Association between serotonin 2C receptor gene (HTR2C) polymorphisms and psychopathological symptoms in children and adolescents

Serotonin 2C receptors (5HT2C) are involved in serotonin-driven dynamic equilibrium adjustments responsible for homeostatic stability in brain structures that modulate behavior and emotions. Single nucleotide polymorphisms (SNPs) from the serotonin 2C receptor gene (HTR2C) have been associated with several neurological and mental disorders, including abnormalities in cognitive and emotional processes. The aim of this study was to evaluate the association between the rs6318 SNP of the HTR2C gene and behavioral characteristics exhibited by children and adolescents based on the Child Behavior Checklist (CBCL/6-18) inventory. Eighty-five psychiatric outpatients between 8 and 18 years of age underwent genotyping of the rs6318 SNP. The CBCL/6-18 scale was administered to their caregivers. The chi-squared test was used to assess differences in the frequency of C and G alleles of the rs6318 SNP relative to the grouped CBCL/6-18 scores; significance level was 5%. The presence of the G allele of rs6318 was found to be associated with characteristics of aggressive behavior and social problems, and aggressive behavior was found to be associated with heterozygosis in females. These findings contribute to the identification of mental and behavioral phenotypes associated with gene expression.

Association of Polymorphisms within the Serotonin Receptor Genes 5-HTR1A, 5-HTR1B, 5-HTR2A and 5-HTR2C and Migraine Susceptibility in a Turkish Population

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.

Sedative-Hypnotic and Receptor Binding Studies of Fermented Marine Organisms

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.

Pharmacotherapy for Obesity

Obesity is an important risk factor for metabolic disease and various cancers. Treatments of obesity include lifestyle intervention, pharmacotherapy, and bariatric surgery. If weight loss with lifestyle intervention is only modest, pharmacotherapy might be needed. Pharmacotherapy agents can be grouped by treatment period as short term or long term use agent. Several sympathomimetic drugs such as benzphetamine, diethylpropion, phendimetrazine and phentermine, are approved for short term treatment due to their safety issues. For long term treatment, orlistat, lorcaserin, and combination of phentermine/topiramate are approved by U.S. Food and Drug Administration (FDA). Orlistat partially blocks intestinal digestion of fat, therefore producing weight loss. Lorcaserin is a serotonin 2C receptor agonist. The combination of phentermine/topiramate produces a mean weight loss of 8-10 kg. Side effects of each drug are quite different. For obesity patient, side effects are important factor when choosing drugs. The goal of this article is to review currently available anti-obesity drugs.

No Association between Serotonin Receptor 2C-759C/T Polymorphism and Weight Change or Treatment Response to Mirtazapine in Korean Depressive Patients

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.

Planejamento e sintese de compostos potencialmente ligantes dos receptores 5-HT2C e H4 / Design and synthesis of compounds potentially ligands of 5-HT2C e H4

A serotonina e a histamina são duas das mais importantes aminas biogênicas do organismo. Regulam série de funções fisiológicas, como fluxo sanguíneo, temperatura corpórea, sono, fome, liberação de hormônios, comportamento afetivo e humor, entre outras. Assim, há grande interesse no planejamento e desenvolvimento de fármacos que interferem na transmissão serotoninérgica e histaminérgica, para futura aplicação como antidepressivos, antipsicóticos, ansiolíticos e anorexígenos, além de perifericamente, apresentarem possíveis ações antiinflamatórias. O objetivo deste trabalho é apresentar a síntese de compostos contendo os núcleos pirrolquinolínico, benzoindólico e benzodiidrofurânico com potencial atividade ligante nos receptores 5-HT2C e H4, assim como avaliar a seletividade desses compostos em comparação aos receptores 5-HT2A/B e H3. Sintetizou-se série de compostos utilizando reações de alilação, adição à carbonila, termociclização, rearranjo de Claisen, iodociclização e substituição nucleofílica para a obtenção dos compostos finais. Estudos de otimização de síntese por metodologia de superfície de resposta também são apresentados, assim como estudos de relações quantitativas entre estrutura química e atividade biológica de compostos ligantes dos receptores 5-HT2C e H4

