has been given to the phenethylamine class. Conformationally constrained phenethylamine analogs have demonstrated that for optimal activity the free lone pair electrons of the 2-oxygen must be oriented syn and the 5-oxygen lone pairs anti relative to the ethylamine moiety. Also the ethyl linker has been constrained providing information about the bioactive conformation of the amine functionality. However, combined 1,2-constriction by cyclization has only been tested with one compound. Here, we present three new 1,2-cyclized phenylethylamines, 9-11, and describe their synthetic routes. Ligand docking in the 5-HT2B crystal structure showed that the 1,2-heterocyclized compounds can be accommodated in the binding site. Conformational analysis showed that 11 can only bind in a higher-energy conformation, which would explain its absent or low affinity. The amine and 2-oxygen interactions with D3.32 and S3.36, respectively, can form but shift the placement of the core scaffold. The constraints in 9-11 resulted in docking poses with the 4-bromine in closer vicinity to 5.46, which is polar only in the human 5-HT2A subtype, for which 9-11 have the lowest affinity. The new ligands, conformational analysis and docking expand the structure-activity relationships of constrained phenethylamines and contributes towards the development of 5-HT2 receptor subtype-selective ligands.

  9. Cafeteria diet and probiotic therapy: cross talk among memory, neuroplasticity, serotonin receptors and gut microbiota in the rat.

    Science.gov (United States)

    Beilharz, J E; Kaakoush, N O; Maniam, J; Morris, M J

    2017-03-14

    The western diet is known to have detrimental effects on cognition and the gut microbiota, but few studies have investigated how these may be related. Here, we examined whether a probiotic could prevent diet-induced memory deficits. Rats were pre-exposed to vehicle, low or high doses of VSL#3 for 2 weeks before half were switched from chow to a cafeteria diet (Caf) for 25 days; VSL#3 treatment continued until death. High-dose VSL#3 prevented the diet-induced memory deficits on the hippocampal-dependent place task, but the probiotic caused deficits on the perirhinal-dependent object task, irrespective of diet or dose. No differences were observed in anxiety-like behaviour on the elevated plus maze. Gut microbial diversity was dramatically decreased by Caf diet and here, VSL#3 was able to increase the abundance of some taxa contained in the probiotic such as Streptococcus and Lactobacillus and also other taxa including Butyrivibrio, which were decreased by the Caf diet. This affected the predicted profile of microbial metabolic pathways related to antioxidant and bile biosynthesis, and fat and carbohydrate metabolism. In the hippocampus, the Caf diet increased the expression of many genes related to neuroplasticity and serotonin receptor (5HT) 1A, which was normalised in Caf-High rats. Distance-based linear modelling showed that these genes were the best predictors of place memory, and related to microbiota principal component (PC) 1. Neuroplasticity genes in the perirhinal cortex were also affected and related to PC1 but object memory performance was correlated with perirhinal 5HT2C expression and microbiota PC3. These results show that probiotics can be beneficial in situations of gut dysbiosis where memory deficits are evident but may be detrimental in healthy subjects.Molecular Psychiatry advance online publication, 14 March 2017; doi:10.1038/mp.2017.38.

  10. Polymorphism in the serotonin receptor 2a (HTR2A gene as possible predisposal factor for aggressive traits.

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    Zsofia Banlaki

    Full Text Available Aggressive manifestations and their consequences are a major issue of mankind, highlighting the need for understanding the contributory factors. Still, aggression-related genetic analyses have so far mainly been conducted on small population subsets such as individuals suffering from a certain psychiatric disorder or a narrow-range age cohort, but no data on the general population is yet available. In the present study, our aim was to identify polymorphisms in genes affecting neurobiological processes that might explain some of the inter-individual variation between aggression levels in the non-clinical Caucasian adult population. 55 single nucleotide polymorphisms (SNP were simultaneously determined in 887 subjects who also filled out the self-report Buss-Perry Aggression Questionnaire (BPAQ. Single marker association analyses between genotypes and aggression scores indicated a significant role of rs7322347 located in the HTR2A gene encoding serotonin receptor 2a following Bonferroni correction for multiple testing (p = 0.0007 both for males and females. Taking the four BPAQ subscales individually, scores for Hostility, Anger and Physical Aggression showed significant association with rs7322347 T allele in themselves, while no association was found with Verbal Aggression. Of the subscales, relationship with rs7322347 was strongest in the case of Hostility, where statistical significance virtually equaled that observed with the whole BPAQ. In conclusion, this is the first study to our knowledge analyzing SNPs in a wide variety of genes in terms of aggression in a large sample-size non-clinical adult population, also describing a novel candidate polymorphism as predisposal to aggressive traits.

  11. Suppression of piriform cortex activity in rat by corticotropin-releasing factor 1 and serotonin 2A/C receptors.

    Science.gov (United States)

    Narla, Chakravarthi; Dunn, Henry A; Ferguson, Stephen S G; Poulter, Michael O

    2015-01-01

    The piriform cortex (PC) is richly innervated by corticotropin-releasing factor (CRF) and serotonin (5-HT) containing axons arising from central amygdala and Raphe nucleus. CRFR1 and 5-HT2A/2CRs have been shown to interact in manner where CRFR activation subsequently potentiates the activity of 5-HT2A/2CRs. The purpose of this study was to determine how the activation of CRFR1 and/or 5-HT2Rs modulates PC activity at both the circuit and cellular level. Voltage sensitive dye imaging showed that CRF acting through CRFR1 dampened activation of the Layer II of PC and interneurons of endopiriform nucleus. Application of the selective 5-HT2A/CR agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) following CRFR1 activation potentiated this effect. Blocking the interaction between CRFR1 and 5-HT2R with a Tat-CRFR1-CT peptide abolished this potentiation. Application of forskolin did not mimic CRFR1 activity but instead blocked it, while a protein kinase A antagonist had no effect. However, activation and antagonism of protein kinase C (PKC) either mimicked or blocked CRF modulation, respectively. DOI had no effect when applied alone indicating that the prior activation of CRFR1 receptors was critical for DOI to show significant effects similar to CRF. Patch clamp recordings showed that both CRF and DOI reduced the synaptic responsiveness of Layer II pyramidal neurons. CRF had highly variable effects on interneurons within Layer III, both increasing and decreasing their excitability, but DOI had no effect on the excitability of this group of neurons. These data show that CRF and 5-HT, acting through both CRFR1 and 5-HT2A/CRs, reduce the activation of the PC. This modulation may be an important blunting mechanism of stressor behaviors mediated through the olfactory cortex.

  12. Central serotonin(2B) receptor blockade inhibits cocaine-induced hyperlocomotion independently of changes of subcortical dopamine outflow.

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    Devroye, Céline; Cathala, Adeline; Di Marco, Barbara; Caraci, Filippo; Drago, Filippo; Piazza, Pier Vincenzo; Spampinato, Umberto

    2015-10-01

    The central serotonin2B receptor (5-HT2BR) is currently considered as an interesting pharmacological target for improved treatment of drug addiction. In the present study, we assessed the effect of two selective 5-HT2BR antagonists, RS 127445 and LY 266097, on cocaine-induced hyperlocomotion and dopamine (DA) outflow in the nucleus accumbens (NAc) and the dorsal striatum of freely moving rats. The peripheral administration of RS 127445 (0.16 mg/kg, i.p.) or LY 266097 (0.63 mg/kg, i.p.) significantly reduced basal DA outflow in the NAc shell, but had no effect on cocaine (10 mg/kg, i.p.)-induced DA outflow in this brain region. Also, RS 127445 failed to modify both basal and cocaine-induced DA outflow in the NAc core and the dorsal striatum. Conversely, both 5-HT2BR antagonists reduced cocaine-induced hyperlocomotion. Furthermore, RS 127445 as well as the DA-R antagonist haloperidol (0.1 mg/kg, i.p.) reduced significantly the late-onset hyperlocomotion induced by the DA-R agonist quinpirole (0.5 mg/kg, s.c.). Altogether, these results demonstrate that 5-HT2BR blockade inhibits cocaine-induced hyperlocomotion independently of changes of subcortical DA outflow. This interaction takes place downstream to DA neurons and could involve an action at the level of dorsostriatal and/or NAc DA transmission, in keeping with the importance of these brain regions in the behavioural responses of cocaine. Overall, this study affords additional knowledge into the regulatory control exerted by the 5-HT2BR on ascending DA pathways, and provides additional support to the proposed role of 5-HT2BRs as a new pharmacological target in drug addiction.

  13. The impact of cue learning, trait anxiety and genetic variation in the serotonin 1A receptor on contextual fear.

    Science.gov (United States)

    Baas, Johanna M P; Heitland, Ivo

    2015-12-01

    In everyday life, aversive events are usually associated with certain predictive cues. Normally, the acquisition of these contingencies enables organisms to appropriately respond to threat. Presence of a threat cue clearly signals 'danger', whereas absence of such cues signals a period of 'safety'. Failure to identify threat cues may lead to chronic states of anxious apprehension in the context in which the threat has been imminent, which may be instrumental in the pathogenesis of anxiety disorders. In this study, existing data from 150 healthy volunteers in a cue and context virtual reality fear conditioning paradigm were reanalyzed. The aim was to further characterize the impact of cue acquisition and trait anxiety, and of a single nucleotide polymorphism in the serotonin 1A receptor gene (5-HTR1A, rs6295), on cued fear and contextual anxiety before and after fear contingencies were explicitly introduced. Fear conditioned responding was quantified with fear potentiation of the eyeblink startle reflex and subjective fear ratings. First, we replicated previous findings that the inability to identify danger cues during acquisition leads to heightened anxious apprehension in the threat context. Second, in subjects who did not identify the danger cue initially, contextual fear was associated with trait anxiety after the contingencies were explicitly instructed. Third, genetic variability within 5-HTR1A (rs6295) was associated with contextual fear independent of awareness or trait anxiety. These findings confirm that failure to acquire cue contingencies impacts contextual fear responding, in association with trait anxiety. The observed 5-HTR1A effect is in line with models of anxiety, but needs further replication.

  14. The 5-hydroxytryptamine4 receptor agonists prucalopride and PRX-03140 increase acetylcholine and histamine levels in the rat prefrontal cortex and the power of stimulated hippocampal θ oscillations.

    Science.gov (United States)

    Johnson, David E; Drummond, Elena; Grimwood, Sarah; Sawant-Basak, Aarti; Miller, Emily; Tseng, Elaine; McDowell, Laura L; Vanase-Frawley, Michelle A; Fisher, Katherine E; Rubitski, David M; Stutzman-Engwall, Kim J; Nelson, Robin T; Horner, Weldon E; Gorczyca, Roxanne R; Hajos, Mihaly; Siok, Chester J

    2012-06-01

    5-Hydroxytryptamine (5-HT)(4) receptor agonists reportedly stimulate brain acetylcholine (ACh) release, a property that might provide a new pharmacological approach for treating cognitive deficits associated with Alzheimer's disease. The purpose of this study was to compare the binding affinities, functional activities, and effects on neuropharmacological responses associated with cognition of two highly selective 5-HT(4) receptor agonists, prucalopride and 6,7-dihydro-4-hydroxy-7-isopropyl-6-oxo-N-[3-(piperidin-1-yl)propyl]thieno[2,3-b]pyridine-5-carboxamide (PRX-03140). In vitro, prucalopride and PRX-03140 bound to native rat brain 5-HT(4) receptors with K(i) values of 30 nM and 110 nM, respectively, and increased cAMP production in human embryonic kidney-293 cells expressing recombinant rat 5-HT(4) receptors. In vivo receptor occupancy studies established that prucalopride and PRX-03140 were able to penetrate the brain and bound to 5-HT(4) receptors in rat brain, achieving 50% receptor occupancy at free brain exposures of 330 nM and 130 nM, respectively. Rat microdialysis studies revealed that prucalopride maximally increased ACh and histamine levels in the prefrontal cortex at 5 and 10 mg/kg, whereas PRX-03140 significantly increased cortical histamine levels at 50 mg/kg, failing to affect ACh release at doses lower than 150 mg/kg. In combination studies, donepezil-induced increases in cortical ACh levels were potentiated by prucalopride and PRX-03140. Electrophysiological studies in rats demonstrated that both compounds increased the power of brainstem-stimulated hippocampal θ oscillations at 5.6 mg/kg. These findings show for the first time that the 5-HT(4) receptor agonists prucalopride and PRX-03140 can increase cortical ACh and histamine levels, augment donepezil-induced ACh increases, and increase stimulated-hippocampal θ power, all neuropharmacological parameters consistent with potential positive effects on cognitive processes.

  15. Serotonin 2A receptor regulation of striatal neuropeptide gene expression is selective for tachykinin, but not enkephalin neurons following dopamine depletion.

    Science.gov (United States)

    Basura, G J; Walker, P D

    2001-08-15

    Serotonin (5-HT) 2A receptor-mediated regulation of striatal preprotachykinin (PPT) and preproenkephalin (PPE) mRNAs was studied in adult rodents that had been subjected to near-total dopamine (DA) depletion as neonates. Two months following bilateral 6-hydroxydopamine (6-OHDA) lesion, PPT mRNA levels decreased 59-73% across dorsal subregions of the rostral and caudal striatum while PPE transcripts increased 61-94%. Four hours after a single injection of the serotonin 2A/2C receptor agonist, (+/-)-1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI; 1 mg/kg), PPT mRNA expression was significantly increased in DA-depleted rats across all dorsal subregions of the rostral and caudal striatum as compared to 6-OHDA-treated animals alone. In the intact rat, DOI did not influence PPT mRNA levels in the rostral striatum, but did raise expression in the caudal striatum where 5-HT2A receptors are prominent. DOI did not regulate PPE mRNA levels in any striatal sub-region of the intact or DA-depleted rat. Prior administration of the 5-HT2A/2C receptor antagonist, ritanserin (1 mg/kg) or the 5-HT2A receptor antagonist, ketanserin (1 mg/kg) completely blocked the DOI-induced increases in striatal PPT mRNA in both lesioned and intact animals. The ability of ketanserin to produce identical results as ritanserin suggests that 5-HT2A receptor-mediated regulation is selectively strengthened within tachykinin neurons of the rostral striatum which are suppressed by DA depletion. The selectivity suggests that 5-HT2A receptor upregulation following DA depletion is capable of regulating tachykinin biosynthesis without influencing enkephalin expression in striatal output neurons.

  16. A Molecular Motor, KIF13A, Controls Anxiety by Transporting the Serotonin Type 1A Receptor

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    Ruyun Zhou

    2013-02-01

    Full Text Available Molecular motors are fundamental to neuronal morphogenesis and function. However, the extent to which molecular motors are involved in higher brain functions remains largely unknown. In this study, we show that mice deficient in the kinesin family motor protein KIF13A (Kif13a−/− mice exhibit elevated anxiety-related behavioral phenotypes, probably because of a reduction in 5HT1A receptor (5HT1AR transport. The cell-surface expression level of the 5HT1AR was reduced in KIF13A-knockdown neuroblastoma cells and Kif13a−/− hippocampal neurons. Biochemical analysis showed that the forkhead-associated (FHA domain of KIF13A and an intracellular loop of the 5HT1AR are the interface between the motor and cargo vesicles. A minimotor consisting of the motor and FHA domains is able to transport 5HT1AR-carrying organelles in in vitro reconstitution assays. Collectively, our results suggest a role for this molecular motor in anxiety control.

  17. Influence of a serotonin receptor antagonist, 5-HTP-DP-hex, on spinal and thalamic nociceptive neurons in rats.

    Science.gov (United States)

    Emmers, R; Tamir, H; Wilchek, M

    1987-06-01

    The antinociceptive properties of a new synthetic dipeptide (N-hexanoyl-5-hydroxytryptophyl-5-hydroxytryptophan amide, or 5-HTP-DP-hex) were studied in rats by an electrophysiological method. After an i.p. injection of alpha-chloralose and urethane, the animals were prepared for stereotaxic approach to the nucleus ventralis posterolateralis of the thalamus. With tungsten microelectrodes, individual nociceptive neurons in the nucleus were identified by the sequence of spikes emitted in response to single-pulse stimulation of the sciatic nerve. In addition to the usual short-latency spikes, a nociceptive neuron fired late spikes at regular intervals within 500 ms following each stimulus. When the spikes were accumulated in poststimulus time histograms, the short-latency spikes compiled an intensity-related (I) peak. The late spikes formed modality-related (M) peaks with spacing characteristic of nociception. Intracarotid infusion of 5-HTP-DP-hex (1 mg/kg) elevated the delayed portion of the I peak and the first M peak. This effect was followed in 25 min by suppression of all M peaks. The control record could be reinstated at any time by 5-hydroxytryptophan (3.5 mg/kg), or by natural recovery in 2.5 h. Responses evoked from a thalamic nociceptive neuron by single-pulse stimulation of the spinothalamic tract were modified by 5-HTP-DP-hex in a similar manner, except that no elevation of the activity peaks was observed. As shown previously, elevation of the delayed I peak and M1 indicated an increased input of A-delta and C fibers, respectively. The increased input lowers the response threshold and may represent hyperalgesia. Suppression of the M peaks may result from altered function of the positive feedback loop in the nociceptive system at the thalamic level, and may represent analgesia. Naloxone, methysergide, as well as ketanserin had no significant effect on the response histograms. These findings suggested that 5-HTP-DP-hex, a known serotonin receptor antagonist

  18. Antinociception by systemically-administered acetaminophen (paracetamol) involves spinal serotonin 5-HT7 and adenosine A1 receptors, as well as peripheral adenosine A1 receptors.

