SLC6A4基因多态性与海洛因依赖的关联性研究

目的:探讨5-羟色胺转运体基因(solute carrier family 6 member 4,SLC6A4)基因4个单核苷酸多态性(single nucleotide polymorphism,SNP)位点与海洛因依赖之间的关系。方法:严格按照诊断标准,选取无亲缘关系的海洛因依赖个体397例(病例组)及健康对照个体402例(对照组)提取基因组DNA,采用SNaPshot SNP分型技术对SLC6A4基因4个SNP位点(rs1042173,rs3813034,rs6354,rs7224199)进行基因分型,比较病例-对照组间各位点等位基因、基因型频率的差异。结果:病例组和对照组SLC6A4基因rs1042173和rs3813034位点的基因型和等位基因频率比较存在显著性差异(P0.05),rs1042173的C等位基因(P=0.031,OR=1.317,95%CI=1.026-1.691)及rs3813034的C等位基因(P=0.013,OR=1.375,95%CI=1.069-1.768)是海洛因依赖的危险因素。病例组TCC单倍型(rs7224199、rs3813034和rs1042173)的比例较对照组显著增高(P0.05)。结论:SLC6A4基因rs1042173和rs3813034多态性可能与海洛因成瘾有关,携带有rs1042173的C等位基因和rs3813034的C等位基因的个体及携带TCC单倍型的个体可能更容易对海洛因产生依赖。     

多巴胺D2受体基因多态性位点与海洛因依赖的关系

目的:探讨多巴胺D2受体(Dopamine D2 receptors,DRD2)基因3'非翻译区Taq ⅠA、启动子区-141 Ins/Del 2个多态性位点和海洛因依赖的相关性.方法:采用聚合酶链反应-限制性片段长度多态(PCR-RFLP)技术检测320例海洛因依赖患者及300例健康对照组的TaqⅠA和-141 Ins/Del2个多态性位点的基因型.采用HaploView4.0及SPSS11.5软件分析这2个多态性位点的基因型、等位基因频率及组间差异.结果:DRD2基因Taq ⅠA位点的基因型及等位基因频率分布在海洛因依赖组与正常对照组存在显著性差异(p<0.01),海洛因依赖组TaqⅠA位点的等位基因A1频率显著高于正常对照组(x2=11.156,p=0.001,OR=1.463,95%CI=1.170～1.830);DRD2基因-141 Ins/Del位点的基因型及等位基因频率分布在海洛因依赖组与正常对照组之间无统计学差异(p<0.05).结论:DRD2基因TaqⅠA位点多态性可能与海洛因依赖有关,携带有TaqⅠA多态性位点A1等位基因的个体可能更容易对海洛因产生依赖.     

中国人群5—羟色胺2A受体基因中T102C多态性与精神分裂症的联系

在研究５－羟色胺２Ａ受体基因多态性与精神分裂症的关联分析中,调查了２０２例精神分裂症患者及２０２例正常对照。各相匹配组间比较未发现基因型和等位基因频率的显著性差异。结果提示,在中国人群中５－羟色胺２Ａ受体的静态Ｔ１０２Ｃ突变与精神分裂症之间不存在关联。     

强啡肽原基因3'非翻译区多态性位点与海洛因依赖的关联研究

目的:探讨强啡肽原(prodynorphin,PDYN)基因3'非翻译区的3个单核苷酸多态性(Single Nucleotide Polymorphism,SNP)位点与海洛因依赖的相关性.方法:严格按照诊断标准,选取无亲缘关系的海洛因依赖患者212例,健康对照200例提取基因组DNA,采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)技术检测PDYN基因3'非翻译区rs1022563、rs2235749、rs9100803个多态性位点的基因型,采用HaploView及SPSS11.5软件分析各位点基因型、等位基因频率及组间差异.结果:PDYN基因rs2235749的基因型及等位基因频率分布在海洛因依赖组与正常对照组存在显著性差异(p＜0.01),在海洛因依赖组中等位基因A的频率显著高于正常对照组(p＜0.01).连锁不平衡结果显示,这3个SNPs位点不连锁,D'=0.215.结论:PDYN基因3'非翻译区rs2235749与海洛因相关联,携带有等位基因A的个体可能对海洛因更容易产生依赖.     