Serotonin and histamine are two major biogenic amines in the body. They regulate several physiological functions such as blood flow, body temperature, sleep, hunger, hormone release, emotional behavior and mood, among others. Thus, there is great interest in the design and development of drugs that interfere with serotoninergic and histaminergic transmission, for future use as antidepressants, antipsychotics, anxiolytics and anorectic, and peripherally, possible anti-inflammatory actions. The aim of this work is to present the synthesis of compounds containing the pyrroloquinoline, benzoindole and benzodihydrofurane nucleus with potential binding activity to 5-HT2C and H4 receptors, as well as to evaluate the selectivity of these compounds in comparison to 5-HT2A/B and H3. Series of compounds were synthesized using allylation, carbonyl addition, thermal cyclization, Claisen rearrangement, iodocyclization and nucleophilic substitution reactions. Optimization studies for the synthesis using response surface methodology are also presented, as well as quantitative structure-activity relationships studies of ligands of 5-HT2C and H4 receptors

Pharmacogenetic Aspects of Antipsychotic Drug-induced Weight Gain: A Critical Review

Treatment with several antipsychotic drugs can result in weight gain, which may lead to further morbidity such as type 2 diabetes and cardiovascular disease via the development of metabolic syndrome. These important and problematic metabolic consequences of antipsychotic drug treatment probably reflect a pharmacological disruption of the mechanisms involved in control of food intake and body weight. The extent of weight gain following antipsychotic drug treatment shows substantial variability between individuals, due in part to genetic factors. Common functional polymorphisms in many candidate genes implicated in the control of body weight and various aspects of energy and lipid metabolism have been investigated for association with weight gain in subjects receiving antipsychotic drug treatment, and with metabolic pathology in chronic schizophrenia. Perhaps the strongest and most replicated findings are the associations with promoter polymorphisms in the 5-HT2C receptor and leptin genes, although many other possible genetic risk factors, including polymorphisms in the fat mass and obesity associated (FTO) gene and genes for the alpha2A adrenoceptor and melanocortin4 receptor, have been reported. Genome-wide association studies (GWAS) have also addressed antipsychotic-induced weight gain and other indicators of metabolic disturbances. However there is as yet little consistency between these studies or between GWAS and classical candidate gene approaches. Identifying common genetic factors associated with drug-induced weight gain and its metabolic consequences may provide opportunities for personalized medicine in the predictive assessment of metabolic risk as well as indicating underlying physiological mechanisms.

Facilitation of synaptic transmission and connections of entorhinal-hippocampal pathway by 5-HT2C receptor subtype: multi-electrode array recordings / 生理学报