    Science.gov (United States)

    Liu, Jean; Reid, Allison R; Sawynok, Jana

    2013-03-01

    Acetaminophen (paracetamol) is a widely used analgesic, but its sites and mechanisms of action remain incompletely understood. Recent studies have separately implicated spinal adenosine A(1) receptors (A(1)Rs) and serotonin 5-HT(7) receptors (5-HT(7)Rs) in the antinociceptive effects of systemically administered acetaminophen. In the present study, we determined whether these two actions are linked by delivering a selective 5-HT(7)R antagonist to the spinal cord of mice and examining nociception using the formalin 2% model. In normal and A(1)R wild type mice, antinociception by systemic (i.p.) acetaminophen 300mg/kg was reduced by intrathecal (i.t.) delivery of the selective 5-HT(7)R antagonist SB269970 3μg. In mice lacking A(1)Rs, i.t. SB269970 did not reverse antinociception by systemic acetaminophen, indicating a link between spinal 5-HT(7)R and A(1)R mechanisms. We also explored potential roles of peripheral A(1)Rs in antinociception by acetaminophen administered both locally and systemically. In normal mice, intraplantar (i.pl.) acetaminophen 200μg produced antinociception in the formalin test, and this was blocked by co-administration of the selective A(1)R antagonist DPCPX 4.5μg. Acetaminophen administered into the contralateral hindpaw had no effect, indicating a local peripheral action. When acetaminophen was administered systemically, its antinociceptive effect was reversed by i.pl. DPCPX in normal mice; this was also observed in A(1)R wild type mice, but not in those lacking A(1)Rs. In summary, we demonstrate a link between spinal 5-HT(7)Rs and A(1)Rs in the spinal cord relevant to antinociception by systemic acetaminophen. Furthermore, we implicate peripheral A(1)Rs in the antinociceptive effects of locally- and systemically-administered acetaminophen.

  19. Schizophrenia-like disruptions of sensory gating by serotonin receptor stimulation in rats: effect of MDMA, DOI and 8-OH-DPAT.

    Science.gov (United States)

    Thwaites, Shane J; Gogos, Andrea; Van den Buuse, Maarten

    2013-11-01

    Schizophrenia pathophysiology is associated with alterations in several neurotransmitter systems, particularly dopamine, glutamate and serotonin (5-HT). Schizophrenia patients also have disruptions in sensory gating, a brain information filtering mechanism in response to repeated sensory stimuli. Dopamine and glutamate have been implicated in sensory gating; however, little is known about the contribution of serotonin. We therefore investigated the effects of several psychoactive compounds that alter serotonergic neuronal activity on event-related potentials (ERP) to paired auditory pulses. Male Sprague-Dawley rats were implanted with cortical surface electrodes to measure ERPs to 150 presentations of two 85 dB bursts of white noise, 500 ms apart (S1 and S2). Saline-treated animals suppressed the response to S2 to less than 50% of S1. In contrast, treatment with the serotonin releaser, MDMA (ecstasy; 2.0mg/kg), the 5-HT2A/2C receptor agonist, DOI (0.5mg/kg), or the 5-HT1A/7 receptor agonist, 8-OH-DPAT (0.5mg/kg), caused an increase in S2/S1 ratios. Analysis of waveform components suggested that the S2/S1 ratio disruption by MDMA was due to subtle effects on the ERPs to S1 and S2; DOI caused the disruption primarily by reducing the ERP to S1; 8-OH-DPAT-induced disruptions were due to an increase in the ERP to S2. These results show that 5-HT receptor stimulation alters S2/S1 ERP ratios in rats. These results may help to elucidate the sensory gating deficits observed in schizophrenia patients.

  20. No Direct Association of Serotonin Transporter (STin2 VNTR and Receptor (HT 102T>C Gene Variants in Genetic Susceptibility to Migraine

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    Gunjan Joshi

    2010-01-01

    Full Text Available We aimed to find out if the serotonin receptor (HT102T>C and serotonin transporter (STin 2 polymorphisms play any role in genetic susceptibility of migraine. For the study, 217 migraine patients and 217 healthy controls (HC were recruited and genotyping was carried out using the Polymerase Chain Reaction and Restriction Fragment Length polymorphism (PCR-RFLP method. All results were Bonferroni corrected. We could not find any significant differences in the genotype or allele frequencies in case of HT 102 T>C polymorphism between migraine patients and healthy controls (P value=0.224. No significant association was seen at allele and carrier levels. Sub-grouping the patients on the basis of gender or on basis of migraine type i.e. with or without aura also did not show any association. Similarly, no difference in genotype (P value=0.236, allele (P value=0.550 or carrier frequency (P value=0.771 in STin 2 VNTR polymorphism was observed between migraine patients. However, HT 102 TC genotype was observed to interact significantly with the STin 2.10/10 genotype in enhancing risk of migraine, both with and without aura. In conclusion, the HT102 T>C receptor and the STin 2 VNTR transporter polymorphisms, did not individually confer any significant risk of migraine or its clinical subtypes but the two polymorphisms appear to synergistically influence susceptibility to migraine. Serotonin transporter (STin2 VNTR and receptor (HT 102T>C polymorphisms; Migraine with aura (MA; Migraine without aura (MO; Genetic susceptibility

  1. Retinal Neuroprotective Effects of Flibanserin, an FDA-Approved Dual Serotonin Receptor Agonist-Antagonist.

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    Aaron S Coyner

    Full Text Available To assess the neuroprotective effects of flibanserin (formerly BIMT-17, a dual 5-HT1A agonist and 5-HT2A antagonist, in a light-induced retinopathy model.Albino BALB/c mice were injected intraperitoneally with either vehicle or increasing doses of flibanserin ranging from 0.75 to 15 mg/kg flibanserin. To assess 5-HT1A-mediated effects, BALB/c mice were injected with 10 mg/kg WAY 100635, a 5-HT1A antagonist, prior to 6 mg/kg flibanserin and 5-HT1A knockout mice were injected with 6 mg/kg flibanserin. Injections were administered once immediately prior to light exposure or over the course of five days. Light exposure lasted for one hour at an intensity of 10,000 lux. Retinal structure was assessed using spectral domain optical coherence tomography and retinal function was assessed using electroretinography. To investigate the mechanisms of flibanserin-mediated neuroprotection, gene expression, measured by RT-qPCR, was assessed following five days of daily 15 mg/kg flibanserin injections.A five-day treatment regimen of 3 to 15 mg/kg of flibanserin significantly preserved outer retinal structure and function in a dose-dependent manner. Additionally, a single-day treatment regimen of 6 to 15 mg/kg of flibanserin still provided significant protection. The action of flibanserin was hindered by the 5-HT1A antagonist, WAY 100635, and was not effective in 5-HT1A knockout mice. Creb, c-Jun, c-Fos, Bcl-2, Cast1, Nqo1, Sod1, and Cat were significantly increased in flibanserin-injected mice versus vehicle-injected mice.Intraperitoneal delivery of flibanserin in a light-induced retinopathy mouse model provides retinal neuroprotection. Mechanistic data suggests that this effect is mediated through 5-HT1A receptors and that flibanserin augments the expression of genes capable of reducing mitochondrial dysfunction and oxidative stress. Since flibanserin is already FDA-approved for other indications, the potential to repurpose this drug for treating retinal

  2. Combined α7 nicotinic acetylcholine receptor agonism and partial serotonin transporter inhibition produce antidepressant-like effects in the mouse forced swim and tail suspension tests

    DEFF Research Database (Denmark)

    Andreasen, Jesper T; Redrobe, John P; Nielsen, Elsebet Ø

    2012-01-01

    Emerging evidence points to an involvement of nicotinic acetylcholine receptors (nAChRs) in major depression. Nicotine improves symptoms of depression in humans and shows antidepressant-like effects in rodents. Monoamine release is facilitated by nAChR stimulation, and nicotine-evoked serotonin (5...... represents a compound displaying the synergistic effect of α7 nAChR agonism combined with partial 5-HT reuptake inhibition previously described. The addition of α7 nAChR agonism to classical monoamine-based mechanisms may represent a novel option for the improved treatment of major depression....

  3. Polymorphisms of serotonin receptor 2A and 2C genes and COMT in relation to obesity and type 2 diabetes

    DEFF Research Database (Denmark)

    Kring, Sofia I I; Werge, Thomas; Holst, Claus

    2009-01-01

    BACKGROUND: Candidate genes of psychological importance include 5HT2A, 5HT2C, and COMT, implicated in the serotonin, noradrenaline and dopamine pathways, which also may be involved in regulation of energy balance. We investigated the associations of single nucleotide polymorphisms (SNPs) of these......BACKGROUND: Candidate genes of psychological importance include 5HT2A, 5HT2C, and COMT, implicated in the serotonin, noradrenaline and dopamine pathways, which also may be involved in regulation of energy balance. We investigated the associations of single nucleotide polymorphisms (SNPs...

  4. Association of the promoter polymorphism -1438G/A of the 5-HT2A receptor gene with behavioral impulsiveness and serotonin function in women with bulimia nervosa.

    Science.gov (United States)

    Bruce, Kenneth R; Steiger, Howard; Joober, Ridha; Ng Ying Kin, N M K; Israel, Mimi; Young, Simon N

    2005-08-05

    Separate lines of research suggest that the functional alterations in the serotonin (5-HT) 2A receptor are associated with 5-HT tone, behavioral impulsiveness, and bulimia nervosa (BN). We explored the effect of allelic variations within the 5-HT2A receptor gene promoter polymorphism -1438G/A on trait impulsiveness and serotonin function in women with BN. Participants included women with BN having the A allele (i.e., AA homozygotes and AG heterozygotes, BNA+, N = 21); women with BN but without the A allele (i.e., GG homozygotes, BNGG, N = 12), and normal eater control women having the A allele (NEA+, N = 19) or without the A allele (NEGG; N = 9). The women were assessed for psychopathological tendencies and eating disorder symptoms, and provided blood samples for measurement of serial prolactin responses following oral administration of the post-synaptic partial 5-HT agonist meta-chlorophenylpiperazine (m-CPP). The BNGG group had higher scores than the other groups on self-report measures of non-planning and overall impulsiveness and had blunted prolactin response following m-CPP. The bulimic groups did not differ from each other on current eating symptoms or on frequencies of other Axis I mental disorders. Findings indicate that women with BN who are GG homozygotes on the -1438G/A promoter polymorphism are characterized by increased impulsiveness and lower sensitivity to post-synaptic serotonin activation. These findings implicate the GG genotype in the co-aggregation of impulsive behaviors and alterations of post-synaptic 5-HT functioning in women with BN.

  5. Genetic Polymorphism of 1019C/G (rs6295) Promoter of Serotonin 1A Receptor and Catechol-O-Methyltransferase in Panic Disorder

    Science.gov (United States)

    Ishiguro, Shin; Aoki, Akiko; Ueda, Mikito; Hayashi, Yuki; Akiyama, Kazufumi; Kato, Kazuko; Shimoda, Kazutaka

    2017-01-01

    Objective Family and twin studies have suggested genetic liability for panic disorder (PD) and therefore we sought to determine the role of noradrenergic and serotonergic candidate genes for susceptibility for PD in a Japanese population. Methods In this age- and gender-matched case-control study involving 119 PD patients and 119 healthy controls, we examined the genotype distributions and allele frequencies of the serotonin transporter gene linked polymorphic region (5-HTTLPR), −1019C/G (rs6295) promoter polymorphism of the serotonin receptor 1A (5-HT1A), and catechol-O-methyltransferase (COMT) gene polymorphism (rs4680) and their association with PD. Results No significant differences were evident in the allele frequencies or genotype distributions of the COMT (rs4680), 5-HTTLPR polymorphisms or the −1019C/G (rs6295) promoter polymorphism of 5-HT1A between PD patients and controls. Although there were no significant associations of these polymorphisms with in subgroups of PD patients differentiated by gender or in subgroup comorbid with agoraphobia (AP), significant difference was observed in genotype distributions of the −1019C/G (rs6295) promoter polymorphism of 5-HT1A between PD patients without AP and controls (p=0.047). Conclusion In this association study, the 1019C/G (rs6295) promoter polymorphism of the 5-HT1A receptor G/G genotype was associated with PD without AP in a Japanese population. PMID:28096880

  6. Mice lacking the serotonin transporter exhibit 5-HT(1A) receptor-mediated abnormalities in tests for anxiety-like behavior.

    Science.gov (United States)

    Holmes, Andrew; Yang, Rebecca J; Lesch, Klaus-Peter; Crawley, Jacqueline N; Murphy, Dennis L

    2003-12-01

    The serotonin transporter (5-HTT) regulates serotonergic neurotransmission via clearance of extracellular serotonin. Abnormalities in 5-HTT expression or function are found in mood and anxiety disorders, and the 5-HTT is a major target for antidepressants and anxiolytics. The 5-HTT is further implicated in the pathophysiology of these disorders by evidence that genetic variation in the promoter region of the HTT (SLC6A4) is associated with individual differences in anxiety and neural responses to fear. To further evaluate the role of the 5-HTT in anxiety, we employed a mouse model in which the 5-HTT gene (htt) was constitutively inactivated. 5-HTT -/- mice were characterized for anxiety-related behaviors using a battery of tests (elevated plus maze, lightdark exploration test, emergence test, and open field test). Male and female 5-HTT -/- mice showed robust phenotypic abnormalities as compared to +/+ littermates, suggestive of increased anxiety-like behavior and inhibited exploratory locomotion. The selective 5-HT(1A) receptor antagonist, WAY 100635 (0.05-0.3 mg/kg), produced a significant anxiolytic-like effect in the elevated plus maze in 5-HTT -/- mice, but not +/+ controls. The present findings demonstrate abnormal behavioral phenotypes in 5-HTT null mutant mice in tests for anxiety-like and exploratory behavior, and suggest a role for the 5-HT(1A) receptor in mediating these abnormalities. 5-HTT null mutant mice provide a model to investigate the role of the 5-HTT in mood and anxiety disorders.

  7. The time course of serotonin 2A receptor expression after spinal transection of rats: an immunohistochemical study

    DEFF Research Database (Denmark)

    Kong, X-Y; Wienecke, Jacob; Chen, M;

    2011-01-01

    Hyperexcitability of motoneurons is one of the key mechanism that has been demonstrated to underlie the pathogenesis of spasticity after spinal injury. Serotonin (5-HT) denervation supersensitivity is one of the mechanisms underlying this increased motoneuron excitability. In this study, to exami...

  8. Lifelong disturbance of serotonin transporter functioning results in fear learning deficits : Reversal by blockade of CRF1 receptors

    NARCIS (Netherlands)

    Bijlsma, Elisabeth Y; Hendriksen, Hendrikus; Baas, Johanna M P; Millan, Mark J; Groenink, Lucianne

    2015-01-01

    The inability to associate aversive events with relevant cues (i.e. fear learning) may lead to maladaptive anxiety. To further study the role of the serotonin transporter (SERT) in fear learning, classical fear conditioning was studied in SERT knockout rats (SERT(-/-)) using fear potentiation of the

  9. Ex vivo evaluation of the serotonin 1A receptor partial agonist [³H]CUMI-101 in awake rats

    DEFF Research Database (Denmark)

    Palner, Mikael; Underwood, Mark D; Kumar, Dileep J S

    2011-01-01

    [³H]CUMI-101 is a 5-HT(1A) partial agonist, which has been evaluated for use as a positron emission tracer in baboon and humans. We sought to evaluate the properties of [³H]CUMI-101 ex vivo in awake rats and determine if [³H]CUMI-101 can measure changes in synaptic levels of serotonin after...

  10. Lifelong disturbance of serotonin transporter functioning results in fear learning deficits : Reversal by blockade of CRF1 receptors

    NARCIS (Netherlands)

    Bijlsma, Elisabeth Y; Hendriksen, Hendrikus; Baas, Johanna M P; Millan, Mark J; Groenink, Lucianne

    2015-01-01

    The inability to associate aversive events with relevant cues (i.e. fear learning) may lead to maladaptive anxiety. To further study the role of the serotonin transporter (SERT) in fear learning, classical fear conditioning was studied in SERT knockout rats (SERT(-/-)) using fear potentiation of the

  11. Targeting Dopamine D3 and Serotonin 5-HT1A and 5-HT2A Receptors for Developing Effective Antipsychotics

    DEFF Research Database (Denmark)

    Brindisi, Margherita; Butini, Stefania; Franceschini, Silvia;

    2014-01-01

    Combination of dopamine D3 antagonism, serotonin 5-HT1A partial agonism, and antagonism at 5-HT2A leads to a novel approach to potent atypical antipsychotics. Exploitation of the original structure-activity relationships resulted in the identification of safe and effective antipsychotics devoid...

  12. Ex vivo evaluation of the serotonin 1A receptor partial agonist [³H]CUMI-101 in awake rats

    DEFF Research Database (Denmark)

    Palner, Mikael; Underwood, Mark D; Kumar, Dileep J S;

    2011-01-01

    -DL-phenylalanine, a serotonin synthesis inhibitor, did not show any effect on the standardized uptake values (SUVs) in any region. Citalopram did alter SBR, but this was due to changes in cerebellar SUVs. Our results indicate that [³H]CUMI-101 is a good radioligand for imaging 5-HT(1A) high-density regions in rats; however...

