5-Hydroxytryptamine-2A receptor gene (HTR 2 A) candidate polymorphism (T 102 C): Role for human platelet function under pharmacological challenge ex vivo

Although the environmental and life-style factors influencing individual predisposition to acute myocardial infarction (AMI) have been well documented, little is known on the identity of genetic loci that may contribute to risk for AMI. Recently, genetic studies in patients with nonfatal AMI have suggested an association with the T 102 C polymorphism in the serotonin 5-HT(2A) receptor gene (HTR 2 A). Considering the significant role of the 5-HT(2A) receptor in serotonin-induced platelet responses and the contribution of platelet (patho)physiology to thromboembolic events, we postulated that the increased susceptibility to AMI in patients with the T 102 homozygosity may be attributable, in part, to altered serotonin-mediated platelet function. In a group of healthy volunteers recruited from the Eskisehir region in central Turkey (N=37), we investigated the functional consequences of HTR 2 A T 102 C polymorphism in relation to platelet pharmacodynamics ex vivo. The platelet shape change and aggregation response to serotonin were measured with use of the platelet aggregometry and expressed as aggregometer output (mm). Because the circulating catecholamine hormone epinephrine can augment platelet aggregation, pharmacodynamic response (aggregation and its inhibition by 5-HT(2A) receptor antagonist cyproheptadine) was measured in the presence of both serotonin and epinephrine, to mimic the clinical situation in patients. The mean platelet aggregation was higher by 38% in subjects with T 10 2 homozygosity (T/T genotype, N=13) when compared with the carriers of the 102 C-allele (T/C and the C/C genotypic groups, N=24) (39.5 mm+/-12.3 vs. 28.7 mm+/-16.8, respectively) (mean+/-SD) (p<0.05). On the other hand, neither the serotonin-induced platelet shape change nor the cyproheptadine inhibition of platelet aggregation was influenced by the HTR 2 A T 102 C genetic variation (p>0.05). These findings in healthy subjects may provide a mechanistic explanation for the previously reported genetic association between HTR 2 A and AMI. Further genetic association studies of the 5-HT(2A) receptor in patients with AMI in different populations are warranted.     

Effects of dopamine D2 receptor Ser311Cys polymorphism and clinical factors on risperidone efficacy for positive and negative symptoms and social function

Risperidone is an atypical antipsychotic agent with efficacy for both positive and negative symptoms of schizophrenia. However, what makes an antipsychotic 'atypical' remains unclear. We recently found that the T102C polymorphism in the 5-HT2A receptor gene could affect risperidone's efficacy for negative symptoms. The present study investigated the effect of the Ser311Cys polymorphism in the dopamine D2 receptor (DRD2) gene on risperidone treatment response. A total of 123 Han Chinese patients with acutely exacerbated schizophrenia were given risperidone for up to 42 days. Clinical manifestations were measured bi-weekly with Positive and Negative Syndrome Scale (PANSS) and Nurses' Observation Scale for Inpatients Evaluation (NOSIE, for assessment of social function). For adjusting the within-subject dependence over repeated assessments, multiple linear regression with generalized estimating equation methods was utilized to analyse the effects of Ser311Cys polymorphism and other covariates on clinical performance. Compared with patients who had the Ser311Ser genotype, patients with the Ser311Cys genotype had lower scores on PANSS Positive, Negative, General Psychopathology and Cognitive subscales and NOSIE, after adjustment for 5-HT2A T102C polymorphisms and other confounders. The 5-HT2A T102C polymorphism had marginal influences on PANSS Total and Negative subscale scores. Male gender, fewer previous hospitalizations, and higher risperidone dose predicted better treatment response after control for other variables. The preliminary results suggest that variations in the DRD2 gene influence risperidone treatment response for positive, negative, and cognitive symptoms, general psychopathology, and social functioning. Several clinical factors may also contribute to inter-individual differences in risperidone treatment response.     

Genetics and personality traits in patients with social anxiety disorder: a case-control study in South Africa.

