精神分裂症患者5-羟色胺2A受体基因T102C基因型频率的地区差异

背景由于分子遗传学技术的发展,关于精神疾病与分子遗传的研究日趋增多,但结论不尽一致,对5-羟色胺2A受体基因T102C基因型频率分布是否有地区、种族差异尚需要更多证实.目的分析精神分裂症患者5-羟色胺2A受体基因T102C基因型频率在地理上的分布设计以精神分裂症患者为脱察对象的抽样调查.单位常州和平医院精神科.对象实验于 1999-01/2003-08在解放军第102医院完成.选取符合中国精神疾病分类和诊断标准第三版关于精神分裂症诊断标准的患者177例,来自不同省区汉族军人,年龄18～45岁,病程1个月～20年.方法采集117例精神分裂症患者的血样进行聚合酶链反应检测,并比较不同省区区正常对照人群5-羟色胺2A受体基因型频率的分布有何差异.应用常规苯酚氯仿法抽提DNA,目的DNA的聚合酶链反应扩增及电泳检测,5-羟色胺2A受体基因T102C基因片断扩增的引物序列5'-TCT GCT ACA AGT TCT GGC TT-3'.5'-CTG CAG CTY TTT CTC TAGGG-3';采用50 μL反应体系,DNA 0.5 μg,引物50 pmol,TagDNA酶2U加dNTP至终浓度200μmol/L.主要观察指标精神分裂症患者DNA电泳检测及5-羟色胺2A受体基因型频率分布.结果5-羟色胺2A受体各基因型频率分布为A1A1,0.07～0.33;A1A2,0.50～0.72;A2A2,0.17～0.29.基因型频率在不同地区的相关分析A1A1,x2=4.44,P=0.617 1,P＞0.05;A1A2,x2=1.14,P=0.942 2,P＞0.05;A2A2,x2=0.93,P=0.985 7,P＞0.05.结论117例精神分裂症患者5-羟色胺2A受体基因T102C基因型频率的地理分布比较均一.     

中国不同省区精神分裂症患者5-羟色胺2A受体基因T102C基因型频率的分布

目的:调查中国不同省区精神分裂症患者5-羟色胺2A(5-hydroxytryptophan2A,5HT2A)受体基因T102C基因型频率在地理上的分布。方法:采用聚合酶链反应的方法对不同省区的177例男性精神分裂症患者5HT2A受体基因T102C多态进行基因型分析。结果:5HT2A受体基因各基因型频率分布为:A1A1为0.07～0.33;A1A2为0.50～0.72;A2A2为0.17～0.29;其中A1A1,χ2=4.44,P=0.617,A1A2,(χ2=1.14,P=0.942);A2A2,(χ2=0.93,P=0.986);基因型频率与地区间差异均无显著相关性。结论:不同省区精神分裂症5HT2A受体基因T102C基因型频率在地理分布上比较均一。     

中国不同省区精神分裂症患者5-羟色胺2A受体基因T102C基因型频率的分布

调查中国不同省区精神分裂症患者5-羟色胺2A(5-hydroxytry ptophan 2A，5HT2A)受体基因T102C基因型频率在地理上的分布。方法：采用聚合酶链反应的方法对不同省区的177例男性精神分裂症患者5HT2A受体基因T102C多态进行基因型分析。结果：5HT2A受体基因各基因型频率分布为：A1A1为0．07-0．33；A1A2为0．50～0．72；A2A2为0．17～0．29；其中A1A1，X^2=4．44，P=0．617。A1A2，(X^2=1．14，P=0．942)；A2A2，(X^2=0．93，P=0．986)；基因型频率与地区间差异均无显著相关性。结论：不同省区精神分裂症5HT2A受体基因T102C基因型频率在地理分布上比较均一。     