  13. Effects of a Cannabinoid1 receptor antagonist and Serotonin2C receptor agonist alone and in combination on motivation for palatable food: a dose-addition analysis study in mice.

    Science.gov (United States)

    Ward, Sara Jane; Lefever, Timothy W; Jackson, Cavario; Tallarida, Ronald J; Walker, Ellen A

    2008-05-01

    The cannabinoid and serotonin systems modulate feeding behavior in humans and laboratory animals. The present study assessed whether a cannabinoid (CB)(1) receptor antagonist and a serotonin (5-HT)(2C) receptor agonist alone and in combination attenuate motivation for the liquid nutritional drink Ensure as measured by a progressive ratio (PR) schedule of reinforcement in male C57BL/6 mice. Pretreatment (15 min i.p.) with either the CB(1) receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR141716) (SR; Rimonabant or Acomplia) or the 5-HT(2C) receptor agonist m-chlorophenylpiperazine (mCPP) dose-dependently decreased the maximum ratio completed under the PR schedule (break point) in mice. ED(25) values for SR and mCPP to decrease break point were determined, and the relative potency of each drug alone was quantified. Fixed dose-ratio pairs of SR/mCPP based on their relative potency were then administered. Dose-addition analysis comparing the experimentally determined potency for SR/mCPP combinations with their predicted additive potency revealed that SR/mCPP combinations in 1:1 and 2:1 ratios based on relative potency produced significant synergistic attenuation of break point for Ensure. The ED(25) values for decreasing break point were consistently lower than ED(25) values for decreasing response rate, and synergistic effects of SR/mCPP combinations on break point were seen independent of synergistic effects on response rate. These results indicate that cannabinoid CB(1) and serotonin 5-HT(2C) receptors are involved in motivated feeding behavior in mice and that these compounds can synergistically modulate motivation for palatable food with the synergy dependent upon the ratio of SR/mCPP in the combination.

  14. We Need 2C but Not 2B: Developing Serotonin 2C (5-HT2C) Receptor Agonists for the Treatment of CNS Disorders.

    Science.gov (United States)

    Cheng, Jianjun; Kozikowski, Alan P

    2015-12-01

    The serotonin 2C (5-HT2C ) receptor has been identified as a potential drug target for the treatment of a variety of central nervous system (CNS) disorders, such as obesity, substance abuse, and schizophrenia. In this Viewpoint article, recent progress in developing selective 5-HT2C agonists for use in treating these disorders is summarized, including the work of our group. Challenges in this field and the possible future directions are described. Homology modeling as a method to predict the binding modes of 5-HT2C ligands to the receptor is also discussed. Compared to known ligands, the improved pharmacological profiles of the 2-phenylcyclopropylmethylamine-based 5-HT2C agonists make them preferred candidates for further studies. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. An Orally Active Phenylaminotetralin-Chemotype Serotonin 5-HT7 and 5-HT1A Receptor Partial Agonist that Corrects Motor Stereotypy in Mouse Models.

    Science.gov (United States)

    Canal, Clinton E; Felsing, Daniel E; Liu, Yue; Zhu, Wanying; Wood, JodiAnne T; Perry, Charles K; Vemula, Rajender; Booth, Raymond G

    2015-07-15

    Stereotypy (e.g., repetitive hand waving) is a key phenotype of autism spectrum disorder, Fragile X and Rett syndromes, and other neuropsychiatric disorders, and its severity correlates with cognitive and attention deficits. There are no effective treatments, however, for stereotypy. Perturbation of serotonin (5-HT) neurotransmission contributes to stereotypy, suggesting that distinct 5-HT receptors may be pharmacotherapeutic targets to treat stereotypy and related neuropsychiatric symptoms. For example, preclinical studies indicate that 5-HT7 receptor activation corrects deficits in mouse models of Fragile X and Rett syndromes, and clinical trials for autism are underway with buspirone, a 5-HT1A partial agonist with relevant affinity at 5-HT7 receptors. Herein, we report the synthesis, in vitro molecular pharmacology, behavioral pharmacology, and pharmacokinetic parameters in mice after subcutaneous and oral administration of (+)-5-(2'-fluorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine ((+)-5-FPT), a new, dual partial agonist targeting both 5-HT7 (Ki = 5.8 nM, EC50 = 34 nM) and 5-HT1A (Ki = 22 nM, EC50 = 40 nM) receptors. Three unique, heterogeneous mouse models were used to assess the efficacy of (+)-5-FPT to reduce stereotypy: idiopathic jumping in C58/J mice, repetitive body rotations in C57BL/6J mice treated with the NMDA antagonist, MK-801, and repetitive head twitching in C57BL/6J mice treated with the 5-HT2 agonist, DOI. Systemic (+)-5-FPT potently and efficaciously reduced or eliminated stereotypy in each of the mouse models without altering locomotor behavior on its own, and additional tests showed that (+)-5-FPT, at the highest behaviorally active dose tested, enhanced social interaction and did not cause behaviors indicative of serotonin syndrome. These data suggest that (+)-5-FPT is a promising medication for treating stereotypy in psychiatric disorders.

  16. Molecular and pharmacological characterization of serotonin 5-HT2α and 5-HT7 receptors in the salivary glands of the blowfly Calliphora vicina.

    Directory of Open Access Journals (Sweden)

    Claudia Röser

    Full Text Available Secretion in blowfly (Calliphora vicina salivary glands is stimulated by the biogenic amine serotonin (5-hydroxytryptamine, 5-HT, which activates both inositol 1,4,5-trisphosphate (InsP(3/Ca(2+ and cyclic adenosine 3',5'-monophosphate (cAMP signalling pathways in the secretory cells. In order to characterize the signal-inducing 5-HT receptors, we cloned two cDNAs (Cv5-ht2α, Cv5-ht7 that share high similarity with mammalian 5-HT(2 and 5-HT(7 receptor genes, respectively. RT-PCR demonstrated that both receptors are expressed in the salivary glands and brain. Stimulation of Cv5-ht2α-transfected mammalian cells with 5-HT elevates cytosolic [Ca(2+] in a dose-dependent manner (EC(50 = 24 nM. In Cv5-ht7-transfected cells, 5-HT produces a dose-dependent increase in [cAMP](i (EC(50 = 4 nM. We studied the pharmacological profile for both receptors. Substances that appear to act as specific ligands of either Cv5-HT(2α or Cv5-HT(7 in the heterologous expression system were also tested in intact blowfly salivary gland preparations. We observed that 5-methoxytryptamine (100 nM activates only the Cv5-HT(2α receptor, 5-carboxamidotryptamine (300 nM activates only the Cv5-HT(7 receptor, and clozapine (1 µM antagonizes the effects of 5-HT via Cv5-HT(7 in blowfly salivary glands, providing means for the selective activation of each of the two 5-HT receptor subtypes. This study represents the first comprehensive molecular and pharmacological characterization of two 5-HT receptors in the blowfly and permits the analysis of the physiological role of these receptors, even when co-expressed in cells, and of the modes of interaction between the Ca(2+- and cAMP-signalling cascades.

  17. Targeted inhibition of serotonin type 7 (5-HT7) receptor function modulates immune responses and reduces the severity of intestinal inflammation.

    Science.gov (United States)

    Kim, Janice J; Bridle, Byram W; Ghia, Jean-Eric; Wang, Huaqing; Syed, Shahzad N; Manocha, Marcus M; Rengasamy, Palanivel; Shajib, Mohammad Sharif; Wan, Yonghong; Hedlund, Peter B; Khan, Waliul I

    2013-05-01

    Mucosal inflammation in conditions ranging from infective acute enteritis or colitis to inflammatory bowel disease is accompanied by alteration in serotonin (5-hydroxytryptamine [5-HT]) content in the gut. Recently, we have identified an important role of 5-HT in the pathogenesis of experimental colitis. 5-HT type 7 (5-HT7) receptor is one of the most recently identified members of the 5-HT receptor family, and dendritic cells express this receptor. In this study, we investigated the effect of blocking 5-HT7 receptor signaling in experimental colitis with a view to develop an improved therapeutic strategy in intestinal inflammatory disorders. Colitis was induced with dextran sulfate sodium (DSS) or dinitrobenzene sulfonic acid (DNBS) in mice treated with selective 5-HT7 receptor antagonist SB-269970, as well as in mice lacking 5-HT7 receptor (5-HT7(-/-)) and irradiated wild-type mice reconstituted with bone marrow cells harvested from 5-HT7(-/-) mice. Inhibition of 5-HT7 receptor signaling with SB-269970 ameliorated both acute and chronic colitis induced by DSS. Treatment with SB-269970 resulted in lower clinical disease, histological damage, and proinflammatory cytokine levels compared with vehicle-treated mice post-DSS. Colitis severity was significantly lower in 5-HT7(-/-) mice and in mice reconstituted with bone marrow cells from 5-HT7(-/-) mice compared with control mice after DSS colitis. 5-HT7(-/-) mice also had significantly reduced DNBS-induced colitis. These observations provide us with novel information on the critical role of the 5-HT7 receptor in immune response and inflammation in the gut, and highlight the potential benefit of targeting this receptor to alleviate the severity of intestinal inflammatory disorders such as inflammatory bowel disease.

  18. Serotonin receptor of type 6 (5-HT6) in human prefrontal cortex and hippocampus post-mortem: an immunohistochemical and immunofluorescence study.

    Science.gov (United States)

    Marazziti, Donatella; Baroni, Stefano; Pirone, Andrea; Giannaccini, Gino; Betti, Laura; Testa, Giovanna; Schmid, Lara; Palego, Lionella; Borsini, Franco; Bordi, Fabio; Piano, Ilaria; Gargini, Claudia; Castagna, Maura; Catena-Dell'osso, Mario; Lucacchini, Antonio

    2013-01-01

    Given the paucity of data on the distribution of serotonin (5-HT) receptors of type 6 (5-HT(6)) in the human brain, the aim of this study was to investigate their distribution in postmortem human prefrontal cortex, striatum and hippocampus by either immunohistochemical or immunofluorescence techniques. The brain samples were obtained from 6 subjects who had died for causes not involving primarily or secondarily the CNS. The 5-HT(6) receptor distribution was explored by the [(125)I]SB-258585 binding to brain membranes followed by immunohistochemical and immunofluorescence evaluations. A specific [(125)I]SB-258585 binding was detected in all the regions under investigation, whilst the content in the hippocampus and cortex being about 10-30 times lower than in the striatum. Immunohistochemistry and double-label immunofluorescence microscopy experiments, carried out in the prefrontal cortex and hippocampus only, since data in the striatum were already published, showed the presence of 5-HT(6) receptors in both pyramidal and glial cells of prefrontal cortex, while positive cells were mainly pyramidal neurons in the hippocampus. The heterogeneous distribution of 5-HT(6) receptors provides a preliminary explanation of how they might regulate different functions in different brain areas, such as, perhaps, brain trophism in the cortex and neuronal firing in the hippocampus. This study, taking into account all the limitations due to the postmortem model used, represents the starting point to explore the 5-HT(6) receptor functionality and its sub-cellular distribution. Copyright © 2012 Elsevier Ltd. All rights reserved.

  19. A small-animal pharmacokinetic/pharmacodynamic PET study of central serotonin 1A receptor occupancy by a potential therapeutic agent for overactive bladder.

    Directory of Open Access Journals (Sweden)

    Yosuke Nakatani

    Full Text Available Serotonin 1A (5-HT1A receptors have been mechanistically implicated in micturition control, and there has been a need for an appropriate biomarker surrogating the potency of a provisional drug acting on this receptor system for developing a new therapeutic approach to overactive bladder (OAB. Here, we analyzed the occupancy of 5-HT1A receptors in living Sprague-Dawley rat brains by a novel candidate drug for OAB, E2110, using positron emission tomography (PET imaging, and assessed the utility of a receptor occupancy (RO assay to establish a pharmacodynamic index translatable between animals and humans. The plasma concentrations inducing 50% RO (EC50 estimated by both direct and effect compartment models were in good agreement. Dose-dependent therapeutic effects of E2110 on dysregulated micturition in different rat models of pollakiuria were also consistently explained by achievement of 5-HT1A RO by E2110 in a certain range (≥ 60%. Plasma drug concentrations inducing this RO range and EC50 would accordingly be objective indices in comparing pharmacokinetics-RO relationships between rats and humans. These findings support the utility of PET RO and plasma pharmacokinetic assays with the aid of adequate mathematical models in determining the in vivo characteristics of a drug acting on 5-HT1A receptors and thereby counteracting OAB.

  20. A new serotonin 5-HT6 receptor antagonist with procognitive activity – Importance of a halogen bond interaction to stabilize the binding

    Science.gov (United States)

    González-Vera, Juan A.; Medina, Rocío A.; Martín-Fontecha, Mar; Gonzalez, Angel; de la Fuente, Tania; Vázquez-Villa, Henar; García-Cárceles, Javier; Botta, Joaquín; McCormick, Peter J.; Benhamú, Bellinda; Pardo, Leonardo; López-Rodríguez, María L.

    2017-01-01

    Serotonin 5-HT6 receptor has been proposed as a promising therapeutic target for cognition enhancement though the development of new antagonists is still needed to validate these molecules as a drug class for the treatment of Alzheimer’s disease and other pathologies associated with memory deficiency. As part of our efforts to target the 5-HT6 receptor, new benzimidazole-based compounds have been designed and synthesized. Site-directed mutagenesis and homology models show the importance of a halogen bond interaction between a chlorine atom of the new class of 5-HT6 receptor antagonists identified herein and a backbone carbonyl group in transmembrane domain 4. In vitro pharmacological characterization of 5-HT6 receptor antagonist 7 indicates high affinity and selectivity over a panel of receptors including 5-HT2B subtype and hERG channel, which suggests no major cardiac issues. Compound 7 exhibited in vivo procognitive activity (1 mg/kg, ip) in the novel object recognition task as a model of memory deficit. PMID:28117458

  1. Rikkunshito, a Japanese Kampo Medicine, Ameliorates Decreased Feeding Behavior via Ghrelin and Serotonin 2B Receptor Signaling in a Novelty Stress Murine Model

    Directory of Open Access Journals (Sweden)

    Chihiro Yamada

    2013-01-01

    Full Text Available We investigated the effects of rikkunshito (RKT, a ghrelin signal enhancer, on the decrease in food intake after exposure to novelty stress in mice. RKT administration (500 mg/kg, per os improved the decrease in 6 h cumulative food intake. In control mice, the plasma acylated ghrelin levels significantly increased by 24 h fasting. In contrast, the acylated ghrelin levels did not increase by fasting in mice exposed to the novelty stress. RKT administration to the novelty stress mice showed a significant increase in the acylated ghrelin levels compared with that in the distilled-water-treated control mice. Food intake after administering serotonin 2B (5-HT2B receptor antagonists was evaluated to clarify the role of 5-HT2B receptor activation in the decrease in feeding behavior after novelty stress. SB215505 and SB204741, 5-HT2B receptor antagonists, significantly improved the decrease in food intake after exposure to novelty stress. A component of RKT, isoliquiritigenin, prevented the decrease in 6 h cumulative food intake. Isoliquiritigenin showed 5-HT2B receptor antagonistic activity in vitro. In conclusion, the results suggested that RKT improves the decrease in food intake after novelty stress probably via 5-HT2B receptor antagonism of isoliquiritigenin contained in RKT.

  2. Chronic escitalopram treatment caused dissociative adaptation in serotonin (5-HT) 2C receptor antagonist-induced effects in REM sleep, wake and theta wave activity.

    Science.gov (United States)

    Kostyalik, Diána; Kátai, Zita; Vas, Szilvia; Pap, Dorottya; Petschner, Péter; Molnár, Eszter; Gyertyán, István; Kalmár, Lajos; Tóthfalusi, László; Bagdy, Gyorgy

    2014-03-01

    Several multi-target drugs used in treating psychiatric disorders, such as antidepressants (e.g. agomelatine, trazodone, nefazodone, amitriptyline, mirtazapine, mianserin, fluoxetine) or most atypical antipsychotics, have 5-hydroxytryptamine 2C (5-HT2C) receptor-blocking property. Adaptive changes in 5-HT2C receptor-mediated functions are suggested to contribute to therapeutic effects of selective serotonin reuptake inhibitor (SSRI) antidepressants after weeks of treatment, at least in part. Beyond the mediation of anxiety and other functions, 5-HT2C receptors are involved in sleep regulation. Anxiety-related adaptive changes caused by antidepressants have been studied extensively, although sleep- and electroencephalography (EEG)-related functional studies are still lacking. The aim of this study was to investigate the effects of chronic SSRI treatment on 5-HT2C receptor antagonist-induced functions in different vigilance stages and on quantitative EEG (Q-EEG) spectra. Rats were treated with a single dose of the selective 5-HT2C receptor antagonist SB-242084 (1 mg/kg, i.p.) or vehicle at the beginning of passive phase following a 20-day-long SSRI (escitalopram; 10 mg/kg/day, osmotic minipump) or VEHICLE pretreatment. Fronto-parietal electroencephalogram, electromyogram and motility were recorded during the first 3 h of passive phase. We found that the chronic escitalopram pretreatment attenuated the SB-242084-caused suppression in rapid eye movement sleep (REMS). On the contrary, the 5-HT2C receptor antagonist-induced elevations in passive wake and theta (5-9 Hz) power density during active wake and REMS were not affected by the SSRI. In conclusion, attenuation in certain, but not all vigilance- and Q-EEG-related functions induced by the 5-HT2C receptor antagonist, suggests dissociation in 5-HT2C receptor adaptation.

