It was aimed to investigate the effect of 5-HT2C receptor modulation on the rat behavioral responses induced by 1-(m-chlorophenyl) piperazine(mCPP), a major metabolite of trazodone. The animal activities(ambulation, stereotypy and total activity) were measured for 3 hours following mCPP administration, using an animal activity meter which accumulates the frequency of light beam interruption. mCPP(1-10 mg / kg, i.p.) induced dose-dependent decreases in ambulation and stereotypy, consequently leading to hypoactivity. The hypoactivity induced by mCPP(1mg / kg, i.p.) was significantly inhibited by pretreatment with mianserin(1mg / kg, i.p.), an antagonist with high affinity for 5-HT2C receptor, whereas pretreatment with 5-HT2 antagonists, ketanserin and ritanserin(1mg / kg, i.p., respectively) was without effect. Furthermore, long-term pretreatment with imipramine(10mg / kg, i.p., b.i.d. for 2 weeks) markedly attenuated the mCPP-induced hypoactivity. Mianserin and imipramine in the absence of mCPP did not increase the animal activity. Taken together, these results indicate that the mCPP-induced hypoactivity is mediated by 5-HT2C receptor, and that selective 5-HT2C antagonists and down regulation of 5-HT2C receptor might be useful for inhibiting the mCPP-induced hypoactivity.
Animals ; Down-Regulation ; Imipramine ; Ketanserin ; Mianserin ; Rats ; Receptor, Serotonin, 5-HT2C* ; Serotonin 5-HT2 Receptor Antagonists ; Trazodone ; Walking

Currently available pharmacotherapies for depression still have a limited antidepressant efficacy with a delayed onset of several weeks, and still cause side effects. These unmet needs represent important reasons to continue to search for novel treatment options. A disorganization of circadian rhythms has been suggested to play an important role in the pathophysiology of major depression. Agomelatine is a new agent with a unique pharmacological profile. Agomelatine is both an agonist of melatonergic MT(1) and MT(2) receptors and a serotonergic 5-HT(2C) receptor antagonist. Many clinical trials have demonstrated the superior efficacy of agomelatine in comparison with placebo in the treatment major depressive disorder at the standard dose of 25 mg/day, with the possibility of increasing doses to 50 mg/day in those patients with insufficient improvement. Agomelatine was even effective in severely depressed patients. The safety and tolerability of agomelatine was comparable to placebo. It does not induce the side effects including serotonin syndrome and sexual dysfunction or discontinuation syndrome typical to other therapies, such as selective serotonin reuptake inhibitors. These properties give agomelatine a definite clinical advantage in the treatment of depression.
Acetamides ; Circadian Rhythm ; Depression ; Depressive Disorder, Major ; Humans ; Imidazoles ; Nitro Compounds ; Receptor, Serotonin, 5-HT2C ; Serotonin Syndrome ; Serotonin Uptake Inhibitors

OBJECTIVE: Activation of one or more serotonin (5-HT) receptors may play a role in mediating the antidepressant effects of serotonergic antidepressants. The serotonin 2C (5HT 2C) receptor is known to be associated with antidepressant action and weight gain. We sought to determine whether the 5-HTR 2C receptor -759C/T polymorphism was associated with weight gain and treatment response to mirtazapine in major depressive disorder (MDD) patients. METHODS: The 5-HT 2C receptor -759C/T polymorphism was analyzed in 323 MDD patients. All patients were evaluated using the 21-item Hamilton Depression Rating Scale at the beginning of the study and at 1, 2, 4, and 8 weeks of mirtazapine treatment. RESULTS: There was no significant difference in the 5-HT 2C receptor -759C/T genotype distribution between responder and non-responder groups. The 5-HT 2C receptor -759C/T polymorphism was not associated with weight change over time after mirtazapine administration. CONCLUSION: The 5-HT 2C receptor -759C/T polymorphism does not appear to be a predictor of treatment response to mirtazapine. This polymorphism was not associated with weight change after 8 weeks of mirtazapine treatment. Further investigation on other polymorphisms of the 5-HT 2C gene is required to determine whether the 5-HT 2C gene influences treatment response and weight change after mirtazapine administration in patients with major depressive disorder.
Antidepressive Agents ; Depression ; Depressive Disorder, Major ; Genotype ; Humans ; Mianserin ; Negotiating ; Receptor, Serotonin, 5-HT2C ; Serotonin ; Weight Gain

AIMTo determine whether serotonin, a major neurotransmitter in brain, can modulate the production of secretory beta-amyloid protein precursor (sAPP) by activation of serotonin 5-HT2C receptor.