汉族人单相躁狂症与5-羟色胺2A受体基因T102C多态性的相关性

目的探讨中国汉族人群单相躁狂症患者与5-羟色胺(5-HT)2A受体基因T102多态性之间的关系。方法采用AmP-RFLP方法,检测单相躁狂症症患者(n=114)和对照组(n=109)的5-HT2A受体基因频率分布。结果单相躁狂症患者5-HT2A受体基因型频率,等位基因频率与对照组无明显差异(χ2=0.02～0.74,P=0.3894-0.8832)。但按性别及有无家族史进行分层比较,男性躁狂患者A1A1基因型频率明显低于男性对照(χ2=0.89-4.38,P=0.0363-0.3458),女性躁狂患者A2A2基因型频率明显低于女性对照(χ2=0.01～7.06,P=0.0091-0.9054),女性患者组等位基因A1频率高于对照组,等位基因A2频率低于对照组。有无家族史患者组与对照组比较,基因型频率和等位基因频率均无明显差异(χ2=0.10-1.09,P=0.2967～0.7535)。结论5-HT2A受体基因多态性与单相躁狂症患者无明显相关,5HT2A受体基因可能不是单相躁狂症发病的风险基因之一,但A1等位基因可能是女性躁狂患者的风险基因。     

核心家系5-羟色胺2A受体T102C多态性与精神分裂症的关联性

背景：精神分裂症是一种常见的病因未明的精神病．是世界各国重点研究课题，其遗传学尤其是分子遗传学研究近来较受瞩目，其中对相关候选功能基因的研究显示出较好的前景。 目的：分析5-羟色胺2A受体基因多态性与精神分裂症的相关性。 设计：以诊断为依据的病例观察，关联性分析。 单位：新乡医学院第二附属医院及中原油田总医院13分院。 对象：患者组为2003-08／2004-04在新乡医学院第二附属医院住院的精神分裂症先证者56例，父母组为患者组的健康双亲112名。 方法：采用聚合酶链式反应方法（PCR-RFLP）对符合精神分裂症（CCMD-3）诊断标准的56个先证者及其父母组成的核心家系进行检测．并对5-羟色胺2A受体基因分型，精神分裂症的5-羟色胺2A受体T102C多态性运用传递不平衡（TDT）检验。 主要观察指标：5-羟色胺2A受体基因的等位基因、基因型频率分布与H-W吻合度检验结果及5-羟色胺2A受体基因的分析结果。 结果：56例患者及其父母112名全部采集到各项指标，均进入结果分析。①患者组与父母组的基因型频数差异无显著性意义（X^2=4．423．P=0．110）．等位基因分布差异亦无显著性意义（X^2=1．147．P=0．563），Hardy-Weinberg平衡吻合度良好。②在56个家系中．采用传递不平衡检验考察39个父亲或母亲为杂合子基因型的核心家系的传递不平衡性，显示精神分裂症与5-羟色胺2A受体基因无显著关联（X^2．703,P=0．10）。结论：5-羟色胺2A受体基因T102C在中国汉族人群中与精神分裂症无关联。     

核心家系5-羟色胺2A受体T102C多态性与精神分裂症的关联性

背景:精神分裂症是一种常见的病因未明的精神病,是世界各国重点研究课题,其遗传学尤其是分子遗传学研究近来较受瞩目,其中对相关候选功能基因的研究显示出较好的前景。目的:分析5-羟色胺2A受体基因多态性与精神分裂症的相关性。设计:以诊断为依据的病例观察,关联性分析。单位:新乡医学院第二附属医院及中原油田总医院13分院。对象:患者组为2003-08/2004-04在新乡医学院第二附属医院住院的精神分裂症先证者56例,父母组为患者组的健康双亲112名。方法:采用聚合酶链式反应方法(PCR-RFLP)对符合精神分裂症(CCMD-3)诊断标准的56个先证者及其父母组成的核心家系进行检测,并对5-羟色胺2A受体基因分型,精神分裂症的5-羟色胺2A受体T102C多态性运用传递不平衡(TDT)检验。主要观察指标:5-羟色胺2A受体基因的等位基因、基因型频率分布与H-W吻合度检验结果及5-羟色胺2A受体基因的分析结果。结果:56例患者及其父母112名全部采集到各项指标,均进入结果分析。①患者组与父母组的基因型频数差异无显著性意义(χ2=4.423,P=0.110),等位基因分布差异亦无显著性意义(χ2=1.147,P=0.563),Hardy-Weinberg平衡吻合度良好。②在56个家系中,采用传递不平衡检验考察39个父亲或母亲为杂合子基因型的核心家系的传递不平衡性,显示精神分裂症与5-羟色胺2A受体基因无显著关联(χ2=2.703,P=0.10)。结论:5-羟色胺2A受体基因T102C在中国汉族人群中与精神分裂症无关联。     