  3. Differentiated effects of the multimodal antidepressant vortioxetine on sleep architecture: Part 2, pharmacological interactions in rodents suggest a role of serotonin-3 receptor antagonism.

    Science.gov (United States)

    Leiser, Steven C; Iglesias-Bregna, Deborah; Westrich, Ligia; Pehrson, Alan L; Sanchez, Connie

    2015-10-01

    Antidepressants often disrupt sleep. Vortioxetine, a multimodal antidepressant acting through serotonin (5-HT) transporter (SERT) inhibition, 5-HT3, 5-HT7 and 5-HT1D receptor antagonism, 5-HT1B receptor partial agonism, and 5-HT1A receptor agonism, had fewer incidences of sleep-related adverse events reported in depressed patients. In the accompanying paper a polysomnographic electroencephalography (sleep-EEG) study of vortioxetine and paroxetine in healthy subjects indicated that at low/intermediate levels of SERT occupancy, vortioxetine affected rapid eye movement (REM) sleep differently than paroxetine. Here we investigated clinically meaningful doses (80-90% SERT occupancy) of vortioxetine and paroxetine on sleep-EEG in rats to further elucidate the serotoninergic receptor mechanisms mediating this difference. Cortical EEG, electromyography (EMG), and locomotion were recorded telemetrically for 10 days, following an acute dose, from rats receiving vortioxetine-infused chow or paroxetine-infused water and respective controls. Sleep stages were manually scored into active wake, quiet wake, and non-REM or REM sleep. Acute paroxetine or vortioxetine delayed REM onset latency (ROL) and decreased REM episodes. After repeated administration, vortioxetine yielded normal sleep-wake rhythms while paroxetine continued to suppress REM. Paroxetine, unlike vortioxetine, increased transitions from non-REM to wake, suggesting fragmented sleep. Next, we investigated the role of 5-HT3 receptors in eliciting these differences. The 5-HT3 receptor antagonist ondansetron significantly reduced paroxetine's acute effects on ROL, while the 5-HT3 receptor agonist SR57227A significantly increased vortioxetine's acute effect on ROL. Overall, our data are consistent with the clinical findings that vortioxetine impacts REM sleep differently than paroxetine, and suggests a role for 5-HT3 receptor antagonism in mitigating these differences.

  4. N(ε)-Carboxymethyllysine (CML), a Maillard reaction product, stimulates serotonin release and activates the receptor for advanced glycation end products (RAGE) in SH-SY5Y cells.

    Science.gov (United States)

    Holik, Ann-Katrin; Rohm, Barbara; Somoza, Mark M; Somoza, Veronika

    2013-07-01

    Maillard reaction products, which are formed in highly thermally treated foods, are commonly consumed in a Western diet. In this study, we investigated the impact of N(ε)-carboxymethyllysine (CML), a well-characterized product of the Maillard reaction, on the gene regulation of the human neuroblastoma cell line SH-SY5Y. Pathway analysis of data generated from customized DNA microarrays revealed 3 h incubation with 50 μM and 500 μM CML to affect serotonin receptor expression. Further experiments employing qRT-PCR showed an up-regulation of serotonin receptors 2A, 1A and 1B after 0.25 h and 3 h. In addition, 500 μM CML increased serotonin release, thus showing effects of CML not only at a genetic, but also at a functional level. Intracellular calcium mobilization, which mediates serotonin release, was increased by CML at concentrations of 0.05-500 μM. Since calcium mobilization has been linked to the activation of the receptor for advanced glycation end products (RAGE), we further investigated the effects of CML on RAGE expression. RAGE was found to be up-regulated after incubation with 500 μM CML for 0.25 h. Co-incubation with the calcium blocker neomycin for 0.25 h blocked the up-regulation of RAGE and the serotonin receptors 2A, 1A and 1B. These results indicate a possible link between a CML-induced calcium-mediated serotonin release and RAGE.

  5. Distribution of serotonin 5-HT2A and 5-HT7 receptors in the Onuf's nucleus of the rat spinal cord

    Institute of Scientific and Technical Information of China (English)

    Fanqing Zeng; Chen Xu; Ge Xu

    2008-01-01

    BACKGROUND: Motoneurons from the Onuf's nucleus of the spinal cord, which innervate the striated muscle of the pelvic floor, play an important role in erection, ejaculation, and urine control. Serotonin (5-hydroxytryptamine, 5-HT) regulates motoneuron activity from the Onuf's nucleus of the spinal cord.However, few studies exist that describe 5-HT receptor distribution in the Onuf's nucleus. In addition, the nature of the effects of 5-HT receptor on the innervating striated muscle of the pelvic floor is controversial.OBJECTIVE: To investigate the distribution of serotonin 5-HT2A and 5-HT7 receptors in motoneurons of Onuf's nucleus in the spinal cord of male rats, and to analyze the relationship of 5-HT2A and 5-H7 receptors to central modulation of urogenital function.DESIGN, TIME AND SETTING: The neural morphology experiment was performed at the Ultramicrostructure Laboratory of Reproductive Medicine, Basic Medical College, Chongqing Medical University, China from April to December 2007.MATERIALS: Ten adult, Sprague Dawley rats (eight males and two females) were randomly divided into a gender control group (n = 4,50% male and 50% female) and a retrograde tracing group (n = 6, 100% male).Recombinant pseudorabies virus (PRV-152) was provided by Professor LW Enquist from Princeton University, USA. Rabbit anti-5-HT2A and 5-HT7 receptor antibodies were purchased from Diasorin, France.METHODS: In the gender control group, the spinal L5-6segments were harvested, sliced, and then incubated antibodies specific against 5-HT2A or 5-HT7 receptors for immunohistochemical staining. In the retrograde tracing group, PRV-152 was separately injected into the right ischiocavernosus (ischiocavernosus subgroup,n = 3) and the fight external urethral sphincter (external urethral sphincter subgroup, n = 3). Four days after injection, L5-6 segments were harvested, sliced, and incubated with antibodies specific against 5-HT2A or 5-HT7 receptors for double-labeling immunofluoresccnce

  6. Selective serotonin receptor stimulation of the medial nucleus accumbens differentially affects appetitive motivation for food on a progressive ratio schedule of reinforcement.

    Science.gov (United States)

    Pratt, Wayne E; Schall, Megan A; Choi, Eugene

    2012-03-09

    Previously, we reported that stimulation of selective serotonin (5-HT) receptor subtypes in the nucleus accumbens shell differentially affected consumption of freely available food. Specifically, activation of 5-HT(6) receptors caused a dose-dependent increase in food intake, while the stimulation of 5-HT(1/7) receptor subtypes decreased feeding [34]. The current experiments tested whether similar pharmacological activation of nucleus accumbens serotonin receptors would also affect appetitive motivation, as measured by the amount of effort non-deprived rats exerted to earn sugar reinforcement. Rats were trained to lever press for sugar pellets on a progressive ratio 2 schedule of reinforcement. Across multiple treatment days, three separate groups (N=8-10) received bilateral infusions of the 5-HT(6) agonist EMD 386088 (at 0.0, 1.0 and 4.0 μg/0.5 μl/side), the 5-HT(1/7) agonist 5-CT (at 0, 0.5, 1.0, or 4.0 μg/0.5 μl/side), or the 5-HT(2C) agonist RO 60-0175 fumarate (at 0, 2.0, or 5.0 μg/0.5 μl/side) into the anterior medial nucleus accumbens prior to a 1-h progressive ratio session. Stimulation of 5-HT(6) receptors caused a dose-dependent increase in motivation as assessed by break point, reinforcers earned, and total active lever presses. Stimulation of 5-HT(1/7) receptors increased lever pressing at the 0.5 μg dose of 5-CT, but inhibited lever presses and break point at 4.0 μg/side. Injection of the 5-HT(2C) agonist had no effect on motivation within the task. Collectively, these experiments suggest that, in addition to their role in modulating food consumption, nucleus accumbens 5-HT(6) and 5-HT(1/7) receptors also differentially regulate the appetitive components of food-directed motivation.

  7. Prophylactic and therapeutic effects of acute systemic injections of EMD 281014, a selective serotonin 2A receptor antagonist on anxiety induced by predator stress in rats.

    Science.gov (United States)

    Adamec, Robert; Creamer, Katherine; Bartoszyk, Gerd D; Burton, Paul

    2004-11-03

    We examined the effect of the selective serotonin 2A (5-HT(2A)) receptor antagonist 7-[4-[2-(4-fluoro-phenyl)-ethyl]-piperazine-1-carbonyl]-1H-indole-3-carbon itrile HCl (EMD 281014) [Bartoszyk, G.D., van Amsterdam, C., Bottcher, H., Seyfried, C.A., 2003. EMD 281014, a new selective serotonin 5-HT2A receptor antagonist. Eur. J. Pharmacol. 473, 229-230.] on change in affect following predator stress. Predator stress involved a 5 min unprotected exposure of rats to a domestic cat. Behavioral effects of stress were evaluated with hole board, plus maze, light/dark box and acoustic startle tests 1 week after stress. Predator stress increased anxiety-like behavior in the plus maze, light/dark box, and elevated response to acoustic startle. EMD 281014 (0.001, 0.01, 0.1, 1 or 10 mg/kg) and vehicle injection (ip) occurred either 10 min after predator stress (prophylactic testing), or 90 min prior to behavioral testing for the effects of predator stress (therapeutic testing 1 week after predator stress). In prophylactic testing, EMD 281014 prevented stress potentiation of startle in a dose dependent manner, though the most effective doses were midrange (0.01 and 0.1 mg/kg). Prophylactic administration of EMD 281014 also prevented stress-induced increase of open arm avoidance in the plus maze in a clear dose dependent manner (from 0.01 mg/kg onward). In therapeutic testing, EMD 281014 had no clear drug dependent effects on stress elevation of startle or on behavior of stressed rats in the elevated plus maze. Finally, EMD 281014 did not block the effects of stress on behavior in the light/dark box when given prophylactically or therapeutically. Findings implicate 5-HT(2A) receptors in initiation of some but not all lasting changes in anxiety-like behavior following predator stress. Potential clinical significance of findings are discussed.

  8. Lipopolysaccharide-induced serotonin transporter up-regulation involves PKG-I and p38MAPK activation partially through A3 adenosine receptor.

    Science.gov (United States)

    Zhao, Rui; Wang, Shoubao; Huang, Zhonglin; Zhang, Li; Yang, Xiuying; Bai, Xiaoyu; Zhou, Dan; Qin, Zhizhen; Du, Guanhua

    2015-12-01

    Serotonin transporter (SERT) is a critical determinant of synaptic serotonin (5-hydroxytryptamine, 5-HT) inactivation which plays a critical role in the pathology of depression and other mood disorders. Lipopolysaccharide (LPS), a potent activator of the inflammatory system, has been reported to cause depression symptoms by the modulation of SERT in vivo and in vitro. This study is aimed to investigate the underlying mechanism of LPS-induced SERT modulation. The 4-(4-(dimethylamino) styryl)-N-methylpyridinium iodide (ASP) assay was used to detect dynamic 5-HT uptake as read out of SERT activities in RBL-2H3 cells, and cytosol Ca(2+) concentrations ([Ca(2+)]i) and nitric oxide (NO) were examined. Using specific cyclic GMP-dependent protein kinase type I (PKG-I), p38 mitogen-activated protein kinases (p38MAPK) and A3 adenosine receptor (A3AR) inhibitors, SERT expression was evaluated by western blot and immunofluorescence analysis. Results showed that 24 h treatment with LPS stimulated 5-HT transport and up-regulate plasma membrane distribution of SERT in RBL-2H3 cells. LPS treatment increased NO and [Ca(2+)]i, and led to significant increases in levels of phosphorylated calcium/calmodulin-dependent protein kinase type II (CaMK-II), inducible NOS (iNOS) and PKG-I as well as active p38 MAPK. Moreover, PKG-I inhibitor KT5823 or p38MAPK inhibitor SB203580 respectively impaired SERT activation and transposition to plasma membrane by LPS. Notably, A3 adenosine receptor inhibitor MRS1191 also hindered SERT stimulation by LPS. In conclusion, LPS-induced 5-HT uptake and transposition to plasma membrane of SERT in RBL-2H3 cells involves CaMK-II/iNOS/PKG-I and p38 MAPK activation, which may be partially mediated by A3 adenosine receptor activation. This finding provides a novel insight into the interrelationship between LPS and depression.

  9. In vivo evaluation in rodents of [{sup 123}I]-3-I-CO as a potential SPECT tracer for the serotonin 5-HT{sub 2A} receptor

    Energy Technology Data Exchange (ETDEWEB)

    Blanckaert, Peter B.M. [Laboratory for Radiopharmacy, Ghent University, B-9000 Ghent (Belgium)], E-mail: peter.blanckaert@hotmail.com; Burvenich, Ingrid; Wyffels, Leonie; Bruyne, Sylvie de; Moerman, Lieselotte; Vos, Filip de [Laboratory for Radiopharmacy, Ghent University, B-9000 Ghent (Belgium)

    2008-11-15

    Introduction: [{sup 123}I]-(4-fluorophenyl)[1-(3-iodophenethyl)piperidin-4-yl]methanone ([{sup 123}I]-3-I-CO) is a potential single photon emission computed tomography tracer with high affinity for the serotonin 5-HT{sub 2A} receptor (K{sub i}=0.51 nM) and good selectivity over other receptor (sub)types. To determine the potential of the radioligand as a 5-HT{sub 2A} tracer, regional brain biodistribution and displacement studies will be performed. The influence of P-glycoprotein blocking on the brain uptake of the radioligand will also be investigated. Methods: A regional brain biodistribution study and a displacement study with ketanserin were performed with [{sup 123}I]-3-I-CO. Also, the influence of cyclosporin A (50 mg/kg) on the brain distribution of the radioligand was investigated. For the displacement study, ketanserin (1 mg/kg) was administered 30 min after injection of [{sup 123}I]-3-I-CO. Results: The initial brain uptake of [{sup 123}I]-3-I-CO was quite high, but a rapid wash-out of radioactivity was observed. Cortex-to-cerebellum binding index ratios were low (1.1 - 1.7), indicating considerable aspecific binding and a low specific 'signal' of the radioligand. Tracer uptake was reduced to the levels in cerebellum (a 60% reduction) after ketanserin displacement. Administration of cyclosporin A resulted in a doubling of the brain radioactivity concentration. Conclusions: Although [{sup 123}I]-3-I-CO showed adequate brain uptake and could be displaced by ketanserin, high aspecific binding to brain tissue was responsible for very low cortex-to-cerebellum binding index ratios, possibly limiting the potential of the radioligand as a serotonin 5-HT{sub 2A} receptor tracer. We also demonstrated that [{sup 123}I]-3-I-CO is probably a weak substrate for the P-glycoprotein efflux transporter.

  10. Modulation of motoneuron activity by serotonin.

    Science.gov (United States)

    Perrier, Jean-François

    2016-02-01

    Serotonin is a major neuromodulator in the central nervous system involved in most physiological functions including appetite regulation, sexual arousal, sleep regulation and motor control. The activity of neurons from the raphe spinal tract, which release serotonin on motoneurons, is positively correlated with motor behaviour. During moderate physical activity, serotonin is released from synaptic terminals onto the dendrites and cell bodies of motoneurons. Serotonin increases the excitability of motoneurons and thereby facilitate muscle contraction by acting on several parallel intracellular pathways. By activating 5-HT1A receptors, serotonin inhibits TWIK-related acid-sensitive potassium channels and small conductance calcium-activated potassium channels. In parallel, serotonin binds to 5-HT2 receptors, which promotes the low-threshold L-type Ca(2+) channels. During intense physical activity, more serotonin is released. The reuptake systems saturate and serotonin spills over to reach extrasynaptic 5-HT1A receptors located on the axon initial segment of motoneurons. This in turn induces the inhibition of the Na(+) channels responsible for the initiation of action potentials. Fewer nerve impulses are generated and muscle contraction becomes weaker. By decreasing the gain of motoneurons, serotonin triggers central fatigue.

  11. Activation of serotonin 2A receptors underlies the psilocybin-induced effects on α oscillations, N170 visual-evoked potentials, and visual hallucinations.