METHODSThe hippocampal slices of rats were incubated with various concentrations of serotonin, M-110, or L-107. sAPP released into the incubation medium were assayed by Western blot analysis assay with monoclonal antibody 22C11 for 2 h.

RESULTSVarious concentrations of serotonin (1.0 x 10(-2) - 1.0 x 10(3) micromol x L(-1)), M-110, a serotonin 5-HT2C agonist (1.5 x 10(-6) - 1.5 x 10(3) micromol x L(-1)), showed positive effect on the production of sAPP while L-107, a serotonin 5-HT2C antagonist (1.0 x 10(-9) - 1.0 x 10(3) micromol x L(-1)), showed negative effect on the production of sAPP over controls.

CONCLUSIONSerotonin modulates production of secretory amyloid beta-protein precursor through serotonin 5-HT2C receptor in incubated rat hippocampal slices.

Amyloid beta-Protein Precursor ; secretion ; Animals ; Hippocampus ; metabolism ; In Vitro Techniques ; Male ; Peptide Fragments ; secretion ; Rats ; Rats, Sprague-Dawley ; Receptor, Serotonin, 5-HT2C ; Serotonin ; pharmacology ; Serotonin 5-HT2 Receptor Agonists ; Serotonin 5-HT2 Receptor Antagonists

Serotonin (5-HT), the endogenous nonselective 5-HT receptor agonist, activates the inositol -1,4,5- triphosphate / calcium (InsP3/Ca2+) signaling pathway and exerts both stimulatory and inhibitory actions on cAMP production and neuromodulin secretion in rat hypothalamic neurons. Specific mRNA transcripts for 5-HT1A, 5-HT2C and 5-HT4 were identified in rat hypothalamic neurons. These experiments were supported by combined techniques such as cAMP and a Ca2+ assays in order to elucidate the associated receptors and signaling pathways. The cAMP production and neuromodulin release were profoundly inhibited during the activation of the Gi-coupled 5-HT1A receptor. Treatment with a selective agonist to activate the Gq-coupled 5-HT2C receptor stimulated InsP3 production and caused Ca2+ release from the sarcoplasmic reticulum. Selective activation of the Gs-coupled 5-HT4 receptor also stimulated cAMP production, and caused an increase in neuromodulin secretion. These findings demonstrate the ability of 5-HT receptor subtypes expressed in neurons to induce neuromodulin production. This leads to the activation of single or multiple G-proteins which regulate the InsP3/Ca2+/PLC-gamma and adenyl cyclase / cAMP signaling pathways.
Animals ; Calcium ; GAP-43 Protein* ; GTP-Binding Proteins ; Inositol ; Neurons* ; Rats* ; Receptor, Serotonin, 5-HT1A ; Receptor, Serotonin, 5-HT2C ; Receptors, Serotonin, 5-HT4 ; RNA, Messenger ; Sarcoplasmic Reticulum ; Serotonin* ; Adenylyl Cyclases