BACKGROUND: Social anxiety disorder (SAD) is among the most common of all psychiatric disorders with lifetime prevalence estimates ranging from 7% to 13%. Although there is evidence that SAD has a strong familial basis, there are few studies of potential candidate genes. In addition to a genetic association, there is also the possibility that temperamental risk factors for the disorder may be genetically transmitted. Against this background, our aims were threefold: i.) to compare patients and controls with respect to personality traits, ii.) to genotype a subgroup of these participants to investigate the role of genes encoding components of serotonergic (5-HT) and dopaminergic (DA) pathways in patients with SAD and iii.) to compare differences in temperament dimensions between carriers of different (dominant vs. recessive) alleles for selected polymorphisms in SAD patients. METHODS: Sixty-three patients (n=63; 35 male, 28 female) with a DSM-IV diagnosis of generalized SAD and SPIN-scores >18, and age-matched control participants (n=150; 31 male, 119 female) were included in the study. The Temperament and Character Inventory (TCI) was used to measure behaviours associated with specific personality dimensions (i.e. temperament/character). DNA was extracted and genotyped to investigate the role of select candidate genes encoding components in serotonergic and dopaminergic pathways in mediating the development of SAD. To achieve this, the frequency of variants in 5-HT and DA genes was compared between a Caucasian subset of SAD patients (n=41) and a convenience sample of Caucasian controls (n=88), using case-control association analyses. We also investigated the frequency of variants in 5-HT and DA-related genes across temperament characteristics in SAD patients, using analyses of variance (ANOVA). RESULTS: Patients scored significantly higher on harm avoidance (p<0.001) but lower on novelty seeking (p=0.04) and self-directedness (p=0.004) compared to controls. In the Caucasian subset, there was a difference between patients and controls in distribution of the 5-HT(2A)T102C polymorphism, with significantly more patients harboring T-containing genotypes (T-containing genotypes: [T/T+T/C] vs. [C/C]) (chi2=7.55; p=0.012). Temperament dimensions did not, however, differ significantly between carriers of different (dominant vs. recessive) alleles for the 5-HT(2A)T102C polymorphism in SAD patients. CONCLUSIONS: The results suggest a possible role for the 5-HT(2A)T102C polymorphism in the development of SAD. To date genetic findings in SAD have been inconsistent; nevertheless, serotonergic variants, and their associations with temperaments (e.g. reward dependence) deserve further exploration, in the hope that endophenotypes relevant to SAD can ultimately be delineated.     

Genetic polymorphisms in the 5-hydroxytryptamine type 3B receptor gene and paroxetine-induced nausea

Selective serotonin reuptake inhibitor (SSRI)-induced nausea can be severe enough to lead to early treatment discontinuation. However, it is currently not possible to predict the occurrence of nausea before the initiation of SSRI treatment. In this study, we investigated the effect of genetic polymorphisms in the 5-hydroxytryptamine type 2A, 3A, and 3B (5-HT3B) receptors, 5-HT transporter, and CYP2D6 genes on the incidence of paroxetine-induced nausea. A consecutive series of 72 Japanese patients with depressive or anxiety disorders were treated with paroxetine. Paroxetine-induced nausea was assessed by a pharmacist and was observed in 29.2% of the patients. A significant (nominal p=0.00286) association was found between the incidence of nausea and the -100_-102AAG insertion/deletion polymorphism of the 5-HT3B receptor gene. No significant associations were observed between the other genetic polymorphisms and the incidence of nausea. The -100_-102AAG deletion variant of the 5-HT3B receptor gene may affect paroxetine-induced nausea.     

Angiotensin II type 2 receptor gene polymorphisms and essential hypertension

AIM: To identify the genetic variants of angiotensin II type 2 receptor (AT2R) gene in a Chinese population and to determine whether the AT2R gene polymorphisms are associated with essential hypertension (EH). METHODS: The detection of single nucleotide polymorphisms (SNPs) was performed in 19 subjects by a direct DNA sequencing. Two hundred fifty patients with EH and 250 nomortensive controls were included in the study to assess the contribution of polymorphism of AT2R gene to hypertension. RESULTS: We identified 9 SNPs in the promoter, intron, exons and 3' untranslated region (3'UTR) of AT2R gene; among them 5 SNPs were novel molecular variants. A case-control study using a most frequent SNP (1334T/C) in the promoter region, showed a significant increase in allele frequency of C1334 in male hypertensive subjects (17.5 % vs 10.3 % for normotensive subjects, P<0.05). CONCLUSION: The catalogue of SNPs of AT2R gene in Chinese population showed ethnic difference in DNA sequence variation. A polymorphism in the promoter region (1334T/C) of AT2R gene might be involved in the development of hypertension in Chinese population.     