    Science.gov (United States)

    Kometer, Michael; Schmidt, André; Jäncke, Lutz; Vollenweider, Franz X

    2013-06-19

    Visual illusions and hallucinations are hallmarks of serotonergic hallucinogen-induced altered states of consciousness. Although the serotonergic hallucinogen psilocybin activates multiple serotonin (5-HT) receptors, recent evidence suggests that activation of 5-HT2A receptors may lead to the formation of visual hallucinations by increasing cortical excitability and altering visual-evoked cortical responses. To address this hypothesis, we assessed the effects of psilocybin (215 μg/kg vs placebo) on both α oscillations that regulate cortical excitability and early visual-evoked P1 and N170 potentials in healthy human subjects. To further disentangle the specific contributions of 5-HT2A receptors, subjects were additionally pretreated with the preferential 5-HT2A receptor antagonist ketanserin (50 mg vs placebo). We found that psilocybin strongly decreased prestimulus parieto-occipital α power values, thus precluding a subsequent stimulus-induced α power decrease. Furthermore, psilocybin strongly decreased N170 potentials associated with the appearance of visual perceptual alterations, including visual hallucinations. All of these effects were blocked by pretreatment with the 5-HT2A antagonist ketanserin, indicating that activation of 5-HT2A receptors by psilocybin profoundly modulates the neurophysiological and phenomenological indices of visual processing. Specifically, activation of 5-HT2A receptors may induce a processing mode in which stimulus-driven cortical excitation is overwhelmed by spontaneous neuronal excitation through the modulation of α oscillations. Furthermore, the observed reduction of N170 visual-evoked potentials may be a key mechanism underlying 5-HT2A receptor-mediated visual hallucinations. This change in N170 potentials may be important not only for psilocybin-induced states but also for understanding acute hallucinatory states seen in psychiatric disorders, such as schizophrenia and Parkinson's disease.

  12. The serotonin-1A receptor distribution in healthy men and women measured by PET and [carbonyl-{sup 11}C]WAY-100635

    Energy Technology Data Exchange (ETDEWEB)

    Stein, Patrycja; Savli, Markus; Fink, Martin; Spindelegger, Christoph; Moser, Ulrike; Kasper, Siegfried; Lanzenberger, Rupert [Medical University of Vienna, Department of Psychiatry and Psychotherapy, Vienna (Austria); Wadsak, Wolfgang; Dudczak, Robert; Kletter, Kurt [Medical University of Vienna, Department of Nuclear Medicine, Vienna (Austria); Mitterhauser, Markus; Mien, Leonhard-Key [Medical University of Vienna, Department of Nuclear Medicine, Vienna (Austria); University of Vienna, Department of Pharmaceutical Technology, Vienna (Austria)

    2008-12-15

    The higher prevalence rates of depression and anxiety disorders in women compared to men have been associated with sexual dimorphisms in the serotonergic system. The present positron emission tomography (PET) study investigated the influence of sex on the major inhibitory serotonergic receptor subtype, the serotonin-1A (5-HT{sub 1A}) receptor. Sixteen healthy women and 16 healthy men were measured using PET and the highly specific radioligand [carbonyl-{sup 11}C]WAY-100635. Effects of age or gonadal hormones were excluded by restricting the inclusion criteria to young adults and by controlling for menstrual cycle phase. The 5-HT{sub 1A} receptor BP{sub ND} was quantified using (1) the 'gold standard' manual delineation approach with ten regions of interest (ROIs) and (2) a newly developed delineation method using a PET template normalized to the Montreal Neurologic Institute space with 45 ROIs based on automated anatomical labeling. The 5-HT{sub 1A} receptor BP{sub ND} was found equally distributed in men and women applying both the manual delineation method and the automated delineation approach. Women had lower mean BP{sub ND} values in every region investigated, with a borderline significant sex difference in the hypothalamus (p=0.012, uncorrected). There was a high intersubject variability of the 5-HT{sub 1A} receptor BP{sub ND} within both sexes compared to the small mean differences between men and women. To conclude, when measured in the follicular phase, women do not differ from men in the 5-HT{sub 1A} receptor binding. To explain the higher prevalence of affective disorders in women, further studies are needed to evaluate the relationship between hormonal status and the 5-HT{sub 1A} receptor expression. (orig.)

  13. Distribution of serotonin 2A and 2C receptor mRNA expression in the cervical ventral horn and phrenic motoneurons following spinal cord hemisection.

    Science.gov (United States)

    Basura, G J; Zhou, S Y; Walker, P D; Goshgarian, H G

    2001-06-01

    Cervical spinal cord injury leads to a disruption of bulbospinal innervation from medullary respiratory centers to phrenic motoneurons. Animal models utilizing cervical hemisection result in inhibition of ipsilateral phrenic nerve activity, leading to paralysis of the hemidiaphragm. We have previously demonstrated a role for serotonin (5-HT) as one potential modulator of respiratory recovery following cervical hemisection, a mechanism that likely occurs via 5-HT2A and/or 5-HT2C receptors. The present study was designed to specifically examine if 5-HT2A and/or 5-HT2C receptors are colocalized with phrenic motoneurons in both intact and spinal-hemisected rats. Adult female rats (250-350 g; n = 6 per group) received a left cervical (C2) hemisection and were injected with the fluorescent retrograde neuronal tracer Fluorogold into the left hemidiaphragm. Twenty-four hours later, animals were killed and spinal cords processed for in situ hybridization and immunohistochemistry. Using (35)S-labeled cRNA probes, cervical spinal cords were probed for 5-HT2A and 5-HT2C receptor mRNA expression and double-labeled using an antibody to Fluorogold to detect phrenic motoneurons. Expression of both 5-HT2A and 5-HT2C receptor mRNA was detected in motoneurons of the cervical ventral horn. Despite positive expression of both 5-HT2A and 5-HT2C receptor mRNA-hybridization signal over phrenic motoneurons, only 5-HT2A silver grains achieved a signal-to-noise ratio representative of colocalization. 5-HT2A mRNA levels in identified phrenic motoneurons were not significantly altered following cervical hemisection compared to sham-operated controls. Selective colocalization of 5-HT2A receptor mRNA with phrenic motoneurons may have implications for recently observed 5-HT2A receptor-mediated regulation of respiratory activity and/or recovery in both intact and injury-compromised states.

  14. Ligand-dependent conformations and dynamics of the serotonin 5-HT(2A receptor determine its activation and membrane-driven oligomerization properties.

    Directory of Open Access Journals (Sweden)

    Jufang Shan

    Full Text Available From computational simulations of a serotonin 2A receptor (5-HT(2AR model complexed with pharmacologically and structurally diverse ligands we identify different conformational states and dynamics adopted by the receptor bound to the full agonist 5-HT, the partial agonist LSD, and the inverse agonist Ketanserin. The results from the unbiased all-atom molecular dynamics (MD simulations show that the three ligands affect differently the known GPCR activation elements including the toggle switch at W6.48, the changes in the ionic lock between E6.30 and R3.50 of the DRY motif in TM3, and the dynamics of the NPxxY motif in TM7. The computational results uncover a sequence of steps connecting these experimentally-identified elements of GPCR activation. The differences among the properties of the receptor molecule interacting with the ligands correlate with their distinct pharmacological properties. Combining these results with quantitative analysis of membrane deformation obtained with our new method (Mondal et al, Biophysical Journal 2011, we show that distinct conformational rearrangements produced by the three ligands also elicit different responses in the surrounding membrane. The differential reorganization of the receptor environment is reflected in (i-the involvement of cholesterol in the activation of the 5-HT(2AR, and (ii-different extents and patterns of membrane deformations. These findings are discussed in the context of their likely functional consequences and a predicted mechanism of ligand-specific GPCR oligomerization.

  15. Behavioral Effects of a Novel Benzofuranyl-Piperazine Serotonin-2C Receptor Agonist Suggest a Potential Therapeutic Application in the Treatment of Obsessive–Compulsive Disorder

    Directory of Open Access Journals (Sweden)

    Michelle M. Rodriguez

    2017-05-01

    Full Text Available Selective serotonin reuptake inhibitors (SSRIs are the only effective pharmacological treatments for obsessive–compulsive disorder (OCD. Nonetheless, their generally limited efficacy, side-effects, and delayed onset of action require improved medications for this highly prevalent disorder. Preclinical and clinical findings have suggested serotonin2C (5-HT2C receptors as a potential drug target. Data in rats and mice are presented here on the effects of a novel 5-HT2C receptor agonist ((3S-3-Methyl-1-[4-(trifluoromethyl-7-benzofuranyl]-piperazine (CPD 1 with high potency and full efficacy at 5-HT2C receptors and less potency and partial agonism at 5-HT2A and 5-HT2B receptors. Effects of CPD 1 on consummatory (schedule-induced polydipsia in rats and non-consummatory behaviors (marble-burying and nestlet-shredding in mice that are repetitive and non-habituating were studied. We also evaluated the effects of CPD 1 in rats with isoproterenol- and deprivation-induced drinking in rats to compare with the polydipsia studies. The SSRIs, fluoxetine, and chlomipramine decreased the high rates of drinking in rats engendered by a schedule of intermittent food delivery (schedule-induced polydipsia. The effects of fluoxetine, but not of d-amphetamine, were prevented by the selective 5-HT2C receptor antagonist SB242084. The 5-HT2C receptor agonists Ro 60-0175 and CPD 1 also decreased drinking, but unlike the SSRIs and Ro 60-0175, CPD 1 dose-dependently decreased excessive drinking without affecting lever press responses that produced food. The effects of CPD 1 were prevented by SB242084. CPD 1 also suppressed drinking induced by isoproterenol and by water deprivation without affecting normative drinking behavior. CPD 1, like fluoxetine, also suppressed marble-burying and nestlet-shredding in mice at doses that did not affect rotarod performance or locomotor activity. The behavioral specificity of effects of CPD 1 against repetitive and excessive behaviors

  16. Development of a multiplex non-radioactive receptor assay : the benzodiazepine receptor, the serotonin transporter and the beta-adrenergic receptor

    NARCIS (Netherlands)

    de Jong, Lutea A. A.; Jeronimus-Stratingh, C. Margot; Cremers, Thomas I. F. H.

    2007-01-01

    Binding assays still form a fundamental part of modem drug development. Receptor binding assays are mostly based on radioactivity because of their speed, ease of use and reproducibility. Disadvantages, such as health hazards and production of radioactive waste, have prompted the development of non-r

  17. Effects of a short-term reduction in brain serotonin synthesis on the availability of the soluble leptin receptor in healthy women.

    Science.gov (United States)

    Zepf, F D; Dingerkus, V L S; Helmbold, K; Bubenzer-Busch, S; Biskup, C S; Herpertz-Dahlmann, B; Schaab, M; Kratzsch, J; Eisert, A; Rink, L; Hagenah, U; Gaber, T J

    2015-03-01

    Serotonin (5-HT) and the hormone leptin have been linked to the underlying neurobiology of appetite regulation with evidence coming from animal and cellular research, but direct evidence linking these two pathways in humans is lacking. We examined the effects of reduced brain 5-HT synthesis due to acute tryptophan depletion (ATD) on levels of soluble leptin receptor (sOb-R), the main high-affinity leptin binding protein, in healthy adults using an exploratory approach. Women, but not men, showed reduced sOb-R concentrations after ATD administration. With females showing reduced baseline levels of central 5-HT synthesis compared to males diminished brain 5-HT synthesis affected the leptin axis through the sOb-R in females, thereby potentially influencing their vulnerability to dysfunctional appetite regulation and co-morbid mood symptoms.

  18. Morphology and distribution of neurons expressing serotonin 5-HT1A receptors in the rat hypothalamus and the surrounding diencephalic and telencephalic areas.

    Science.gov (United States)

    Marvin, Eric; Scrogin, Karie; Dudás, Bertalan

    2010-07-01

    Disorders of serotonergic neurotransmission are involved in disturbances of numerous hypothalamic functions including circadian rhythm, mood, neuroendocrine functions, sleep and feeding. Among the serotonin receptors currently recognized, 5-HT(1A) receptors have received considerable attention due to their importance in the etiology of mood disorders. While previous studies have shown the presence of 5-HT(1A) receptors in several regions of the rat brain, there is no detailed map of the cellular distribution of 5-HT(1A) receptors in the rat diencephalon. In order to characterize the distribution and morphology of the neurons containing 5-HT(1A) receptors in the diencephalon and the adjacent telencephalic areas, single label immunohistochemistry was utilized. Large, multipolar, 5-HT(1A)-immunoreactive (IR) neurons were mainly detected in the magnocellular preoptic nucleus and in the nucleus of diagonal band of Broca, while the supraoptic nucleus contained mainly fusiform neurons. Medium-sized 5-HT(1A)-IR neurons with triangular or round-shaped somata were widely distributed in the diencephalon, populating the zona incerta, lateral hypothalamic area, anterior hypothalamic nucleus, substantia innominata, dorsomedial and premamillary nuclei, paraventricular nucleus and bed nucleus of stria terminalis. The present study provides schematic mapping of 5-HT(1A)-IR neurons in the rat diencephalon. In addition, the morphology of the detected 5-HT(1A)-IR neural elements is also described. Since rat is a widely used laboratory animal in pharmacological models of altered serotoninergic neurotransmission, detailed mapping of 5-HT(1A)-IR structures is pivotal for the neurochemical characterization of the neurons containing 5-HT(1A) receptors.

  19. Polymorphisms of serotonin receptor 2A and 2C genes and COMT in relation to obesity and type 2 diabetes

    DEFF Research Database (Denmark)

    Kring, Sofia I I; Werge, Thomas; Holst, Claus

    2009-01-01

    BACKGROUND: Candidate genes of psychological importance include 5HT2A, 5HT2C, and COMT, implicated in the serotonin, noradrenaline and dopamine pathways, which also may be involved in regulation of energy balance. We investigated the associations of single nucleotide polymorphisms (SNPs......) of these genes with obesity and metabolic traits. METHODOLOGY/PRINCIPAL FINDINGS: In a population of 166 200 young men examined at the draft boards, obese men (n = 726, BMI> or =31.0 kg/m(2)) and a randomly selected group (n = 831) were re-examined at two surveys at mean ages 46 and 49 years (S-46, S-49...

  20. The Type 7 Serotonin Receptor, 5-HT7, Is Essential in the Mammary Gland for Regulation of Mammary Epithelial Structure and Function

    Directory of Open Access Journals (Sweden)

    Vaibhav P. Pai

    2015-01-01

    Full Text Available Autocrine-paracrine activity of serotonin (5-hydroxytryptamine, 5-HT is a crucial homeostatic parameter in mammary gland development during lactation and involution. Published studies suggested that the 5-HT7 receptor type was important for mediating several effects of 5-HT in the mammary epithelium. Here, using 5-HT7 receptor-null (HT7KO mice we attempt to understand the role of this receptor in mediating 5-HT actions within the mammary gland. We demonstrate for the first time that HT7KO dams are inefficient at sustaining their pups. Histologically, the HT7KO mammary epithelium shows a significant deviation from the normal secretory epithelium in morphological architecture, reduced secretory vesicles, and numerous multinucleated epithelial cells with atypically displaced nuclei, during lactation. Mammary epithelial cells in HT7KO dams also display an inability to transition from lactation to involution as normally seen by transition from a columnar to a squamous cell configuration, along with alveolar cell apoptosis and cell shedding. Our results show that 5-HT7 is required for multiple actions of 5-HT in the mammary glands including core functions that contribute to changes in cell shape and cell turnover, as well as specialized secretory functions. Understanding these actions may provide new interventions to improve lactation performance and treat diseases such as mastitis and breast cancer.

  1. Synthesis and evaluation of 1-[2-(4-[(11)C]methoxyphenyl)phenyl]piperazine for imaging of the serotonin 5-HT7 receptor in the rat brain.

    Science.gov (United States)

    Shimoda, Yoko; Yui, Joji; Xie, Lin; Fujinaga, Masayuki; Yamasaki, Tomoteru; Ogawa, Masanao; Nengaki, Nobuki; Kumata, Katsushi; Hatori, Akiko; Kawamura, Kazunori; Zhang, Ming-Rong

    2013-09-01

    1-[2-(4-Methoxyphenyl)phenyl]piperazine (4) is a potent serotonin 5-HT7 receptor antagonist (Ki=2.6nM) with a low binding affinity for the 5-HT1A receptor (Ki=476nM). As a potential positron emission tomography (PET) radiotracer for the 5-HT7 receptor, [(11)C]4 was synthesized at high radiochemical yield and specific activity, by O-[(11)C]methylation of 2'-(piperazin-1-yl)-[1,1'-biphenyl]-4-ol (6) with [(11)C]methyl iodide. Autoradiography revealed that [(11)C]4 showed in vitro specific binding with 5-HT7 in the rat brain regions, such as the thalamus which is a region with high 5-HT7 expression. Metabolite analysis indicated that intact [(11)C]4 in the brain exceeded 90% of the radioactive components at 15min after the radiotracer injection, although two radiolabeled metabolites were found in the rat plasma. The PET study of rats showed moderated uptake of [(11)C]4 in the brain (1.2SUV), but no significant regional difference in radioactivity in the brain. Pretreatment with 5-HT7-selective antagonist SB269970 (3) did not decrease the uptake of [(11)C]4 in the rat brain. Further studies are warranted that focus on the development of PET ligand candidates with higher binding affinity for 5-HT7 and higher in vivo stability in brain than 4.

  2. The Type 7 Serotonin Receptor, 5-HT7, Is Essential in the Mammary Gland for Regulation of Mammary Epithelial Structure and Function

    Science.gov (United States)

    Pai, Vaibhav P.; Hernandez, Laura L.; Stull, Malinda A.; Horseman, Nelson D.