PURPOSE: Although serotonin (5-HT) has been implicated in central control of sexual desire, erection and ejaculation, its peripheral effect has been poorly studied. Here, we investigated the peripheral effects of 5-HT on ejaculation using in vivo and in vitro experiments. MATERIALS AND METHODS: Male Sprague-Dawley rats (weighed 250-300 g) were injected intravenously with serotonergic agents (serotonin, fluoxetine, clomipramine) at various concentrations 20 min before electrical nerve stimulation of the hypogastric nerve. Intraluminal pressure of seminal vesicle and vas deferens was measured on each side in the same animal and compared. Total RNA was isolated from brain, seminal vesicle and vas deferens. Expressions of mRNAs for 5-HT(1A), 5-HT(1B) and 5-HT(2C) receptors, which have been suggested for ejaculatory responses, were examined using semi-quantitative reverse-transcriptase polymerase chain reaction. RESULTS: All serotonergic agents caused dose-dependent inhibition of elevation in intraluminal pressure of the seminal vesicle. Vasal pressure responses were effectively inhibited by clomipramine and serotonin (clomipramine>serotonin), whereas no effect was seen by fluoxetine. There was no significant difference in relative expression levels of 5-HT(1A) receptor mRNAs between the seminal vesicle and vas deferens. However, the expression levels of 5-HT(1B) and 5-HT(2C) receptors mRNAs were lower in the vas deferens when comparing to those in the seminal vesicle. CONCLUSIONS: These results of in vivo and in vitro experiments provide evidence for the peripheral role of 5-HT in regulating ejaculatory response of male rats. Regional differences in distributions of 5-HT receptor subtypes between seminal vesicle and vas may contribute to the different response to serotonergic agents in these organs.
Animals ; Brain ; Clomipramine ; Ejaculation ; Fluoxetine ; Humans ; Male ; Polymerase Chain Reaction ; Rats ; Rats, Sprague-Dawley ; Receptor, Serotonin, 5-HT1A ; Receptor, Serotonin, 5-HT2C ; RNA ; RNA, Messenger ; Seminal Vesicles ; Serotonin Agents ; Serotonin* ; Vas Deferens

OBJECTIVE: Weight gain is one of the troublesome adverse reaction to clozapine treatment. This problem can lead to poor adherence to treatment. Clozapine-induced weight gain may be associated with genetic predisposition. Recent studies have shown that a polymorphism of the promoter region of the serotonin 5-HT2C receptor gene is associated with antipsychotic-induced weight gain. This study is to investigate the association of clozapine-induced weight gain with -759C/T polymorphism of serotonin 5-HT2C receptor promoter gene in schizophrenic patients. METHODS: Fifty three patients with schizophrenia were included in this study. The subjects were divided into two groups according to body weight change between the start and 10 weeks of clozapine. The cutoff level of weight change is 5% increase of initial body weight. Genotypes of -759C/T polymorphism were identified from AciI-digested fragments of two-primer products amplified by polymerase chain reaction corresponding to -885 to -634 of the serotonin 5-HT2C receptor gene promoter region on chromosome X. RESULTS: There were no differences of baseline variables between patient groups with and without weight gain. 4 of 32 male patients and 6 of 21 female patients had -759T allele, respectively. The authors found that patients with -759T allele had tendency to show less weight gain than those without this allele. CONCLUSION: These findings suggest that clozapine- induced weight gain may be associated with genetic predisposition in schizophrenic patients.
Alleles ; Body Weight ; Body Weight Changes ; Clozapine ; Female ; Genetic Predisposition to Disease ; Genotype ; Humans ; Male ; Polymerase Chain Reaction ; Promoter Regions, Genetic ; Receptor, Serotonin, 5-HT2C* ; Schizophrenia* ; Serotonin* ; Weight Gain*

OBJECTIVE: Migraine, a highly prevelant headache disorder, is regarded as a polygenic multifactorial disease. Serotonin (5-HT) and their respective receptors have been implicated in the patogenesis. METHODS: We investigated the 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT2C receptor gene polymorphisms and their association with migraine in Turkish patients. The rs6295, rs1300060, rs1228814, rs6311, rs6313, rs6314, rs6318, rs3813929 (−759C/T) and rs518147 polymorphisms were analyzed in 135 patients with migraine and 139 healthy subjects, using a BioMark 96.96 dynamic array system. RESULTS: We found no difference in the frequency of the analyzed eight out of nine polymorpisms between migraine and control groups. However, a significant association was found between the rs3813929 polymorphism in the promoter region of 5-HTR2C gene and migraine. Also, the allele of rs3813929 was more common in the migraine group. CONCLUSION: This result suggests that the 5-HTR2C rs3813929 polymorphism can be a genetic risk factor for migraine in a Turkish population.
Alleles ; Genetic Association Studies ; Headache ; Headache Disorders ; Healthy Volunteers ; Humans ; Migraine Disorders* ; Polymorphism, Single Nucleotide ; Promoter Regions, Genetic ; Receptor, Serotonin, 5-HT2C ; Risk Factors ; Serotonin*