多巴胺受体与5-羟色胺2A受体基因多态性与迟发性运动障碍的关联

目的：观察分析多巴胺D2受体基因TaqIA多态性、多巴胺D3受体基因Ser9GIy功能多态性、5-羟色胺2A受体基因A-1438G、T102C多态性与精神分裂症伴发迟发性运动障碍的相关性。方法：于2000-10／2001-11选择江苏省扬州五台山医院长期住院的符合CCMD-2-R精神分裂症的诊断标准的籍贯江苏省的男性精神分裂症患者94例为观察对象。患者住院时间至少8年以上。在住院期间一直服用第一代抗精神病药物。并使用异常不自主运动量表评定精神分裂症患者有无迟发性运动障碍，异常不自主运动量表总分≥3分（躯体有一处≥3分，躯体有两处或多处等于2分）即可诊断为迟发性运动障碍；量表评定先后于半年内进行3次，3次异常不自主运动量表评分均大于3分者为迟发性运动障碍患者。其中迟发性运动障碍者42例，非迟发性运动障碍者52例。常规氯仿一饱和酚白细胞提取法提取DNA，引导引物和折返引物的合成、PCR的反应条件及扩增产物经MspI限制性内切酶消化方法参考文献进行。应用聚合酶链反应-限制性片段长度多态性法分析两组多巴胺D2受体基因TaqIA多态性、多巴胺D3受体功能基因Ser9Gly多态性、5-羟色胺2A受体基因A-1438G、T102C多态性位点的等位基因频率和基因型分布。结果：94例患者的各项指标均测得，全部进入结果分析。①两组患者的多巴胺D2受体基因TaqIA多态性位点的等位基因频率和基因型分布差异无显著性意义[X^2=0．19，P〉0．05）；（r=0.51，P〉0．05）]。②两组患者多巴胺D3受体基因Ser9Gly多态性基因型和等位基因频率的分布差异无显著性意义[0（2=4．98，P=0．08）；（r=0.84，P〉0．05）1。③5-羟色胺2A受体基因T102C多态性位点与A-1438G为完全连锁不平衡，迟发性运动障碍组与非迟发性运动障碍组的基因型总体分布的差异无显著性意义（X^2=4．37，P〉0．05），等位基因频率分布的差异有显著性意义[（等位基因A54／64．3，50／49．1），（等位基因G30／35．7，52／50．9），r=4．36，P〈0．05]。结论：在中国汉族男性精神分裂症患者中多巴胺D2受体基因的TaqIA多态性、多巴胺D3受体功能基因的Ser9Gly多态性可能不是影响迟发性运动障碍发生的主要危险因素。5-羟色胺2A受体基因的T102C、A-1438G多态性可能与男性精神分裂症患者的迟发性运动障碍相关联。     