    2015-01-01

    Autocrine-paracrine activity of serotonin (5-hydroxytryptamine, 5-HT) is a crucial homeostatic parameter in mammary gland development during lactation and involution. Published studies suggested that the 5-HT7 receptor type was important for mediating several effects of 5-HT in the mammary epithelium. Here, using 5-HT7 receptor-null (HT7KO) mice we attempt to understand the role of this receptor in mediating 5-HT actions within the mammary gland. We demonstrate for the first time that HT7KO dams are inefficient at sustaining their pups. Histologically, the HT7KO mammary epithelium shows a significant deviation from the normal secretory epithelium in morphological architecture, reduced secretory vesicles, and numerous multinucleated epithelial cells with atypically displaced nuclei, during lactation. Mammary epithelial cells in HT7KO dams also display an inability to transition from lactation to involution as normally seen by transition from a columnar to a squamous cell configuration, along with alveolar cell apoptosis and cell shedding. Our results show that 5-HT7 is required for multiple actions of 5-HT in the mammary glands including core functions that contribute to changes in cell shape and cell turnover, as well as specialized secretory functions. Understanding these actions may provide new interventions to improve lactation performance and treat diseases such as mastitis and breast cancer. PMID:25664318

  3. Discovery of N-Substituted (2-Phenylcyclopropyl)methylamines as Functionally Selective Serotonin 2C Receptor Agonists for Potential Use as Antipsychotic Medications.

    Science.gov (United States)

    Zhang, Guiping; Cheng, Jianjun; McCorvy, John D; Lorello, Paul J; Caldarone, Barbara J; Roth, Bryan L; Kozikowski, Alan P

    2017-07-27

    A series of N-substituted (2-phenylcyclopropyl)methylamines were designed and synthesized, with the aim of finding serotonin 2C (5-HT2C)-selective agonists with a preference for Gq signaling. A number of these compounds exhibit 5-HT2C selectivity with a preference for Gq-mediated signaling compared with β-arrestin recruitment. Furthermore, the N-methyl compound (+)-15a, which displayed an EC50 of 23 nM in the calcium flux assay while showing no β-arrestin recruitment activity, is the most functionally selective 5-HT2C agonist reported to date. The N-benzyl compound (+)-19, which showed an EC50 of 24 nM at the 5-HT2C receptor, is fully selective over the 5-HT2B receptor. In an amphetamine-induced hyperactivity model, compound (+)-19 showed significant antipsychotic-drug-like activity. These novel compounds shed light on the role of functional selectivity at the 5-HT2C receptor with respect to antipsychotic activity.

  4. Serotonin-1A receptors in the dorsal periaqueductal gray matter mediate the panicolytic-like effect of pindolol and paroxetine combination in the elevated T-maze.

    Science.gov (United States)

    Sela, Vânia Ramos; Biesdorf, Carla; Ramos, Diego Henrique; Zangrossi, Hélio; Graeff, Frederico Guilherme; Audi, Elisabeth Aparecida

    2011-05-01

    The β-adrenergic blocker and 5-HT(1A) receptor antagonist pindolol has been combined with selective serotonin reuptake inhibitors (SSRIs) in patients with depressive and anxiety disorders to shorten the onset of the clinical action and/or increase the proportion of responders. The results of a previous study have shown that pindolol potentiates the panicolytic effect of paroxetine in rats submitted to the elevated T-maze (ETM). Since reported evidence has implicated the 5-HT(1A) receptors of the dorsal periaqueductal gray matter (DPAG) in the panicolytic effect of antidepressants, rats treated with pindolol (5.0mg/kg, i.p.) and paroxetine (1.5mg/kg, i.p.) received a previous intra-DPAG injection of the selective 5-HT(1A) antagonist, WAY-100635 (0.4 μg) and were submitted to the ETM. Pretreatment with WAY-100635 reversed the increase in escape latency, a panicolytic effect, determined by the pindolol-paroxetine combination. These results implicate the 5-HT(1A) receptors of the DPAG in the panicolytic effect of the pindolol-paroxetine combination administered systemically. They also give further preclinical support for the use of this drug combination in the treatment of panic disorder.

  5. G protein- and agonist-bound serotonin 5-HT2A receptor model activated by steered molecular dynamics simulations

    DEFF Research Database (Denmark)

    Ísberg, Vignir; Balle, Thomas; Sander, Tommy

    2011-01-01

    A 5-HT(2A) receptor model was constructed by homology modeling based on the ß(2)-adrenergic receptor and the G protein-bound opsin crystal structures. The 5-HT(2A) receptor model was transferred into an active conformation by an agonist ligand and a G(aq) peptide in four subsequent steered...

  6. Prolonged Activation of the Htr2b Serotonin Receptor Impairs Glucose Stimulated Insulin Secretion and Mitochondrial Function in MIN6 Cells

    Science.gov (United States)

    Cataldo, Luis Rodrigo; Mizgier, María L.; Bravo Sagua, Roberto; Jaña, Fabián; Cárdenas, César; Llanos, Paola; Busso, Dolores; Olmos, Pablo; Galgani, José E.; Santos, José L.; Cortés, Víctor A.

    2017-01-01

    Aims Pancreatic β-cells synthesize and release serotonin (5 hydroxytryptamine, 5HT); however, the role of 5HT receptors on glucose stimulated insulin secretion (GSIS) and the mechanisms mediating this function is not fully understood. The aims of this study were to determine the expression profile of 5HT receptors in murine MIN6 β-cells and to examine the effects of pharmacological activation of 5HT receptor Htr2b on GSIS and mitochondrial function. Materials and Methods mRNA levels of 5HT receptors in MIN6 cells were quantified by RT qPCR. GSIS was assessed in MIN6 cells in response to global serotonergic activation with 5HT and pharmacological Htr2b activation or inhibition with BW723C86 or SB204741, respectively. In response to Htr2b activation also was evaluated the mRNA and protein levels of PGC1α and PPARy by RT-qPCR and western blotting and mitochondrial function by oxygen consumption rate (OCR) and ATP cellular content. Results We found that mRNA levels of most 5HT receptors were either very low or undetectable in MIN6 cells. By contrast, Htr2b mRNA was present at moderate levels in these cells. Preincubation (6 h) of MIN6 cells with 5HT or BW723C86 reduced GSIS and the effect of 5HT was prevented by SB204741. Preincubation with BW723C86 increased PGC1α and PPARy mRNA and protein levels and decreased mitochondrial respiration and ATP content in MIN6 cells. Conclusions Our results indicate that prolonged Htr2b activation in murine β-cells decreases glucose-stimulated insulin secretion and mitochondrial activity by mechanisms likely dependent on enhanced PGC1α/PPARy expression. PMID:28129327

  7. Dopamine D2 and serotonin 5-HT1A receptor interaction in the context of the effects of antipsychotics - in vitro studies.

    Science.gov (United States)

    Łukasiewicz, Sylwia; Błasiak, Ewa; Szafran-Pilch, Kinga; Dziedzicka-Wasylewska, Marta

    2016-05-01

    The serotonin 5-HT1A receptor (5-HT1 A R) and dopamine D2 receptor (D2 R) have been implicated as important sites of action in antipsychotics. Several lines of evidence indicate the key role of G protein-coupled receptors (GPCRs) heteromers in pathophysiology of schizophrenia and highlight these complexes as novel drug targets. Because heterodimers can form only on those cells co-expressing constituent receptors, they present a target of high pharmacological specificity in the context of biochemical effects induced by antipsychotic drugs. In studies conducted in the HEK 293 cell line, we demonstrated that 5-HT1 A R and D2 R are able to form constitutive heterodimers, and antipsychotic drugs (clozapine, olanzapine, aripiprazole, and lurasidone) enhanced this process, with clozapine being most effective. Various functional tests (cAMP and IP1 as well as ERK activation) indicated that the drugs had different effects on signal transduction by the heteromer. Interestingly, co-incubation of heterodimer-expressing HEK 293 cells with clozapine and the 5-HT1 A R agonist 8-OH DPAT potentiated post-synaptic effects, especially with respect to ERK activation. Our results indicate that the D2 -5-HT1A complex possesses biochemical, pharmacological, and functional properties distinct from those of mono- and homomers. This result has implications for the development of improved pharmacotherapy for schizophrenia or other disorders (activating the heteromer might be cognitive enhancing, since it is expressed in frontal cortex) through the specific targeting of heterodimers. We reported the constitutive formation of D2 -5-HT1A heteromers, which possess biochemical, pharmacological, and functional properties distinct from those of mono- and homomers, as revealed by antipsychotics action. We also showed that these two receptors are co-expressed in mouse cortical neurons; therefore their potential to heterodimerize may comprise an essential target for the development of novel strategies

  8. Familial risk for mood disorder and the personality risk factor, neuroticism, interact in their association with frontolimbic serotonin 2A receptor binding.

    Science.gov (United States)

    Frokjaer, Vibe G; Vinberg, Maj; Erritzoe, David; Baaré, William; Holst, Klaus Kähler; Mortensen, Erik Lykke; Arfan, Haroon; Madsen, Jacob; Jernigan, Terry L; Kessing, Lars Vedel; Knudsen, Gitte Moos

    2010-04-01

    Life stress is a robust risk factor for later development of mood disorders, particularly for individuals at familial risk. Likewise, scoring high on the personality trait neuroticism is associated with an increased risk for mood disorders. Neuroticism partly reflects stress vulnerability and is positively correlated to frontolimbic serotonin 2A (5-HT(2A)) receptor binding. Here, we investigate whether neuroticism interacts with familial risk in relation to frontolimbic 5-HT(2A) receptor binding. Twenty-one healthy twins with a co-twin history of mood disorder and 16 healthy twins without a co-twin history of mood disorder were included. They answered self-report personality questionnaires and underwent [(18)F]altanserin positron emission tomography. We found a significant interaction between neuroticism and familial risk in predicting the frontolimbic 5-HT(2A) receptor binding (p=0.026) in an analysis adjusting for age and body mass index. Within the high-risk group only, neuroticism and frontolimbic 5-HT(2A) receptor binding was positively associated (p=0.0037). In conclusion, our data indicate that familial risk and neuroticism interact in their relation to frontolimbic 5-HT(2A) receptor binding. These findings point at a plausible neurobiological link between genetic and personality risk factors and vulnerability to developing mood disorders. It contributes to our understanding of why some people at high risk develop mood disorders while others do not. We speculate that an increased stress reactivity in individuals at high familial risk for mood disorders might enhance the effect of neuroticism in shaping the impact of potential environmental stress and thereby influence serotonergic neurotransmission.

  9. Serotonin receptors are involved in the spinal mediation of descending facilitation of surgical incision-induced increase of Fos-like immunoreactivity in rats

    Directory of Open Access Journals (Sweden)

    Prado Wiliam A

    2010-03-01

    Full Text Available Abstract Background Descending pronociceptive pathways may be implicated in states of persistent pain. Paw skin incision is a well-established postoperative pain model that causes behavioral nociceptive responses and enhanced excitability of spinal dorsal horn neurons. The number of spinal c-Fos positive neurons of rats treated intrathecally with serotonin, noradrenaline or acetylcholine antagonists where evaluated to study the descending pathways activated by a surgical paw incision. Results The number of c-Fos positive neurons in laminae I/II ipsilateral, lamina V bilateral to the incised paw, and in lamina X significantly increased after the incision. These changes: remained unchanged in phenoxybenzamine-treated rats; were increased in the contralateral lamina V of atropine-treated rats; were inhibited in the ipsilateral lamina I/II by 5-HT1/2B/2C (methysergide, 5-HT2A (ketanserin or 5-HT1/2A/2C/5/6/7 (methiothepin receptors antagonists, in the ipsilateral lamina V by methysergide or methiothepin, in the contralateral lamina V by all the serotonergic antagonists and in the lamina X by LY 278,584, ketanserin or methiothepin. Conclusions We conclude: (1 muscarinic cholinergic mechanisms reduce incision-induced response of spinal neurons inputs from the contralateral paw; (2 5-HT1/2A/2C/3 receptors-mediate mechanisms increase the activity of descending pathways that facilitates the response of spinal neurons to noxious inputs from the contralateral paw; (3 5-HT1/2A/2C and 5-HT1/2C receptors increases the descending facilitation mechanisms induced by incision in the ipsilateral paw; (4 5-HT2A/3 receptors contribute to descending pronociceptive pathways conveyed by lamina X spinal neurons; (5 α-adrenergic receptors are unlikely to participate in the incision-induced facilitation of the spinal neurons.

  10. The role of RNA editing of the serotonin 2C receptor in a rat model of oro-facial neuropathic pain.

    Science.gov (United States)

    Nakae, Aya; Nakai, Kunihiro; Tanaka, Tatsuya; Hagihira, Saotoshi; Shibata, Masahiko; Ueda, Koichi; Masimo, Takashi

    2008-05-01

    We examined whether infraorbital nerve injury affected the RNA editing efficiency of the serotonin (5HT) 2C receptor in the cervical spinal cord, in association with increased pain thresholds, and whether a 5HT reuptake inhibitor (fluvoxamine; Depromel, Meiji Seika, Tokyo, Japan) altered this editing. Accordingly, we injured rats with an infraorbital nerve loose ligation and examined the pain thresholds, mRNA and mRNA editing of the 5HT2C receptor. We evaluated changes in mRNA editing and 5HT2C mRNA expression using cloning along with sequence analysis and quantitative reverse transcription-polymerase chain reaction to compare samples taken at post-injury day 28 from spinal cord sites, including the trigeminal nucleus caudalis, in naive, sham and injured rats (groups of each type had also received fluvoxamine). 5HT2C receptor expression was maintained post-injury. The RNA editing efficiency was statistically significantly lower at molecular sites A and B in ipsilateral spinal cord samples from injured rats than in bilateral samples from naive and sham rats, and in contralateral samples from injured rats. After injury, the proportional presence of two receptor isoforms changed, i.e. statistically significantly less VNV and significantly more INV and ISV. The proportions reverted after fluvoxamine administration. The post-injury change might be evidence of a functional adaptation mechanism that increases the expression of 5HT2C mRNA isoforms that encode receptors that are more sensitive to 5HT. This would activate the brainstem-spinal descending 5HT systems and, in effect, suppress nociceptive signals from primary afferent neurons to the spinal trigeminal nucleus caudalis.

  11. Activation of serotonin2A receptors in the medial septum-diagonal band of Broca complex enhanced working memory in the hemiparkinsonian rats.

    Science.gov (United States)

    Li, Li-Bo; Zhang, Li; Sun, Yi-Na; Han, Ling-Na; Wu, Zhong-Heng; Zhang, Qiao-Jun; Liu, Jian

    2015-04-01

    Serotonin2A (5-HT2A) receptors are highly expressed in the medial septum-diagonal band of Broca complex (MS-DB), especially in parvalbumin (PV)-positive neurons linked to hippocampal theta rhythm, which is involved in cognition. Cognitive impairments commonly occur in Parkinson's disease. Here we performed behavioral, electrophysiological, neurochemical and immunohistochemical studies in rats with complete unilateral 6-hydroxydopamine lesions of the medial forebrain bundle (MFB) to assess the importance of dopamine (DA) depletion and MS-DB 5-HT2A receptors for working memory. The MFB lesions resulted in working memory impairment and decreases in firing rate and density of MS-DB PV-positive neurons, peak frequency of hippocampal theta rhythm, and DA levels in septohippocampal system and medial prefrontal cortex (mPFC) compared to control rats. Intra-MS-DB injection of high affinity 5-HT2A receptor agonist TCB-2 enhanced working memory, increased firing rate of PV-positive neurons and peak frequency of hippocampal theta rhythm, elevated DA levels in the hippocampus and mPFC, and decreased 5-HT level in the hippocampus in control and lesioned rats. Compared to control rats, the duration of the excitatory effect produced by TCB-2 on the firing rate of PV-positive neurons was markedly shortened in lesioned rats, indicating dysfunction of 5-HT2A receptors. These findings suggest that unilateral lesions of the MFB in rats induced working memory deficit, and activation of MS-DB 5-HT2A receptors enhanced working memory, which may be due to changes in the activity of septohippocampal network and monoamine levels in the hippocampus and mPFC.

  12. Central PGE2 exhibits anxiolytic-like activity via EP1 and EP4 receptors in a manner dependent on serotonin 5-HT1A, dopamine D1 and GABAA receptors.

    Science.gov (United States)

    Suzuki, Chihiro; Miyamoto, Chihiro; Furuyashiki, Tomoyuki; Narumiya, Shuh; Ohinata, Kousaku

    2011-07-21

    We found that centrally administered prostaglandin (PG) E(2) exhibited anxiolytic-like activity in the elevated plus-maze and open field test in mice. Agonists selective for EP(1) and EP(4) receptors, among four receptor subtypes for PGE(2), mimicked the anxiolytic-like activity of PGE(2). The anxiolytic-like activity of PGE(2) was blocked by an EP(1) or EP(4) antagonist, as well as in EP(4) but not EP(1) knockout mice. Central activation of either EP(1) or EP(4) receptors resulted in anxiolytic-like activity. The PGE(2)-induced anxiolytic-like activity was inhibited by antagonists for serotonin 5-HT(1A), dopamine D(1) and GABA(A) receptors. Taken together, PGE(2) exhibits anxiolytic-like activity via EP(1) and EP(4) receptors, with downstream involvement of 5-HT(1A), D(1) and GABA(A) receptor systems. Copyright © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  13. Aromatic interactions impact ligand binding and function at serotonin 5-HT2C G protein-coupled receptors: receptor homology modelling, ligand docking, and molecular dynamics results validated by experimental studies

    Science.gov (United States)

    Córdova-Sintjago, Tania; Villa, Nancy; Fang, Lijuan; Booth, Raymond G.