Association of serotonin 5-HT2A receptor binding and the T102C polymorphism in depressed and healthy Caucasian subjects.

Serotonin 5-HT2A receptor (5-HT2A) binding is reported to be altered in individuals with suicidal behavior, mood disorders, and aggressive-impulsive traits. Genetic association with major depression, suicidal behavior, and aggressive-impulsive traits has not been established. This study examines the possible association of the 5-HT2A gene C102T polymorphism with the receptor binding kinetics, and clinical overt phenotypes. The study population included 63 healthy volunteers and 152 subjects with mood disorders, 56 of whom had a history of suicide attempts. All were Caucasian. Platelet 5-HT2A binding kinetics (Bmax and KD) were assayed and adjusted for seasonal variation. All subjects were genotyped for the T102C polymorphism. Clinical phenotype was determined by structured clinical interview. The TT genotype was associated with higher Bmax in all subjects (F=3.53, df=2,211; p=0.03), controlling for diagnosis. Bonferroni-adjusted post hoc testing showed higher binding in the TT compared with TC genotype in the control group (F=7.56, df=2,60, p=0.001), but not in the mood-disordered subjects. No difference was found in genotype and allele distribution between the mood-disordered subjects, with and without suicide attempt history, and controls. Bmax was not related to a diagnosis of mood disorders. The TT genotype appears associated with higher platelet 5-HT2A Bmax in the healthy population, but this genotypic effect appears absent in mood disorders and unrelated to psychopathology.     

Pharmacogenetic studies of response to risperidone and other newer atypical antipsychotics

Risperidone and other newer atypical antipsychotics are becoming the mainstay for schizophrenia treatment. Recent studies suggest that the 5-hydroxytryptamine receptor 2A (5-HT2A) gene (HTR2A) T102C and G-1438A polymorphisms may influence treatment response of risperidone or olanzapine for schizophrenia's negative symptoms (e.g., blunted affect and social withdrawal). In addition, the HTR6 T267C polymorphism has been linked to risperidone response for positive symptoms (delusions and hallucinations). The dopamine D2 receptor (DRD2) Ser311Cys polymorphism may also play a role in determining risperidone efficacy for positive, negative and cognitive symptoms, the DRD2 Ins-A2/Del-A1 diplotype may predict better risperidone response, and the DRD3 Ser311Cys variant may affect general treatment response of several atypical agents. Although investigators have started to explore genetic effects on cognitions of schizophrenia patients receiving antipsychotics, future larger sized pharmacogenetic studies on both psychotic symptoms and cognitive functions are warranted.     

Combined analysis of 635 patients confirms an age-related association of the serotonin 2A receptor gene with tardive dyskinesia and specificity for the non-orofacial subtype

Tardive dyskinesia (TD) is an important limiting factor in the use of typical antipsychotic drugs. Genetic variability in the serotonin 2A (5-HT(2A)) receptor may influence risk for TD but the results of prior studies are not confirmatory. The objective of this study was to determine association of T102C and His452Tyr polymorphisms in the 5-HT(2A) receptor gene (HTR(2A)) with TD in a large, multicentre patient sample. The design employed case-control analysis controlling for possible confounders using pooled, original data from published and available unpublished samples and employing logistic regression, analysis of variance and meta-analysis. The study sample consisted of 635 patients with schizophrenia or schizoaffective disorder (256 with TD and 379 without TD) drawn from five research centres, divided into six groups based on population origin. The main outcome measure was association of a categorical diagnosis of TD based on the Research Diagnostic Criteria for TD with HTR(2A) T102C and His452Tyr genotypes and haplotypes. The findings indicate significant association of TD with HTR(2A) T102C genotype (p=0.002) over and above the effect of population group, also when controlling for age and gender (p=0.0008), but not with His452Tyr genotype. The T102C genotype was significantly associated with TD in older (>median age 47 yr, p=0.002) but not younger patients and in patients with non-orofacial (limb-truncal) (p=0.001) but not orofacial TD. By meta-analysis the Mantel-Haenszel (M-H) pooled odds ratio (OR) across all the available data was 1.64. A T102C-His452Tyr haplotype was significantly associated with TD (p=0.0008). These findings confirm that genetic variability in HTR(2A) contributes a small but significant degree of risk for the expression of TD, particularly in older patients and specifically for the non-orofacial (limb-truncal) type. Together with other genetic variants associated with TD the findings could be used to assess risk in patients who are candidates for treatment with typical antipsychotic medications.     