Using 64-channels (8 × 8) multi-electrode array technique (MED-64 system), the modulatory actions of 5-hydroxytryptamine (5-HT) 2C receptor subtype on the entorhinal (EC)-hippocampal synaptic transmission and connections were studied. One of freshly dissociated acute hippocampal slices of rats which was placed on the MED-64 probe, was subject to constant perfusion with oxygenated artificial cerebrospinal fluid (ACSF, 95% O2 and 5% CO2). Two hours after ACSF incubation, simultaneous multi-site electrophysiological recordings were performed. One electrode was selected to be used for perforant path (PP) stimulation, and the remaining 63 electrodes were used for recordings of network field excitatory postsynaptic potentials (fEPSPs) within both CA1 and dentate gyrus (DG) that have been previously proved to be mediated by glutamate non-NMDA receptors. After stability of network fEPSPs was achieved, (±)-1(2, 5-Dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI, an agonist of 5-HT2C receptor subtype), or SB242084 (6-Chloro-2,3-dihydro-5-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]-1H-indole-1-carboxyamide dihydrochloride hydrate) (a selective antagonist of 5-HT2C receptor subtype) was applied for 10 min perfusion, respectively. Two-dimensional current source density (2D-CSD) analysis was also transformed by bilinear interpolation at each point of the 64 electrodes for spatial imaging of the fEPSP network responses. Based upon the polarities of fEPSP and 2D-CSD imaging, it was clearly shown that synaptic activations were evoked to occur within the molecular layer of DG and pyramidal cell layer of CA1 by the PP stimulation in which negative-going field potentials and current sink (blue) could be recorded. While, positive-going field potentials and current source (yellow) were mainly localized within the granule cell layer and hilus of DG and alveus of CA1, reflecting spread of electrical signals derived from depolarized region toward CA3 area or subiculum and fimbria along the axons. Perfusion of the hippocampal slices with DOI resulted in a significant enlargement of synaptic connection size at network level and enhancement of synaptic efficacy. However, on the contrary, perfusion with SB242084 produced reversal effect with either reduction in synaptic network size or decreased magnitude of fEPSPs (amplitude and slope) in the CA1 and DG. These results suggest that endogenous 5-HT causes facilitation of EC-CA1 and EC-DG synaptic transmission and connections via acting on 5-HT2C receptor subtype, leading to gain in synaptic transmission and enlargement of synaptic connections.

Agomelatine: Antidepressant with a New Mechanism of Action / 대한정신약물학회지

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.

Association of HTR2C-759C/T and -697G/C polymorphisms with antipsychotic agent-induced weight gain / 中南大学学报(医学版)

OBJECTIVE@#To determine whether antipsychotic agent-induced weight gain was associated with 5-hydroxytryptamine 2C receptor (HTR2C) gene-759C/T and -697G/C polymorphisms.@*METHODS@#A case-matching controlled study was done. Eighty-five patients who had gained more than 7% of their pre-drug body weight served as a study group, and 85 patients who had gained less than 7% of their pre-drug body weight served as a control group. The control group were matched with the study group in the kinds of antipsychotic agents and the course of antipsychotic treatment. The ligation diction reaction technique was used to analyse the frequencies of HTR2C gene-759C/T and -697G/C polymorphisms.@*RESULTS@#The study group were more likely to be hemizygous for the -759C (for male) and the -759CC genotype (for female) than the control group. The study group were more likely to be hemizygous for the -697G (for male) and the -697CG/GG genotype (for female) (all P<0.05) than the control group.@*CONCLUSION@#The -759C/T and -697G/C polymorphisms of the promoter region of HTR2C gene may be associated with antipsychotic agent-induced weight gain.

Behavioral effects of l-[m-chlorophenyl] piperazine [m-CPP] in a rat model of tardive dyskinesia

The present study was designed to monitor the responsiveness of 5-hydroxy tryptamine [5-HT]-2C receptor in rats treated with haloperidol exhibiting tardive dyskinesia [TD]. Results show that haloperidol injected at a dose of 1 mg/kg twice a day for two weeks elicited vacuous chewing movements [VCMs]. Which increased in a time dependent manner following the drug administration for 3-5 weeks. The behavioral effects of 1-[m-chlorophenyl]piperazine [m-CPP] a 5-HT-2C and 5-HT-1B agonist were monitored 2 days after 5 weeks of saline or haloperidol administration. The results show that hypophagic as well as anxiogenic-like effects of m-CPP are greater in repeated haloperidol than repeated saline injected animals, while hypolocomotive effects of m-CPP are not different in repeated saline and haloperidol injected animals. Results are discussed in the context of role of 5-HT-2C receptors in the regulation of the activity of dopaminergic neuron and its possible impact on elicitation of TD

Serotonin (5-HT) Receptor Subtypes Mediate Regulation of Neuromodulin Secretion in Rat Hypothalamic Neurons

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.