    2014-02-01

    The serotonin (5-hydroxytryptamine, 5-HT) 5-HT2 G protein-coupled receptor (GPCR) family consists of types 2A, 2B, and 2C that share ∼75% transmembrane (TM) sequence identity. Agonists for 5-HT2C receptors are under development for psychoses; whereas, at 5-HT2A receptors, antipsychotic effects are associated with antagonists - in fact, 5-HT2A agonists can cause hallucinations and 5-HT2B agonists cause cardiotoxicity. It is known that 5-HT2A TM6 residues W6.48, F6.51, and F6.52 impact ligand binding and function; however, ligand interactions with these residues at the 5-HT2C receptor have not been reported. To predict and validate molecular determinants for 5-HT2C-specific activation, results from receptor homology modelling, ligand docking, and molecular dynamics simulation studies were compared with experimental results for ligand binding and function at wild type and W6.48A, F6.51A, and F6.52A point-mutated 5-HT2C receptors.

  14. Expression of the 5-HT1A serotonin receptor in the hippocampus is required for social stress resilience and the antidepressant-like effects induced by the nicotinic partial agonist cytisine.

    Science.gov (United States)

    Mineur, Yann S; Einstein, Emily B; Bentham, Matthew P; Wigestrand, Mattis B; Blakeman, Sam; Newbold, Sylvia A; Picciotto, Marina R

    2015-03-01

    Nicotinic acetylcholine receptor (nAChR) blockers potentiate the effects of selective serotonin reuptake inhibitors (SSRIs) in some treatment-resistant patients; however, it is not known whether these effects are independent, or whether the two neurotransmitter systems act synergistically. We first determined that the SSRI fluoxetine and the nicotinic partial agonist cytisine have synergistic effects in a mouse model of antidepressant efficacy, whereas serotonin depletion blocked the effects of cytisine. Using a pharmacological approach, we found that the 5-HT1A agonist 8-OH-DPAT also potentiated the antidepressant-like effects of cytisine, suggesting that this subtype might mediate the interaction between the serotonergic and cholinergic systems. The 5-HT1A receptors are located both presynaptically and postsynaptically. We therefore knocked down 5-HT1A receptors in either the dorsal raphe (presynaptic autoreceptors) or the hippocampus (a brain area with high expression of 5-HT1A heteroreceptors sensitive to cholinergic effects on affective behaviors). Knockdown of 5-HT1A receptors in hippocampus, but not dorsal raphe, significantly decreased the antidepressant-like effect of cytisine. This study suggests that serotonin signaling through postsynaptic 5-HT1A receptors in the hippocampus is critical for the antidepressant-like effects of a cholinergic drug and begins to elucidate the molecular mechanisms underlying interactions between the serotonergic and cholinergic systems related to mood disorders.

  15. Expression of the 5-HT1A Serotonin Receptor in the Hippocampus Is Required for Social Stress Resilience and the Antidepressant-Like Effects Induced by the Nicotinic Partial Agonist Cytisine

    Science.gov (United States)

    Mineur, Yann S; Einstein, Emily B; Bentham, Matthew P; Wigestrand, Mattis B; Blakeman, Sam; Newbold, Sylvia A; Picciotto, Marina R

    2015-01-01

    Nicotinic acetylcholine receptor (nAChR) blockers potentiate the effects of selective serotonin reuptake inhibitors (SSRIs) in some treatment-resistant patients; however, it is not known whether these effects are independent, or whether the two neurotransmitter systems act synergistically. We first determined that the SSRI fluoxetine and the nicotinic partial agonist cytisine have synergistic effects in a mouse model of antidepressant efficacy, whereas serotonin depletion blocked the effects of cytisine. Using a pharmacological approach, we found that the 5-HT1A agonist 8-OH-DPAT also potentiated the antidepressant-like effects of cytisine, suggesting that this subtype might mediate the interaction between the serotonergic and cholinergic systems. The 5-HT1A receptors are located both presynaptically and postsynaptically. We therefore knocked down 5-HT1A receptors in either the dorsal raphe (presynaptic autoreceptors) or the hippocampus (a brain area with high expression of 5-HT1A heteroreceptors sensitive to cholinergic effects on affective behaviors). Knockdown of 5-HT1A receptors in hippocampus, but not dorsal raphe, significantly decreased the antidepressant-like effect of cytisine. This study suggests that serotonin signaling through postsynaptic 5-HT1A receptors in the hippocampus is critical for the antidepressant-like effects of a cholinergic drug and begins to elucidate the molecular mechanisms underlying interactions between the serotonergic and cholinergic systems related to mood disorders. PMID:25288485

  16. Serotonin Transporter Genotype Affects Serotonin 5-HT1A Binding in Primates

    OpenAIRE

    Christian, Bradley T; Wooten, Dustin W; Hillmer, Ansel T.; Tudorascu, Dana L.; Converse, Alexander K.; Moore, Colleen F.; Ahlers, Elizabeth O.; Barnhart, Todd E.; Kalin, Ned H.; Barr, Christina S.; Schneider, Mary L.

    2013-01-01

    Disruption of the serotonin system has been implicated in anxiety and depression and a related genetic variation has been identified that may predispose individuals for these illnesses. The relationship of a functional variation of the serotonin transporter promoter gene (5-HTTLPR) on serotonin transporter binding using in vivo imaging techniques have yielded inconsistent findings when comparing variants for short (s) and long (l) alleles. However, a significant 5-HTTLPR effect on receptor bi...

  17. Involvement of the 5-HT(1A) receptor in the anti-immobility effects of fluvoxamine in the forced swimming test and mouse strain differences in 5-HT(1A) receptor binding.

    Science.gov (United States)

    Sugimoto, Yumi; Furutani, Sachiko; Kajiwara, Yoshinobu; Hirano, Kazufumi; Yamada, Shizuo; Tagawa, Noriko; Kobayashi, Yoshiharu; Hotta, Yoshihiro; Yamada, Jun

    2010-03-10

    We previously demonstrated the presence of strain differences in baseline immobility time and sensitivity to the selective serotonin reuptake inhibitor (SSRI) fluvoxamine in five strains of mice (ICR, ddY, C57BL, DBA/2 and BALB/c mice). Furthermore, variations in serotonin (5-HT) transporter binding in the brain were strongly related to strain differences in baseline immobility and sensitivity to fluvoxamine. In the present study, we examined the involvement of the 5-HT(1A) receptor in anti-immobility effects in DBA/2 mice, which show high sensitivity to fluvoxamine. The anti-immobility effects of fluvoxamine in DBA/2 mice were inhibited by the 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide (WAY 100635). However, the 5-HT(1B) receptor antagonist 3-[3-(dimethylamino)propyl]-4-hydroxy-N-[4-(4-pyridinyl)phenyl]benzamide (GR55562), the 5-HT(2) receptor antagonist 6-methyl-1-(methylethyl)-ergoline-8beta-carboxylic acid 2-hydroxy-1-methylpropyl ester (LY 53857), the 5-HT(3) receptor antagonist ondansetron and the 5-HT(4) receptor antagonist 4-amino-5-chloro-2-methoxy-benzoic acid 2-(diethylamino)ethyl ester (SDZ 205,557) did not influence the anti-immobility effects of fluvoxamine in DBA/2 mice. These results suggest that fluvoxamine-induced antidepressant-like effects in DBA/2 mice are mediated by the 5-HT(1A) receptor. We analyzed 5-HT(1A) receptor binding in the brains of five strains of mice. Strain differences in 5-HT(1A) receptor binding were observed. 5-HT(1A) receptor binding in brain was not correlated with baseline immobility time in the five strains of mice examined. These results suggest that, although the anti-immobility effects of fluvoxamine in DBA/2 mice are mediated by the 5-HT(1A) receptor, strain differences in 5-HT(1A) receptor binding are not related to variation in immobility time and responses to fluvoxamine.

  18. Altered brain serotonin 5-HT1A receptor binding after recovery from anorexia nervosa measured by positron emission tomography and [carbonyl11C]WAY-100635.

    Science.gov (United States)

    Bailer, Ursula F; Frank, Guido K; Henry, Shannan E; Price, Julie C; Meltzer, Carolyn C; Weissfeld, Lisa; Mathis, Chester A; Drevets, Wayne C; Wagner, Angela; Hoge, Jessica; Ziolko, Scott K; McConaha, Claire W; Kaye, Walter H

    2005-09-01

    Previous studies have shown that women with anorexia nervosa (AN), when ill and after recovery, have alterations of serotonin (5-HT) neuronal activity and core eating disorder symptoms, such as anxiety. To further characterize the 5-HT system in AN, we investigated 5-HT1A receptor activity using positron emission tomography imaging because this receptor is implicated in anxiety and feeding behavior. To avoid the confounding effects of malnutrition, we studied 13 women who had recovered from restricting-type AN (mean age, 23.3 +/- 5.2 years) and 12 women who had recovered from bulimia-type AN (mean age, 28.6 +/- 7.3 years) (>1 year normal weight, regular menstrual cycles, no bingeing or purging). These subjects were compared with 18 healthy control women (mean age, 25.1 +/- 5.8 years). Intervention The 5-HT1A receptor binding was measured using positron emission tomography imaging and a specific 5-HT1A receptor antagonist, [carbonyl-11C]WAY-100635. Specific 5-HT1A receptor binding was assessed using the binding potential measure. Binding potential values were derived using both the Logan graphical method and compartmental modeling. The binding potential in a region of interest was calculated with the formula: binding potential = distribution volume of the region of interest minus distribution volume of the cerebellum. Women recovered from bulimia-type AN had significantly (P<.05) increased [11C]WAY-100635 binding potential in cingulate, lateral and mesial temporal, lateral and medial orbital frontal, parietal, and prefrontal cortical regions and in the dorsal raphe compared with control women. No differences were found for women recovered from restricting-type AN relative to controls. For women recovered from restricting-type AN, the 5-HT1A postsynaptic receptor binding in mesial temporal and subgenual cingulate regions was positively correlated with harm avoidance. We observed increased 5-HT1A receptor binding in women who had recovered from bulimia-type AN but not

  19. Serotonin neurotransmission in anorexia nervosa.

    Science.gov (United States)

    Haleem, Darakhshan Jabeen

    2012-09-01

    Patients with anorexia nervosa (AN) show extreme dieting weight loss, hyperactivity, depression/anxiety, self-control, and behavioral impulsivity. 5-Hydroxytryptamine (5-HT; serotonin) is involved in almost all the behavioral changes observed in AN patients. Both genetic and environmental factors contribute toward the pathogenesis of AN. It is a frequent disorder among adolescent girls and young women and starts as an attempt to lose weight to look beautiful and attractive. Failure to see the turning point when fasting becomes unreasonable leads to malnutrition and AN. Tryptophan, the precursor of serotonin and an essential amino acid, is only available in the diet. It is therefore likely that excessive diet restriction and malnutrition decrease brain serotonin stores because the precursor is less available to the rate-limiting enzyme of 5-HT biosynthesis, which normally exists unsaturated with its substrate. Evidence shows that diet restriction-induced exaggerated feedback control over 5-HT synthesis and the smaller availability of tryptophan decreases serotonin neurotransmission at postsynaptic sites, leading to hyperactivity, depression, and behavioral impulsivity. A compensatory upregulation of postsynaptic 5-HT-1A receptors and hypophagic serotonin receptors may be involved in anxiety and suppression of appetite. It is suggested that tryptophan supplementation may improve pharmacotherapy in AN.

  20. Activation of serotonin 5-HT2C receptor suppresses behavioral sensitization and naloxone-precipitated withdrawal symptoms in morphine-dependent mice

    Science.gov (United States)

    Zhang, Gongliang; Wu, Xian; Zhang, Yong-Mei; Liu, Huan; Jiang, Qin; Pang, Gang; Tao, Xinrong; Dong, Liuyi; Stackman, Robert W.

    2015-01-01

    Opioid abuse and dependence have evolved into an international epidemic as a significant clinical and social problem with devastating consequences. Repeated exposure to the opioid, for example morphine, can induce profound, long-lasting behavioral sensitization and physical dependence, which are thought to reflect neuroplasticity in neural circuitry. Central serotonin (5-HT) neurotransmission participates in the development of dependence on and the expression of withdrawal from morphine. Serotonin 5-HT2C receptor (5-HT2CR) agonists suppress psychostimulant nicotine or cocaine-induced behavioral sensitization and drug-seeking behavior; however, the impact of 5-HT2CR agonists on behaviors relevant to opioid abuse and dependence has not been reported. In the present study, the effects of 5-HT2CR activation on the behavioral sensitization and naloxone-precipitated withdrawal symptoms were examined in mice underwent repeated exposure to morphine. Male mice received morphine (10 mg/kg, s.c.) to develop behavioral sensitization. Lorcaserin, a 5-HT2CR agonist, prevented the induction and expression, but not the development, of morphine-induced behavioral sensitization. Another cohort of mice received increasing doses of morphine over a 7-day period to induce morphine-dependence. Pretreatment of lorcaserin, or the positive control clonidine (an alpha 2-adrenoceptor agonist), ameliorated the naloxone-precipitated withdrawal symptoms. SB 242084, a selective 5-HT2CR antagonist, prevented the lorcaserin-mediated suppression of behavioral sensitization and withdrawal. Chronic morphine treatment was associated with an increase in the expression of 5-HT2CR protein in the ventral tegmental area, locus coeruleus and nucleus accumbens. These findings suggest that 5-HT2CR can modulate behavioral sensitization and withdrawal in morphine-dependent mice, and the activation of 5-HT2CR may represent a new avenue for the treatment of opioid addiction. PMID:26432939

  1. Serotonin modulates glutamatergic transmission to neurons in the lateral habenula.

    Science.gov (United States)

    Xie, Guiqin; Zuo, Wanhong; Wu, Liangzhi; Li, Wenting; Wu, Wei; Bekker, Alex; Ye, Jiang-Hong

    2016-04-01

    The lateral habenula (LHb) is bilaterally connected with serotoninergic raphe nuclei, and expresses high density of serotonin receptors. However, actions of serotonin on the excitatory synaptic transmission to LHb neurons have not been thoroughly investigated. The LHb contains two anatomically and functionally distinct regions: lateral (LHbl) and medial (LHbm) divisions. We compared serotonin's effects on glutamatergic transmission across the LHb in rat brains. Serotonin bi-directionally and differentially modulated glutamatergic transmission. Serotonin inhibited glutamatergic transmission in higher percentage of LHbl neurons but potentiated in higher percentage of LHbm neurons. Magnitude of potentiation was greater in LHbm than in LHbl. Type 2 and 3 serotonin receptor antagonists attenuated serotonin's potentiation. The serotonin reuptake blocker, and the type 2 and 3 receptor agonists facilitated glutamatergic transmission in both LHbl and LHbm neurons. Thus, serotonin via activating its type 2, 3 receptors, increased glutamate release at nerve terminals in some LHb neurons. Our data demonstrated that serotonin affects both LHbm and LHbl. Serotonin might play an important role in processing information between the LHb and its downstream-targeted structures during decision-making. It may also contribute to a homeostatic balance underlying the neural circuitry between the LHb and raphe nuclei.

  2. Similarities between the Binding Sites of SB-206553 at Serotonin Type 2 and Alpha7 Acetylcholine Nicotinic Receptors: Rationale for Its Polypharmacological Profile.

    Directory of Open Access Journals (Sweden)

    Patricia Möller-Acuña

    Full Text Available Evidence from systems biology indicates that promiscuous drugs, i.e. those that act simultaneously at various protein targets, are clinically better in terms of efficacy, than those that act in a more selective fashion. This has generated a new trend in drug development called polypharmacology. However, the rational design of promiscuous compounds is a difficult task, particularly when the drugs are aimed to act at receptors with diverse structure, function and endogenous ligand. In the present work, using docking and molecular dynamics methodologies, we established the most probable binding sites of SB-206553, a drug originally described as a competitive antagonist of serotonin type 2B/2C metabotropic receptors (5-HT2B/2CRs and more recently as a positive allosteric modulator of the ionotropic α7 nicotinic acetylcholine receptor (nAChR. To this end, we employed the crystal structures of the 5-HT2BR and acetylcholine binding protein as templates to build homology models of the 5-HT2CR and α7 nAChR, respectively. Then, using a statistical algorithm, the similarity between these binding sites was determined. Our analysis showed that the most plausible binding sites for SB-206553 at 5-HT2Rs and α7 nAChR are remarkably similar, both in size and chemical nature of the amino acid residues lining these pockets, thus providing a rationale to explain its affinity towards both receptor types. Finally, using a computational tool for multiple binding site alignment, we determined a consensus binding site, which should be useful for the rational design of novel compounds acting simultaneously at these two types of highly different protein targets.