多巴胺受体与5-羟色胺2A受体基因多态性与迟发性运动障碍的关联

目的:观察分析多巴胺D2受体基因TaqIA多态性、多巴胺D3受体基因Ser9Gly功能多态性、5-羟色胺2A受体基因A-1438G、T102C多态性与精神分裂症伴发迟发性运动障碍的相关性。方法:于2000-10/2001-11选择江苏省扬州五台山医院长期住院的符合CCMD-2-R精神分裂症的诊断标准的籍贯江苏省的男性精神分裂症患者94例为观察对象。患者住院时间至少8年以上。在住院期间一直服用第一代抗精神病药物。并使用异常不自主运动量表评定精神分裂症患者有无迟发性运动障碍,异常不自主运动量表总分≥3分(躯体有一处≥3分,躯体有两处或多处等于2分)即可诊断为迟发性运动障碍;量表评定先后于半年内进行3次,3次异常不自主运动量表评分均大于3分者为迟发性运动障碍患者。其中迟发性运动障碍者42例,非迟发性运动障碍者52例。常规氯仿-饱和酚白细胞提取法提取DNA,引导引物和折返引物的合成、PCR的反应条件及扩增产物经MspI限制性内切酶消化方法参考文献进行。应用聚合酶链反应-限制性片段长度多态性法分析两组多巴胺D2受体基因TaqIA多态性、多巴胺D3受体功能基因Ser9Gly多态性、5-羟色胺2A受体基因A-1438G、T102C多态性位点的等位基因频率和基因型分布。结果:94例患者的各项指标均测得,全部进入结果分析。①两组患者的多巴胺D2受体基因TaqIA多态性位点的等位基因频率和基因型分布差异无显著性意义犤(χ2=0.19,P>0.05);(χ2=0.51,P>0.05)犦。②两组患者多巴胺D3受体基因Ser9Gly多态性基因型和等位基因频率的分布差异无显著性意义犤(χ2=4.98,P=0.08);(χ2=0.84,P>0.05)犦。③5-羟色胺2A受体基因T102C多态性位点与A-1438G为完全连锁不平衡,迟发性运动障碍组与非迟发性运动障碍组的基因型总体分布的差异无显著性意义(χ2=4.37,P>0.05),等位基因频率分布的差异有显著性意义犤(等位基因A54/64.3,50/49.1),(等位基因G30/35.7,52/50.9),χ2=4.36,P<0.05犦。结论:在中国汉族男性精神分裂症患者中多巴胺D2受体基因的TaqIA多态性、多巴胺D3受体功能基因的Ser9Gly多态性可能不是影响迟发性运动障碍发生的主要危险因素。5-羟色胺2A受体基因的T102C、A-1438G多态性可能与男性精神分裂症患者的迟发性运动障碍相关联。     

汉族人单相躁狂症与5—羟色胺2A受体基因T102C多态性的相关性

目的 探讨中国汉族人群单相躁狂症患与5-羟色胺（5-HT）2A受体基因T102多态性之间的关系。方法 采用AmP-RFLP方法，检测单相躁狂症症患（n=114)和对照组（n=109)的5-HT2A受体基因频率分布。结果 单相躁狂症患5-HT2A受体基因型频率，等位基因频率与对照组无明显差异（x^2=0.02-0.74,P=0.3894-0.8832)。但按性别及有无家族史进行分层比较，男性躁狂患A1A1基因型频率明显低于男性对照（x^2=0.89-4.38,P=0.0363-0.3458)，女性躁狂患A2A2基因型频率明显低于女性对照（x^2=0.01-7.06,P=0.0091-0.9054），女性患组等位基因A1频率高于对照组，等位基因A2频率低于对照组。有无家族史患组与对照组比较，基因型频率和等位基因频率均无明显差异（x^2=0.10-1.09,P=0.2967-0.7535)。结论 5-HT2A受体基因多态性与单相躁狂症患无明显相关，5HT2A受体基因可能不是单相躁狂症发病的风险基因之一，但A1等位基因可能是女性躁狂患的风险基因。     

精神分裂症与5-羟色胺系统基因多态性

本文综述5-羟色胺(5-HT)的生物学特性、受体药理遗传学、转运蛋白以及代谢酶等近年来在精神分裂症分子遗传学相关领域的研究进展。随着分子克隆,放射性配体方法和FMRI等现代技术应用于精神药理学研究,特别是近10年来发现新一类属于5-HT2／D2拮抗剂(SDAs)的非典型抗精神病药物(如氯氮平,等)逐渐成为治疗精神分裂症的一线药物。从这两个系统的已知受体、     

Ligand dependency of 5-hydroxytryptamine 2C receptor internalization

Agonist-induced internalization of G protein-coupled receptors (GPCRs) is a well characterized phenomenon believed to contribute to receptor desensitization. The 5-hydroxytryptamine (5-HT)2C subtype of serotonin receptor is a GPCR that we have shown to internalize upon agonist incubation. In this study, we have examined the effects of 5-HT2C receptor agonists serotonin, Ro 60-0175 [(S)-2-(6-chloro-5-fluoroindol-1-yl)-1-methylethylamine], and WAY-161503 [(4aR)-8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one]; partial agonists mCPP [1-(m-chlorophenyl)piperazine] and DOI [(+)-1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane]; inverse agonists SB-206553 [N-3-pyridinyl-3,5-dihydro-5-methylbenzo(1,2-b:4,5-b')dipyrrole-1(2H)carboxamide] and mianserin; and neutral antagonists SB-242084 [6-chloro-5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-indoline] and 5-methoxygramine on the internalization of a C-terminal green fluorescent protein (GFP)-tagged 5-HT2C receptor (VSV isoform) expressed in transiently transfected human embryonic kidney cells. We detected internalization with an automated, cell-based fluorescence-imaging system (Arrayscan) and monitored function with intracellular Ca2+ measurements (flourometric imaging plate reader). The 5-HT2C-GFP construct exhibited appropriate pharmacology, and we observed that although all three agonists resulted in similar magnitudes of dose-dependent internalization, the partial agonists resulted in approximately 50% less internalization, and the inverse agonists and neutral antagonists failed to induce internalization. These results were confirmed by confocal microscopy. They demonstrate that the 5-HT2C receptor is internalized by incubation with agonists and partial agonists but not with inverse agonists or neutral antagonists.     