Association between serotonin 2C gene polymorphisms and attention deficit hyperactivity disorder in children with or without comorbidity of disruptive behavior disorder / 中华儿科杂志

<p><b>OBJECTIVE</b>Disruptive behavior disorder (DBD) is one of the main comorbidity of attention deficit hyperactivity disorder (ADHD). Previous studies showed significantly different serotonin function between ADHD children with and without the comorbidity of DBD. Therefore, it is needed to compare these two groups in terms of serotonin receptor gene polymorphisms, which may provide further evidence for the previous studies. The current study aimed to investigate the relationship between two serotonin receptor 2C (HTR2C) gene polymorphisms, that are C-759T and G-697C polymorphisms, and ADHD with or without concomitant DBD.</p><p><b>METHOD</b>Blood samples were taken from 237 trios with probands of ADHD with DBD comorbidity and 251 trios with probands of ADHD without comorbidity of DBD. All the subjects were from the ADHD clinic of Peking University Sixth Hospital. DNA was extracted and PCR was performed to amplify the fragments containing both C-759T and G-697C polymorphisms. AciI was used to detect different alleles of the two polymorphisms. Both allele-based and haplotype-based TDT analyses were used to test the association of the two polymorphisms of HTR2C gene and ADHD with or without comorbidity of DBD.</p><p><b>RESULTS</b>The haplotypes -759C (chi(2) = 4.25, P = 0.04), -697G(chi(2) = 3.21, P = 0.07), as well as -759C/-697G were over-transmitted (chi(2) = 4.31, P = 0.04) to the probands of ADHD without DBD. No biased transmission of any allele and haplotype were found in families with probands of ADHD with DBD.</p><p><b>CONCLUSION</b>ADHD with or without the comorbidity DBD was different at the level of HTR2C gene polymorphisms of C-759T and G-697C. HTR2C is related to ADHD without DBD, while not related to ADHD with DBD. The results suggested that the two groups may have different genetic background, at least in HTR2C.</p>

Outlook of Future Serotonergic Drugs and Their Clinical Usefulness: Focused on Schizophrenia and Depression / 대한정신약물학회지

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.

Polymorphisms and Serotonin Dopamine Antagonist-Induced Weight Gain in Patients with Schizophrenia / 대한정신약물학회지

OBJECTIVE: Several lines of pharmacological evidences including the data of animal studies indicate that serotonin 2C receptor (5HT2C) is involved in the pharmacodynamic process of serotonin dopamine antagonists (SDA)-induced weight gain. Controversial data have been reported on the association between the polymorphisms of 5HT2C receptor gene and antipsychotics-induced weight gain. This study aims at investigating the association between the polymorphisms of 5HT2C receptor gene and SDA-induced weight gain in korean schizophrenic patients. METHODS: Seventy-seven schizophrenia patients in their first episode or patients who did not take any antipsychotics for the previous two months were recruited. All the patients were administered with one of the SDAs (risperidone, olanzapine, quetiapine, clozapine) for 8weeks. Body mass index (BMI) were measured weekly during the 8weeks. The subjects were genotyped for the -759 C/T and -697 G/C polymorphism of the 5HT2C receptor gene. RESULTS: The degree of linkage disequilibrium between the two polymorphic loci genotyped are almost 100%. Significant association was not observed between polymorphisms of the 5HT2C receptor gene (-759 C/T and -697 G/C) and SDA-induced weight gain after 8 weeks of treatment. CONCLUSION: Our data do not support the involvement of the polymorphisms of 5HT2C receptor gene (-759 C/T and -697 G/C) in SDA- induced weight gain. Further studies with sufficient sample size are warranted to follow up on the trend of high weight gain in the male patients having -759 T (-697 C) allele.

Association between Clozapine-Induced Weight Gain and Serotonin 5-HT2C Receptor Gene Polymorphism in Patients with Schizophrenia / 대한정신약물학회지

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.