  3. Test-retest variability of high resolution positron emission tomography (PET imaging of cortical serotonin (5HT2A receptors in older, healthy adults

    Directory of Open Access Journals (Sweden)

    Graff-Guerrero Ariel

    2009-07-01

    Full Text Available Abstract Background Position emission tomography (PET imaging using [18F]-setoperone to quantify cortical 5-HT2A receptors has the potential to inform pharmacological treatments for geriatric depression and dementia. Prior reports indicate a significant normal aging effect on serotonin 5HT2A receptor (5HT2AR binding potential. The purpose of this study was to assess the test-retest variability of [18F]-setoperone PET with a high resolution scanner (HRRT for measuring 5HT2AR availability in subjects greater than 60 years old. Methods: Six healthy subjects (age range = 65–78 years completed two [18F]-setoperone PET scans on two separate occasions 5–16 weeks apart. Results The average difference in the binding potential (BPND as measured on the two occasions in the frontal and temporal cortical regions ranged between 2 and 12%, with the lowest intraclass correlation coefficient in anterior cingulate regions. Conclusion We conclude that the test-retest variability of [18F]-setoperone PET in elderly subjects is comparable to that of [18F]-setoperone and other 5HT2AR radiotracers in younger subject samples.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1985-06-17

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

  5. Effects of serotonin on expression of the LDL receptor family member LR11 and 7-ketocholesterol-induced apoptosis in human vascular smooth muscle cells

    Energy Technology Data Exchange (ETDEWEB)

    Nagayama, Daiji; Ishihara, Noriko [Center of Diabetes, Endocrinology and Metabolism, Toho University, Sakura Medical Center, 564-1, Shimoshizu, Sakura-City, Chiba 285-8741 (Japan); Bujo, Hideaki [Department of Clinical Laboratory Medicine, Toho University, Sakura Medical Center, 564-1, Shimoshizu, Sakura-City, Chiba 285-8741 (Japan); Shirai, Kohji [Department of Vascular Function, Toho University, Sakura Medical Center, 564-1, Shimoshizu, Sakura-City, Chiba 285-8741 (Japan); Tatsuno, Ichiro, E-mail: ichiro.tatsuno@med.toho-u.ac.jp [Center of Diabetes, Endocrinology and Metabolism, Toho University, Sakura Medical Center, 564-1, Shimoshizu, Sakura-City, Chiba 285-8741 (Japan)

    2014-04-18

    Highlights: • The dedifferentiation of VSMCs in arterial intima is involved in atherosclerosis. • 5-HT showed proliferative effect on VSMCs which was abolished by sarpogrelate. • 5-HT enhanced expression of LR11 mRNA in VSMCs which was abolished by sarpogrelate. • 5-HT suppressed 7KCHO-induced apoptosis of VSMCs via caspase-3/7-dependent pathway. • The mechanisms explain the 5-HT-induced remodeling of arterial structure. - Abstract: Serotonin (5-HT) is a known mitogen for vascular smooth muscle cells (VSMCs). The dedifferentiation and proliferation/apoptosis of VSMCs in the arterial intima represent one of the atherosclerotic changes. LR11, a member of low-density lipoprotein receptor family, may contribute to the proliferation of VSMCs in neointimal hyperplasia. We conducted an in vitro study to investigate whether 5-HT is involved in LR11 expression in human VSMCs and apoptosis of VSMCs induced by 7-ketocholesterol (7KCHO), an oxysterol that destabilizes plaque. 5-HT enhanced the proliferation of VSMCs, and this effect was abolished by sarpogrelate, a selective 5-HT2A receptor antagonist. Sarpogrelate also inhibited the 5-HT-enhanced LR11 mRNA expression in VSMCs. Furthermore, 5-HT suppressed the 7KCHO-induced apoptosis of VSMCs via caspase-3/7-dependent pathway. These findings provide new insights on the changes in the differentiation stage of VSMCs mediated by 5-HT.

  6. Serotonin hyperinnervation and upregulated 5-HT2A receptor expression and motor-stimulating function in nigrostriatal dopamine-deficient Pitx3 mutant mice.

    Science.gov (United States)

    Li, Li; Qiu, Guozhen; Ding, Shengyuan; Zhou, Fu-Ming

    2013-01-23

    The striatum receives serotonin (5-hydroxytryptamine, 5-HT) innervation and expresses 5-HT2A receptors (5-HT2ARs) and other 5-HT receptors, raising the possibility that the striatal 5-HT system may undergo adaptive changes after chronic severe dopamine (DA) loss and contribute to the function and dysfunction of the striatum. Here we show that in transcription factor Pitx3 gene mutant mice with a selective, severe DA loss in the dorsal striatum mimicking the DA denervation in late Parkinson's disease (PD), both the 5-HT innervation and the 5-HT2AR mRNA expression were increased in the dorsal striatum. Functionally, while having no detectable motor effect in wild type mice, the 5-HT2R agonist 2,5-dimethoxy-4-iodoamphetamine increased both the baseline and l-dopa-induced normal ambulatory and dyskinetic movements in Pitx3 mutant mice, whereas the selective 5-HT2AR blocker volinanserin had the opposite effects. These results demonstrate that Pitx3 mutant mice are a convenient and valid mouse model to study the compensatory 5-HT upregulation following the loss of the nigrostriatal DA projection and that the upregulated 5-HT2AR function in the DA deficient dorsal striatum may enhance both normal and dyskinetic movements. Copyright © 2012 Elsevier B.V. All rights reserved.

  7. Interaction between serotonin 5-HT2A receptor gene and dopamine transporter (DAT1) gene polymorphisms influences personality trait of persistence in Austrian Caucasians.

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    Schosser, Alexandra; Fuchs, Karoline; Scharl, Theresa; Schloegelhofer, Monika; Kindler, Jochen; Mossaheb, Nilufar; Kaufmann, Rainer M; Leisch, Friedrich; Kasper, Siegfried; Sieghart, Werner; Aschauer, Harald N

    2010-03-01

    We examined 89 normal volunteers using Cloninger's Temperament and Character Inventory (TCI). Genotyping the 102T/C polymorphism of the serotonin 5HT2A receptor gene and the ser9gly polymorphism in exon 1 of the dopamine D3 receptor (DRD3) gene was performed using PCR-RFLP, whereas the dopamine transporter (DAT1) gene variable number of tandem repeats (VNTR) polymorphism was investigated using PCR amplification followed by electrophoresis in an 8% acrylamide gel with a set of size markers. We found a nominally significant association between gender and harm avoidance (P=0.017; women showing higher scores). There was no association of either DAT1, DRD3 or 5HT2A alleles or genotypes with any dimension of the TCI applying Kruskal-Wallis rank-sum tests. Comparing homozygote and heterozygote DAT1 genotypes, we found higher novelty seeking scores in homozygotes (P=0.054). We further found a nominally significant interaction between DAT1 and 5HT2A homo-/heterozygous gene variants (P=0.0071; DAT1 and 5HT2A genotypes P value of 0.05), performing multivariate analysis of variance (MANOVA). Examining the temperamental TCI subscales, this interaction was associated with persistence (genotypes: P=0.004; homo-/heterozygous gene variants: P=0.0004). We conclude that an interaction between DAT1 and 5HT2A genes might influence the temperamental personality trait persistence.

  8. 5-HT(2C) serotonin receptor blockade prevents tau protein hyperphosphorylation and corrects the defect in hippocampal synaptic plasticity caused by a combination of environmental stressors in mice.

    Science.gov (United States)

    Busceti, Carla Letizia; Di Pietro, Paola; Riozzi, Barbara; Traficante, Anna; Biagioni, Francesca; Nisticò, Robert; Fornai, Francesco; Battaglia, Giuseppe; Nicoletti, Ferdinando; Bruno, Valeria

    2015-09-01

    Exposure to multimodal sensory stressors is an everyday occurrence and sometimes becomes very intense, such as during rave parties or other recreational events. A growing body of evidence suggests that strong environmental stressors might cause neuronal dysfunction on their own in addition to their synergistic action with illicit drugs. Mice were exposed to a combination of physical and sensory stressors that are reminiscent of those encountered in a rave party. However, this is not a model of rave because it lacks the rewarding properties of rave. A 14-h exposure to environmental stressors caused an impairment of hippocampal long-term potentiation (LTP) and spatial memory, and an enhanced phosphorylation of tau protein in the CA1 and CA3 regions. These effects were transient and critically depended on the activation of 5-HT2C serotonin receptors, which are highly expressed in the CA1 region. Acute systemic injection of the selective 5-HT2C antagonist, RS-102,221 (2 mg/kg, i.p., 2 min prior the onset of stress), prevented tau hyperphosphorylation and also corrected the defects in hippocampal LTP and spatial memory. These findings suggest that passive exposure to a combination of physical and sensory stressors causes a reversible hippocampal dysfunction, which might compromise mechanisms of synaptic plasticity and spatial memory for a few days. Drugs that block 5-HT2C receptors might protect the hippocampus against the detrimental effect of environmental stressors.

  9. Serotonin 2A and 2C receptor biosynthesis in the rodent striatum during postnatal development: mRNA expression and functional linkage to neuropeptide gene regulation.

    Science.gov (United States)

    Basura, G J; Walker, P D

    2000-11-01

    The present study was designed to determine if there are region-specific differences in serotonin (5-HT) neurotransmission and 5-HT receptor expression that may limit the stimulatory effects of the 5-HT releaser p-chloroamphetamine (pCA) on striatal neuropeptide gene expression to the posterior striatum (P-STR) during postnatal maturation. Sprague-Dawley rat brains from postnatal days (PND) 1-35 were processed for 5-HT(2A) and 5-HT(2C) receptor mRNA expression by in situ hybridization and monoamine analysis by HPLC. Within the P-STR, 5-HT(2A) receptor mRNA expression reached young adult (PND 35) levels by PND 3, while levels in the A-STR were significantly less (range: 1.43 +/- 0.219-6. 36 +/- 0.478) than P-STR (5.36 +/- 0.854-12.11 +/- 1.08) at each respective age throughout the time course. 5-HT(2C) receptor mRNA expression reached young adult levels at PND 7 in the A-STR and by PND 3 in the P-STR. At each PND age 5-HT(2C) receptor mRNA levels within the P-STR were significantly less (6.23 +/- 1.02-12.32 +/- 0.427) than the A-STR (7.31 +/- 1.65-26.84 +/- 2.24). 5-HT content increased across the developmental time course within the P-STR (5.01 +/- 0.327-15.7 +/- 1.03 ng/mg protein) and A-STR (2.97 +/- 0. 223-11.2 +/- 0.701 ng/mg protein). Four hours following injection (i. p.) of pCA (10 mg/kg), preprotachykinin (PPT) mRNA levels increased 89% in the P-STR but not the anterior (A-STR) striatum of the 3-week-old rat, which were prevented by preinjection (30 min, i.p.) of the 5-HT(2) receptor antagonist ritanserin (1 mg/kg). Together, these data suggest that faster maturity of 5-HT(2A) receptor expression in the P-STR may be sufficient to convey the region-specific acute stimulatory effects of pCA on PPT mRNA transcription in the developing rodent striatum. These results provide further evidence that the influence of 5-HT on neuropeptide gene expression is far stronger in caudal vs. rostral striatal regions during postnatal development.

  10. Acute serotonin 2A receptor blocking alters the processing of fearful faces in the orbitofrontal cortex and amygdala

    DEFF Research Database (Denmark)

    Hornboll, Bettina; Macoveanu, Julian; Rowe, James;

    2013-01-01

    blockade reduced the neural response to fearful faces in the medial orbitofrontal cortex (OFC), independently of 5-HT2A receptor occupancy or neocortical 5-HT2A receptor BPp . The medial OFC also showed increased functional coupling with the left amygdala during processing of fearful faces depending...

  11. Human-derived gut microbiota modulates colonic secretion in mice by regulating 5-HT3 receptor expression via acetate production.

    Science.gov (United States)

    Bhattarai, Yogesh; Schmidt, Bradley A; Linden, David R; Larson, Eric D; Grover, Madhusudan; Beyder, Arthur; Farrugia, Gianrico; Kashyap, Purna C

    2017-07-01

    Serotonin [5-hydroxytryptamine (5-HT)], an important neurotransmitter and a paracrine messenger in the gastrointestinal tract, regulates intestinal secretion by its action primarily on 5-HT3 and 5-HT4 receptors. Recent studies highlight the role of gut microbiota in 5-HT biosynthesis. In this study, we determine whether human-derived gut microbiota affects host secretory response to 5-HT and 5-HT receptor expression. We used proximal colonic mucosa-submucosa preparation from age-matched Swiss Webster germ-free (GF) and humanized (HM; ex-GF colonized with human gut microbiota) mice. 5-HT evoked a significantly greater increase in short-circuit current (ΔIsc) in GF compared with HM mice. Additionally, 5-HT3 receptor mRNA and protein expression was significantly higher in GF compared with HM mice. Ondansetron, a 5-HT3 receptor antagonist, inhibited 5-HT-evoked ΔIsc in GF mice but not in HM mice. Furthermore, a 5-HT3 receptor-selective agonist, 2-methyl-5-hydroxytryptamine hydrochloride, evoked a significantly higher ΔIsc in GF compared with HM mice. Immunohistochemistry in 5-HT3A-green fluorescent protein mice localized 5-HT3 receptor expression to enterochromaffin cells in addition to nerve fibers. The significant difference in 5-HT-evoked ΔIsc between GF and HM mice persisted in the presence of tetrodotoxin (TTX) but was lost after ondansetron application in the presence of TTX. Application of acetate (10 mM) significantly lowered 5-HT3 receptor mRNA in GF mouse colonoids. We conclude that host secretory response to 5-HT may be modulated by gut microbiota regulation of 5-HT3 receptor expression via acetate production. Epithelial 5-HT3 receptor may function as a mediator of gut microbiota-driven change in intestinal secretion.NEW & NOTEWORTHY We found that gut microbiota alters serotonin (5-HT)-evoked intestinal secretion in a 5-HT3 receptor-dependent mechanism and gut microbiota metabolite acetate alters 5-HT3 receptor expression in colonoids.View this article

  12. Antagonism of lateral saphenous vein serotonin receptors from steers grazing endophyte-free, wild-type, or novel endophyte-infected tall fescue.

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    Klotz, J L; Aiken, G E; Johnson, J M; Brown, K R; Bush, L P; Strickland, J R

    2013-09-01

    Pharmacologic profiling of serotonin (5HT) receptors of bovine lateral saphenous vein has shown that cattle grazing endophyte-infected (Neotyphodium coenophialum) tall fescue (Lolium arundinaceum) have altered responses to ergovaline, 5HT, 5HT2A, and 5HT7 agonists. To determine if 5HT receptor activity of tall fescue alkaloids is affected by grazing endophyte-free (EF), wild-type [Kentucky-31 (KY31)], novel endophyte AR542-infected (MAXQ), or novel endophyte AR584-infected (AR584) tall fescue, contractile responses of lateral saphenous veins biopsied from cattle grazing these different fescue-endophyte combinations were evaluated in presence or absence of antagonists for 5HT2A (ketanserin) or 5HT7 (SB-269970) receptors. Biopsies were conducted over 2 yr on 35 mixed-breed steers (361.5 ± 6.3 kg) grazing EF (n = 12), KY31 (n = 12), MAXQ (n = 6), or AR584 (n = 5) pasture treatments (3 ha) between 84 and 98 d (Yr 1) or 108 to 124 d (Yr 2). Segments (2 to 3 cm) of vein were surgically biopsied, sliced into 2- to 3-mm cross-sections, and suspended in a myograph chamber containing 5 mL of oxygenated Krebs-Henseleit buffer (95% O2/5% CO2; pH = 7.4; 37°C). Veins were exposed to increasing concentrations of 5HT, ergovaline, and ergovaline + 1 × 10(-5) M ketanserin or + 1 × 10(-6) M SB-269970 in Yr 1. In Yr 2, ergotamine and ergocornine were evaluated in presence or absence of 1 × 10(-5) M ketanserin. Contractile response data were normalized to a reference addition of 1 × 10(-4) M norepinephrine. In Yr 1, contractile response to 5HT and ergovaline were least (P endophyte-fescue combinations.

  13. Serotonin receptor B may lock the gate of PTTH release/synthesis in the Chinese silk moth, Antheraea pernyi; a diapause initiation/maintenance mechanism?

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    Qiushi Wang

    Full Text Available The release of prothoracicotropic hormone, PTTH, or its blockade is the major endocrine switch regulating the developmental channel either to metamorphosis or to pupal diapause in the Chinese silk moth, Antheraea pernyi. We have cloned cDNAs encoding two types of serotonin receptors (5HTRA and B. 5HTRA-, and 5HTRB-like immunohistochemical reactivities (-ir were colocalized with PTTH-ir in two pairs of neurosecretory cells at the dorsolateral region of the protocerebrum (DL. Therefore, the causal involvement of these receptors was suspected in PTTH release/synthesis. The level of mRNA(5HTRB responded to 10 cycles of long-day activation, falling to 40% of the original level before activation, while that of 5HTRA was not affected by long-day activation. Under LD 16:8 and 12:12, the injection of dsRNA(5HTRB resulted in early diapause termination, whereas that of dsRNA(5HTRA did not affect the rate of diapause termination. The injection of dsRNA(5HTRB induced PTTH accumulation, indicating that 5HTRB binding suppresses PTTH synthesis also. This conclusion was supported pharmacologically; the injection of luzindole, a melatonin receptor antagonist, plus 5th inhibited photoperiodic activation under LD 16:8, while that of 5,7-DHT, induced emergence in a dose dependent fashion under LD 12:12. The results suggest that 5HTRB may lock the PTTH release/synthesis, maintaining diapause. This could also work as diapause induction mechanism.

  14. Lateral/Basolateral Amygdala Serotonin Type-2 Receptors Modulate Operant Self-administration of a Sweetened Ethanol Solution via Inhibition of Principal Neuron Activity

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    Brian eMccool

    2014-01-01

    Full Text Available The lateral/basolateral amygdala (BLA forms an integral part of the neural circuitry controlling innate anxiety and learned fear. More recently, BLA dependent modulation of self-administration be