Differences in rapid desensitization of 5-hydroxytryptamine2A and 5-hydroxytryptamine2C receptor-mediated phospholipase C activation

The serotonin (5-HT)2A and 5-HT2C receptors share a high degree of sequence homology and have very similar pharmacological profiles. Although it is generally believed that the cellular signal transduction mechanisms activated by these receptors are indistinguishable, recent data suggest significant differences in their signaling cascades. In this study we explored differences in the characteristics and mechanisms of rapid desensitization between the 5-HT2A and 5-HT2C receptor systems. For both receptor systems, pretreatment with 5-HT reduced the ability of a maximal concentration of 5-HT to stimulate phospholipase C-mediated inositol phosphate accumulation by about 65%, although the 5-HT2C receptor system was more sensitive to the desensitizing stimulus. Differences in the concentration dependence of the rate constant for desensitization (k(des)) suggested different mechanisms of desensitization for the 5-HT2A and 5-HT2C receptor systems. At very high receptor occupancy (>99%), the responsiveness of the 5-HT2A, but not the 5-HT2C, receptor system returned to control levels despite the continued presence of the agonist. This resensitization was dependent upon the activity of protein kinase C (PKC). Agonist-induced desensitization of the 5-HT2A, but not the 5-HT2C, receptor system was reduced by the PKC inhibitors staurosporine and bisindolylmaleimide, and by down-regulation of PKC. In addition, inhibitors of calmodulin (W-7) or of calmodulin-dependent protein kinase II, reduced 5-HT2A, but not 5-HT2C, desensitization. Desensitization of the 5-HT2C, but not the 5-HT2A, receptor system was dependent on G protein receptor kinase activity. These data further emphasize the major differences in the signaling systems coupled to 5-HT2A/2C receptors.     

5-hydroxytryptamine2A receptor inverse agonists as antipsychotics

We have used a cell-based functional assay to define the pharmacological profiles of a wide range of central nervous system active compounds as agonists, competitive antagonists, and inverse agonists at almost all known monoaminergic G-protein-coupled receptor (GPCR) subtypes. Detailed profiling of 40 antipsychotics confirmed that as expected, most of these agents are potent competitive antagonists of the dopamine D2 receptor. Surprisingly, this analysis also revealed that most are potent and fully efficacious 5-hydroxytryptamine (5-HT)2A receptor inverse agonists. No other molecular property was shared as universally by this class of compounds. Furthermore, comparisons of receptor potencies revealed that antipsychotics with the highest extrapyramidal side effects (EPS) liability are significantly more potent at D2 receptors, the EPS-sparing atypical agents had relatively higher potencies at 5-HT2A receptors, while three were significantly more potent at 5-HT2A receptors. Functional high-throughput screening of a diverse chemical library identified 530 ligands with inverse agonist activity at 5-HT2A receptors, including several series of compounds related to known antipsychotics, as well as a number of novel chemistries. An analog of one of the novel chemical series, AC-90179, was pharmacologically profiled against the remaining monoaminergic GPCRs and found to be a highly selective 5-HT2A receptor inverse agonist. The behavioral pharmacology of AC-90179 is characteristic of an atypical antipsychotic agent.     