沙坦类药物代谢酶CYP2C9和受体AT1基因的遗传多态性在高血压患者中的分布特征

目的本研究旨在观察沙坦类药物代谢酶CYP2C9和反应受体AT1的遗传多态性在高血压患者中的分布特征。方法采用聚合酶链式反应-限制性片断长度多态性方法(PCR-RFLP)对高血压患者进行CYP2C9和血管紧张素AT1受体基因型分析。结果对120名高血压患者CYP2C9和血管紧张素AT1受体进行基因型分析,发现高血压人群中CYP2C9*3的1 061位T等位基因和AT1受体突变1 166位C等位基因的分布频率分别为2.9%、8.0%,而这2个等位基因在中国正常人群的分布频率分别为1.5%、4.3%。结论高血压人群中CYP2C9*3的1061位T等位基因和AT1受体1 166位C等位基因的频率均高于正常人群。     

Polymorphisms in the 5-hydroxytryptamine 2A receptor and CytochromeP4502D6 genes synergistically predict fluvoxamine-induced side effects in japanese depressed patients.

5-Hydroxytryptamine (5-HT) receptors are thought to be associated with the gastrointestinal side effects induced by selective serotonin reuptake inhibitors. CytochromeP450 (CYP) 2D6 may also be associated with the side effects induced by fluvoxamine, since the plasma fluvoxamine concentration depends on a CYP2D6 gene polymorphism. This study investigated whether 5-HT receptor and CYP2D6 gene polymorphisms could predict the occurrence of the side effects. The effects of 5-HT receptor and CYP2D6 gene polymorphisms on the incidence of gastrointestinal side effects induced by fluvoxamine were investigated in 100 depressed outpatients who gave written consent to participate in the study. The patients visited every 2 weeks until the week 12 end point and the fluvoxamine dose was changed in response to their clinical symptoms. All side effects, including the gastrointestinal side effects, were assessed at each visit. Polymerase chain reaction was used to determine A-1438G of the 5-HT2A receptor, C195T and Pro16Ser of the 5-HT3A receptor, Tyr129Ser of the 5-HT3B receptor, and the *5 and *10 alleles of CYP2D6. Both the A-1438G polymorphism of the 5-HT2A receptor gene and the CYP2D6 gene polymorphism had significant effects on the incidence of gastrointestinal side effects. Cox regression was used to analyze the combination effect of the two polymorphisms on the gastrointestinal side effects. Cox regression analysis showed that lower metabolizers (LMs) of CYP2D6 with the G/G genotype of the 5-HT2A A-1438G polymorphism had a 4.242-fold (P = 0.009) and LMs with the A/G genotype had a 4.147-fold (P = 0.004) higher risk of developing gastrointestinal side effects than normal metabolizers with the A/A genotype. The 5-HT3A and 3B gene polymorphisms had no significant effects on the incidence of gastrointestinal side effects. 5-HT2A receptor and CYP2D6 gene polymorphisms had a synergistic effect for the prediction of fluvoxamine-induced gastrointestinal side effects.     