5-HT2C receptor subtype modulate production of secretory beta-amyloid protein precursor in incubated rat hippocampal slices / 药学学报

<p><b>AIM</b>To 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.</p><p><b>METHODS</b>The 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.</p><p><b>RESULTS</b>Various 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.</p><p><b>CONCLUSION</b>Serotonin modulates production of secretory amyloid beta-protein precursor through serotonin 5-HT2C receptor in incubated rat hippocampal slices.</p>

Pharmacogenetic assessment of antipsychotic-induced tardive dyskinesia: contribution of 5-hydroxytryptamine 2C receptor gene and of a combination of dopamine D3 variant allele (Gly) and MnSOD wild allele (Val) / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To further investigate whether the functional polymorphisms of dopamine D2 receptor (DRD2) and dopamine D3 receptor (DRD3) genes associate with the development of tardive dyskinesia (TD) in schizophrenia, and whether the interactive effects of DRD2, DRD3, 5-hydroxytryptamine 2C receptor (HTR2C) and manganese superoxide dismutase (MnSOD) genes contribute to the severity of TD.</p><p><b>METHODS</b>The patients with schizophrenia were assessed for TD by the Abnormal Involuntary Movement Scale (AIMS). Eventually, 42 schizophrenics with persistent TD were in the TD group, and 59 schizophrenics without TD were in the non-TD group. The polymorphism of each candidate gene was analyzed using a polymerase chain reaction-based restriction fragment length polymorphism analysis.</p><p><b>RESULTS</b>The genotype distributions of the candidate genes in the groups were all consistent with the Hardy-Weinberg equilibrium. Allele frequencies for -759C/T and -697G/C polymorphisms in HTR2C gene showed a significant excess of -697 variant (P<0.05) in the patients with TD, compared against those in patients without TD. There were no differences in the distributions of the allelic frequencies and genotypes of Taq I. A polymorphism in DRD2 gene, of Ser/Gly polymorphism in DRD3 gene, and of Ala-9Val polymorphism in MnSOD gene between the TD group and non-TD group (P>0.05). Interestingly, as compared with the other joint allelic types, a significant excess of carrying both DRD3 variant allele (Gly) and MnSOD wild allele (Val) was found in the TD group (P<0.05). However, neither the allele and genotypes nor the clinical demographic characteristics contributed to the higher total AIMS scores in the patients of the TD group. There were no significant differences in any of the clinical demographic characteristics between the subgroups of any genotype in TD and non-TD groups.</p><p><b>CONCLUSION</b>The excess of -697 variant in the promoter regulation region of the HTR2C gene may be a risk factor for the susceptibility to the occurrence of TD in Chinese male patients with schizophrenia. A combination of DRD3 variant allele (Gly) and MnSOD wild allele (Val) may increase the susceptibility to the development of TD.</p>

Serotonin/dopamine interaction--focus on 5-HT2C receptor, a new target of psychotropic drugs.

Several hypotheses regarding physiopathology of major psychiatric diseases exist. Attention has been focused on cerebral monoaminergic systems, the dysfunction of which is thought to underlie various aspects of their symptomatology. There are reports describing the involvement of serotonergic and dopaminergic systems in the mechanism of action of psychotropic drugs. This article reviews current knowledge on interaction between 5-hydroxytryptamine (5-HT), acting at 5-HT2C receptors in the central dopamine (DA) systems. Since 90s, a growing body of behavioural, neurochemical and electrophysiological evidence from animal studies have demonstrated a clear role for 5-HT2C receptors in modulation of activity of dopamine neurones. This evidence has led to the suggestion that drugs acting on 5-HT2C receptors have potential as novel antipsychotic and antidepressant agents and may also be used in the treatment of other neuropsychiatric disorders such as Parkinson's disease and psychoactive substance abuse.

Evidence for Peripheral Effect of Serotonin on Ejaculatory Response / 대한남성과학회지

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.