Serotonin 5-hydroxytryptamine 2A receptor-coupled phospholipase C and phospholipase A2 signaling pathways have different receptor reserves

NIH3T3 cells stably expressing the rat 5-hydroxytryptamine 2A (5-HT 2A) receptor (5500 fmol/mg) were used to explore further the capacity of structurally distinct ligands to elicit differential signaling through the phospholipase C (PLC) or phospholipase A 2 (PLA 2) signal transduction pathways. Initial experiments were designed to verify that 5-HT 2A receptor-mediated PLA 2 activation in NIH3T3 cells is independent from, and not a subsequent result of, 5-HT 2A receptor-mediated PLC activation. In addition, we also explored the extent of receptor reserve for the endogenous ligand, 5-HT, for both PLC and PLA 2 activation. Finally, we employed structurally diverse ligands from the tryptamine, phenethylamine, and ergoline families of 5-HT 2A receptor agonists to test the hypothesis of agonist-directed trafficking of 5-HT 2A receptor-mediated PLC and PLA 2 activation. To measure agonist-induced pathway activation, we determined the potency and intrinsic activity of each compound to activate either the PLA 2 pathway or the PLC pathway. The results showed that a larger receptor reserve exists for 5-HT-induced PLA 2 activation than for 5-HT-induced PLC activation. Furthermore, the data support the hypothesis of agonist-directed trafficking in NIH3T3-5HT 2A cells because structurally distinct ligands were able to induce preferential activation of the PLC or PLA 2 signaling pathway. From these data we conclude that structurally distinct ligands can differentially regulate 5-HT 2A receptor signal transduction.     

Association between T102C and A-1438G polymorphisms in the serotonin receptor 2A (5-HT2A) gene and schizophrenia: relevance for treatment with antipsychotic drugs.

BACKGROUND: An involvement of serotonin receptor 2A (5-HT2A) in the aetiology of schizophrenia has been hypothesised. The 5-HT2A receptor also appears to be an important site of action of atypical antipsychotic drugs. Indeed, association between schizophrenia and the T102C silent polymorphism of the 5-HTR2A gene has been reported. Another polymorphism in the promoter region of 5-HTR2A (A-1438G) in linkage disequilibrium with the T102C polymorphism has also been reported. It has been suggested that the A-1438G polymorphism alters promoter activity and expression of 5-HT2A receptors and might be responsible for the associations with schizophrenia and the efficacy of atypical antipsychotics such as risperidone. METHODS: We analysed the 5-HTR2A T102C and A-1438G polymorphisms in clinically stable schizophrenia patients (SPs) and healthy volunteers (HVs). We developed an allele-specific PCR-based restriction fragment length polymorphism (PCR-RFLP) method. In SPs, we also described differences across both diagnosis subtypes (paranoid vs. non-paranoid) and antipsychotic drug treatment (risperidone vs. other classical antipsychotic drugs). RESULTS: Two groups of 114 SPs and 142 HVs were studied. The frequency of the 5-HTR2A -1438A allele was higher in SPs than in HVs (0.54 vs. 0.44; p<0.05). The frequency of the 102T allele was also higher among SPs than HVs (0.56 vs. 0.46; p<0.05). These two polymorphisms were in linkage disequilibrium. The percentage of carriers of the 1438A/A and 102T/T alleles was 26% and 15% for SPs and HVs, respectively (p<0.05; odds ratio 1.9). No differences in genotype or allele frequencies were found between paranoid and non-paranoid SPs or between SPs on risperidone and those on classical antipsychotic treatment. CONCLUSIONS: The present study demonstrates a higher frequency of 5-HTR2A -1438A and 102T alleles in SPs compared to HVs.     

SRD5A1 genotype frequency differences in women with mild versus severe premenstrual symptoms

The aims of this small pilot study were to explore the association between premenstrual symptom severity and two genes from the gamma-aminobutyric acid (GABA) pathway: steroid-5-alpha-reductase, alpha polypeptide 1 (SRD5A1) and gamma-aminobutyric acid receptor subunit alpha-4 (GABRA4). Saliva samples were obtained from a convenience sample of 19 Caucasian females ages 18-25 years, ten cases and nine controls. Deoxyribonucleic acid (DNA) was isolated, and genotyping performed on ten single nucleotide polymorphisms (SNPs). Ten percent of cases and 44% of controls had the cytosine/cytosine (C/C) genotype for the SRD5A1 SNP, rs501999 indicating that this genotype may protect women against severe premenstrual symptoms. Replication of this study using an adequately powered sample size is warranted.