中国汉族人群5-HT_（2A）受体基因1438A/G多态性与海洛因依赖的Meta分析

目的：探讨中国汉族人群5-羟色胺2A受体（Serotonin 2A receptor,5-HT2A受体）基因1438A/G多态性与海洛因依赖的关联性。方法：检索中国知网、万方、维普、Pub Med等中外数据库于建库至2014年3月公开发表的文献,收集有关中国汉族人群5-HT2A受体基因1438A/G（rs6311）多态性与海洛因依赖的病例对照研究,在评价纳入文献质量,提取有效数据后,使用Stata12.0软件进行Meta分析。结果：共纳入9项关于5-HT2A受体基因1438A/G（rs6311）多态性与海洛因依赖的病例对照研究,其中病例组2654人,对照组2089人。Meta分析结果显示：中国汉族人群5-HT2A受体基因1438A/G多态性与海洛因依赖之间无显著相关性（A VS.G：OR=1.05,95%CI=0.89-1.25;AA＋AG VS.GG：OR=1.11,95%CI=0.84-1.47;AA VS.GG：OR=1.10,95%CI=0.57-1.57;AG VS.GG：OR=0.92,95%CI=0.71-1.18;AA VS.AG＋GG：OR=1.02,95%CI=0.66-1.58）。Meta回归对异质性来源分析发现异质性主要来源于出版年份,基于地域的亚组分析显示：5-HT2A受体基因1438A/G多态性对于南方和北方人群的海洛因依赖风险无明显相关（南方：OR=0.95,95%CI=0.68-1.33;北方：OR=0.82,95%CI=0.49-1.37）,敏感性分析显示Meta分析结果稳定,可信度较高。结论：中国汉族人群5-HT2A受体基因1438A/G多态性与海洛因依赖之间不存在关联性。     

Human 5-HT1A receptor C(-1019)G polymorphism and psychopathology

Dysfunction of the serotonin (5-HT1A) receptor (5-HTR1A) has been implicated in mood disorders, anxiety disorders, psychosis and the action of antidepressants. A common C(-1018)G [C(-1019)G] functional polymorphism in the promoter region of the human 5-HT1A receptor gene has been reported, which may be useful in identifying psychopathology associated with altered function of the human 5-HT1A receptor. We studied the relationship of this polymorphism to psychopathology and 5-HT1A binding in prefrontal cortex. The 5-HT1A receptor genotype for the C(-1019)G polymorphism was typed in 696 unrelated psychiatric subjects, 107 unrelated healthy volunteers, and in post-mortem brain samples from 241 cases. 5-HT1A receptor binding was assayed in post-mortem prefrontal cortex using [3H]8-OH-DPAT, and specific binding determined by 1 microM 5-HT. An association of genotype distribution and allele frequency of the 5-HTR1A C(-1019)G locus was observed in schizophrenia (chi2=9.51, d.f.=2, p=0.009; chi2=9.52, d.f.=1, p=0.002; Armitage's trend test: chi2=9.07, d.f.=1, p=0.003), in substance use disorder (chi2=8.41, d.f.=2, p=0.015; chi2=8.35, d.f.=1, p=0.004; Armitage's trend test: chi2=6.27, d.f.=1, p=0.0012), and in panic attack (chi2=6.31, d.f.=2, p=0.043; chi2=6.14, d.f.=1, p=0.013; Armitage's trend test: chi2=6.27, d.f.=1, p=0.012). An association of the 5-HTR1A C(-1019)G locus with schizophrenia, substance use disorder, and panic attack was suggested by our results. In post-mortem brain samples, 5-HT1A receptor binding in prefrontal cortex and suicide were not associated with genotype. The relationship does not appear to be explained by binding differences, although we cannot rule out altered receptor affinity and transduction.     

Enhanced G-protein coupled receptors-mediated contraction and reduced endothelium-dependent relaxation in hypertension

The present study was designed to demonstrate a hypothesis that some G-protein coupled receptors are up-regulated and a dysfunction of endothelium occurs in hypertension. The arteries from hypertensive patients and spontaneously hypertensive rats (SHR) were tested. An in vitro myograph system was used to obtain concentration-contraction curves mediated by endothelin ET(A), endothelin ET(B), 5-hydroxytryptamine 2A (5-HT2A)-receptors and alpha1-adrenoceptors in the arterial segments. In hypertensive patients, the maximum contractions (Emax) induced by endothelin ET(B), endothelin ET(A) and 5-HT receptors were significantly increased with elevated pEC50 values, while a significantly leftward shift of alpha1-adrenoceptor-mediated contraction was seen. Similar results were obtained in SHR. Specific antagonists for 5-HT2A receptors or alpha1-adrenoceptors rightward shifted the concentration-contractile curves induced by 5-HT or noradrenaline, while the Emax were not significantly altered, suggesting that the contractions were mediated by 5-HT2A receptors and alpha1-adrenoceptors, respectively. Endothelium-dependent maximum relaxation (Rmax) in the arterial segments induced by acetylcholine was significantly decreased in both hypertensive patients and SHR. In addition, nitric oxide- and endothelium-derived hyperpolarizing factor-mediated dilatations were decreased significantly and the arterial endothelial cells were in part lost in SHR. In conclusion, endothelin ET(B), endothelin ET(A), 5-HT2A receptor- and alpha-adrenoceptor-mediated contractions were increased in hypertension, while the endothelium and its functions were damaged.     