Serotonin has been implicated in the etiology and pathophysiology of mental illness such as depression, schizophrenia, anxiety disorder, eating disorder, obsessive compulsive disorder, and panic disorder. Many current used treatments of these disorders are thought to act through the modulation of the serotonergic tone. To improve on the efficacy of antipsychotics that are potent D2 receptor blockers, much interest has evolved around complimenting or replacing D2 dopaminergic antagonism by the action on serotonergic transmission. 5-HT2A receptor blockade, under the condition of weaker D2 receptor antagonism, may contribute to the ability of atypical antipsychotics to increase dopamine release in the medical prefrontal cortex while having a smaller effect on mesolimbic dopamine release. These effects may contribute to their advantage for cognition, negative symptoms and psychotic activity. The use of 5-HT1A receptor agonists may substitute for 5-HT2A antagonism and achieve many of the same benefits in combination with weak D2 receptors blockade. Antagonism of 5-HT2C receptors may also useful for improving cortical function. Thus, 5-HT has joined dopamine as a critical target for developing effective antipsychotics in schizophrenia. In the development of new first-line pharmacological treatment for major depressive disorder, 5-HT system will most likely remain important especially if agents can be developed with improved tolerability, faster onset of response or greater efficacy. The promising area for development of serotonergic antidepressants are agents that target the specific 5-HT receptor subtypes, and agents that affect 5-HT plus one or more of the noradrenaline, CRF, dopamine and glucocorticoids systems. Selective targeting of serotonin receptors such as 5-HT1, 5-HT2, or 5-HT7 may have considerable potential in the treatment of depressive disorders. Trophic agents that increased neuroplasticity or neurogenesis via the activation of cyclic AMP-CREB pathway may be beneficial as a target for novel antidepressants.
Antidepressive Agents ; Antipsychotic Agents ; Anxiety Disorders ; Cognition ; Depression* ; Depressive Disorder ; Depressive Disorder, Major ; Dopamine ; Feeding and Eating Disorders ; Glucocorticoids ; Neurogenesis ; Neuronal Plasticity ; Norepinephrine ; Obsessive-Compulsive Disorder ; Panic Disorder ; Prefrontal Cortex ; Receptor, Serotonin, 5-HT1A ; Receptor, Serotonin, 5-HT2A ; Receptor, Serotonin, 5-HT2C ; Receptors, Serotonin ; Schizophrenia* ; Serotonin ; Serotonin Agents*

This study was performed to investigate the sedative-hypnotic activity of gamma-aminobutyric acid (GABA)-enriched fermented marine organisms (FMO), including sea tangle (FST) and oyster (FO) by Lactobacillus brevis BJ20 (L. brevis BJ20). FST and FO were tested for their binding activity of the GABA(A)-benzodiazepine and 5-HT(2C) receptors, which are well-known molecular targets for sleep aids. We also measured the sleep latency and sleep duration during pentobarbital-induced sleep in mice after oral administration of FST and FO. In GABA(A) and 5-HT(2C) receptor binding assays, FST displayed an effective concentration-dependent binding affinity to GABA(A) receptor, similar to the binding affinity to 5-HT(2C) receptor. FO exhibited higher affinity to 5-HT(2C) receptor, compared with the GABA(A) receptor. The oral administration of FST and FO produced a dose-dependent decrease in sleep latency and increase in sleep duration in pentobarbital-induced hypnosis. The data demonstrate that FST and FO possess sedative-hypnotic activity possibly by modulating GABA(A) and 5-HT(2C) receptors. We propose that FST and FO might be effective agents for treatment of insomnia.
Administration, Oral ; Animals ; Aquatic Organisms* ; gamma-Aminobutyric Acid ; Hypnosis ; Lactobacillus brevis ; Mice ; Ostreidae ; Receptor, Serotonin, 5-HT2C ; Receptors, GABA-A ; Sleep Initiation and Maintenance Disorders