5-HT2A receptor promoter polymorphism, -1438G/A and negative symptom response to olanzapine in schizophrenia

The 5-HT2A receptor promoter -1438G/A polymorphism, which is in complete linkage disequilibrium with the 5-HT2A 102T/C polymorphism, may be related to antipsychotic response. The aim of this paper is to determine relationships between the -1438G/A polymorphism and olanzapine negative symptom response. DNA from 41 subjects with schizophrenia (as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) was analyzed for the -1438G/A polymorphism. Olanzapine (7.5-20 mg/day) was given for 6 weeks and response was assessed using the Scale for Assessment of Negative Symptoms (SANS). A linear regression used a dependent variable of percent change in SANS. Independent variables included 5-HT2A polymorphisms and interactions. The -1438G/A polymorphism and percent change in SANS showed a significant trend (P=.0542). The A/A genotype group had a 45% reduction in SANS compared with 19% in the other groups. We conclude that the A/A genotype may be associated with olanzapine negative symptom response, seen as a 2-fold greater percent reduction in SANS, and may be clinically relevant.     

Risperidone-related weight gain: genetic and nongenetic predictors

OBJECTIVE: A serious side effect of atypical antipsychotics is increased body weight, which leads to further morbidity and nonadherence to medication. It has been suggested that both genetic and nongenetic variables may influence antipsychotics-related weight gain. This study aimed to simultaneously explore the effects of multiple candidate genes and environment factors on body weight of schizophrenia patients who received risperidone, a commonly used atypical antipsychotic agent. METHODS: One hundred twenty-three ethnically Han Chinese inpatients with acutely exacerbated schizophrenia were given risperidone monotherapy for up to 42 days. Body weight and clinical manifestations were assessed biweekly. Drug efficacy was measured by the Positive and Negative Syndrome Scale (PANSS), and safety was evaluated by the Extrapyramidal Symptom Rating Scale (ESRS) and the UKU Side Effect Rating Scale. We collected body weight as the response value. Potential prognostic factors were baseline body weight, age, sex, diagnosis subtypes, risperidone dosage, PANSS total scores, treatment duration (weeks 0-6), and 15 genetic variants [across 10 candidate genes: 5-HT1A, 5-HT2A, 5-HT2C, 5-HT6, D1, D2, D3, and alpha1-adrenergic receptors, brain-derived neurotrophic factor (BDNF), and cytochrome P450 2D6 (CYP2D6)]. Because there were repeated assessments, multiple linear regression with the generalized estimating equation (GEE) method was used to adjust the within-subject dependence. RESULTS: Of 15 genetic polymorphisms examined, 5-HT2A 102-T/C, 5-HT2C -759-C/T, 5-HT6 267-C/T, BDNF 66-Val/Met, and CYP2D6 188-C/T significantly influenced body weight, and so did baseline body weight, age, gender, schizophrenia subtype, and treatment duration and efficacy. CONCLUSIONS: These results suggest that numerous genetic and nongenetic factors affect antipsychotics-related weight gain.     

Association studies of 5-HT2A and 5-HT2C serotonin receptor gene polymorphisms with prophylactic lithium response in bipolar patients

Lithium is one of the most commonly used drugs in the prophylaxis and treatment of bipolar disorder. The mechanisms of mood stabilization by lithium incorporate its effect on serotonergic neurotransmission. This paper investigates a relationship between response to lithium prophylaxis and polymorphisms in two genes: T102C of 5-HT2A receptor and G68C (Cys23Ser) of 5-HT2C serotonin receptor gene. Genotypes were estimated in 92 bipolar patients (39 males and 53 females) who have been taking lithium for at least 5 years. The patients were classified as excellent responders, partial responders and non-responders to lithium. The obtained results suggest that these polymorphisms may not be related to the degree of prophylactic lithium response.     

5-HT(2A) and 5-HT(2C) receptor stimulation are differentially involved in the cortical dopamine efflux-Studied in 5-HT(2A) and 5-HT(2C) genetic mutant mice

Both 5-HT(2A) and 5-HT(2C) receptors modulate cortical dopamine efflux, but in opposite directions. We have now compared the ability of the three 5-HT(2A/2C) receptor agonists, DOI (R(-)-2,5-dimethoxy-4-iodoamphetamine), mCPP (meta-chlorophenylpiperazine) and MK-212 (6-Chloro-2-(piperazinyl) pyrazine), to modulate cortical dopamine efflux in 5-HT(2A) and 5-HT(2C) genetic mutant mice. In the 5-HT(2A) mice, the preferential 5-HT(2A) receptor agonist DOI (2.5mg/kg, s.c.) induced a slight but significant increase in cortical dopamine efflux only in the wild type (WT) mice; MK-212 (2.5mg/kg) reduced dopamine efflux in both WT and receptor knockout (KO) mice; moreover, MCPP, 2.5mg/kg, had no effect in either types. In 5-HT(2C) mice, DOI increased dopamine efflux in both types; while MK-212 decreased dopamine efflux in the WT, but not the receptor KO mice. These results provide new evidence that 5-HT(2A) receptor stimulation enhances and 5-HT(2C) receptor stimulation inhibits cortical dopamine efflux, and suggest the effects of DOI, MK-212 and mCPP on the cortical dopamine efflux are due to their different abilities on 5-HT(2A) and 5-HT(2C) receptors stimulation. Of these three agents, only DOI, the more selective 5-HT(2A) receptor agonist, is hallucinogenic. The absence of hallucinations with mCPP may be due to its relatively more potent 5-HT(2C) receptor agonist effect, inhibiting the ability of mCPP to enhance dopamine efflux in cortical and perhaps limbic regions as well. The present data provide additional evidence that hallucinations are due, in part, to 5-HT(2A) rather than 5-HT(2C) receptor stimulation. These findings suggest that 5-HT(2C) receptor agonists may be useful as antipsychotics, consistent with previous suggestions.     

Vasoconstrictor responses to 5-hydroxytryptamine in the autoperfused hindquarters of spontaneously hypertensive rats

In this work we studied the responses and receptors involved in the effects of intra-arterial 5-hydroxytryptamine (5-HT) in the in situ autoperfused hindquarters of spontaneously hypertensive rats (SHR). Intra-arterial administration of the highest doses (50-1,000 ng/kg) produced a vasoconstrictor effect that was inhibited by ritanserin (a selective 5-HT2 receptor antagonist), SB 206553 (a selective 5-HT(2B/2C) receptor antagonist) and spiperone (a nonspecific 5-HT(1/2A) receptor antagonist), and was mimicked by alpha-methyl-5-HT (a selective 5-HT2 receptor agonist) and m-CPP (a selective 5-HT2C receptor agonist), but not by the intra-arterial administration of BW 723C86, a selective 5HT2B receptor agonist. SB 206553 and spiperone inhibited alpha-methyl-5HT-induced vasoconstriction in the hindquarters of SHR. Our data suggest that the vasoconstrictor response induced by 5-HT in the autoperfused hindquarters of SHR is mainly mediated by the activation of 5-HT2A and 5-HT2C receptors.     

Role of serotonergic gene polymorphisms on response to transcranial magnetic stimulation in depression.

Transcranial magnetic stimulation (TMS) has been extensively studied as a treatment for Major Depression. However, no data are available about the role of genetic variables on the response to this treatment. We analysed the role of two polymorphisms that influence the response to antidepressants: the polymorphisms of the serotonin transporter promoter region (SERTPR) and of the 5-HT(1A) serotonergic receptor promoter region (-1019C/G). Ninety-nine patients from two double-blind, randomised, sham-controlled TMS trials were enrolled. There was a significant influence (p=0.016) of the SERTPR polymorphism on treatment outcome, without differences between active and sham stimulation. Conversely, there was a significant (p=0.014) interaction between 5-HT(1A) genotype and type of stimulation: C/C patients showed a higher difference between active and sham stimulation, indicating that these patients benefited more by TMS than C/G and G/G subjects. Our sample has not the power to control for the possible influence of different medications on these results.