5-羟色胺与Toll样受体及肠道菌群之间关系的研究

5-羟色胺(5-HT)是参与调节胃肠道运动、内脏敏感性、分泌等功能的重要神经递质和信号分子。肠道菌群对5-HT的产生有重要影响,已发现一些产芽孢细菌(spore-forming bacteria,SP)类肠道微生物能刺激肠嗜铬细胞(enterochromaffin cell,EC)产生5-HT。微生物通过Toll样受体(Toll-like receptors,TLR)激活神经分泌机制来调节胃肠运动,某些TLR通过作用于5-HT受体调节小鼠回肠的自主收缩和5-HT诱导的收缩反应。通过调节肠道菌群可以对5-HT综合征及其相关生理和病理状况产生重要影响。因此,对5-HT与TLR及肠道菌群相互之间的关系进行进一步的研究有重要意义。     

中国人群5-羟色胺2A受体基因中T102C多态性与精神分裂症的联系 Analysis of Association Between T102C Polymorphism in theSerotonin 2A Receptor Gene and Schizophrenia in Chinese Population

在研究5-羟色胺2A受体基因多态性与精神分裂症的关联分析中,调查了20 2例精神分裂症患者及202例正常对照。各相匹配组间比较未发现基因型和等位基因频率的显著性差异。结果提示,在中国人群中5-羟色胺2A受体的静态T102C突变与精神分裂症之间不存在关联。 Abstract:Association study between in the T102C polymorphism serotonin 2A receptor gene and schizoprenia was performed in 202 schizophrenics and 202 normal controls.No significant differences of genotype and allele frequencies between the matched groups were found.Our results,which are different from some other studies,excluded the association between a silent T102C change and schizophrenia in the Chinese population.     

重庆居民5-HT2A基因多态性与原发性高血压关系

以聚合酶链PCR法分析重庆市一般人群的5-HT2A基因C102T多态性(样本总数348人,其中高血压组:HT=137例,非高血压组:NT=211例)的临床指标间的相关性与频率分布。了解重庆地区汉族人群5-羟色胺受体2基因(5-hydroxytryptamine receptor gene,5-HT2A)C102T多态性与原发性高血压病(essential hypertension,EH)的关系。卡方检验结果显示5-HT2A的C102T基因多态性(P=0.549)与等位基因频率(P=0.263)在HT与NT之间没有显著性统计学差异;5-HT2A的C102T基因多态性与高血压logistic回归模型分析结果显示也未见显著性差异,卡方值(Wald)为0.399;比值比为0.884;95%的可信区间为0.603~1.296,P值为0.528。一般线性模型分析结果:5-HT2A基因C102T多态性与收缩压,舒张压之间没有显著性统计学差异,PSBP=0.868,PDBP=709。5-HT2A的C102T多态性可能与重庆汉族人群EH无关。     

云南汉族人群5-羟色胺转运体基因启动子区多态性与酒精依赖的相关性

为了探讨云南汉族人群中5-羟色胺转运体基因启动子区多态性(5-HTTLPR)与酒精依赖的关联性, 文章采用PCR扩增和DNA测序技术, 对云南地区118例酒精依赖患者和214例健康对照个体进行了5-HTTLPR的基因多态性分析。结果表明: 酒精依赖患者组和正常对照组的5-HTTLPR的基因型分布存在显著性差异, L/L和L/S基因的携带者人群嗜酒发生率显著低于S/S基因型人群(OR: 0.581, P=0.026)。S和L等位基因频率在两组间无统计学差异(χ²=2.594, P=0.107), 但其分布存在种族差异性。因此, 云南地区人群中5-HTTLPR多态与酒精依赖存在相关性, L/L和L/S基因型可能是降低酒精依赖发病的影响因子之一。     

5—羟色胺受体的分子生物学

把含有编码5-羟色胺受体(5-HTR)的mRNA注入非洲爪蟾卵母细胞内,借助卵母细胞的翻译系统,把5-HTR“移植”到卵母细胞的细胞膜上,借此深入研究5-HTR的配体结合特性以及受体后的信息传递机制。5-HT_(IC)R、5-HT_(IA)R以及5-HT_2R的cDNA相继克隆化成功,确定了这三种5-HTR的一级结构,并对受体的配体结合点、G蛋白的作用部位以及5-HTR的分子构象进行了推测。     

多巴胺D4受体基因启动子区功能多态性与海洛因依赖的相关性研究

目的:探讨多巴胺D4受体(DRD4)基因启动子区的3个功能多态性位点与海洛因依赖的相关性.方法:严格按照诊断标准,选取无亲缘关系的海洛因依赖患者212例及健康对照组200例提取基因组DNA,采用聚合酶链反应及等位基因特异性扩增技术检测DRD4基因启动子区-521C/T、-616C/G、及-1240L/S 3个功能多态性位点的基因型,采用HaploView及SPSS11.5软件分析各位点基因型、等位基因频率及组间差异.结果:DRD4基因-521C/T的基因型及等位基因频率分布在海洛因依赖组与正常对照组存在显著性差异(p＜0.05).结论:多巴胺D4受体(DRD4)基因-521C/T多态性与海洛因依赖相关联,T等位基因可能是海洛因依赖的风险因子.     

HTR2A基因多态性与云南彝族酒精依赖关联性研究

目的：探讨酒精依赖和云南彝族5-羟色胺2A受体（HTR2A）基因多态之间的关系。方法：采用PCR-RFLP技术对330健康人（对照组）和110名酒精依赖者（病例组）的5-HT2A受体基因的遗传多态性进行检测。结果：在440例样本中共检测到2种等位基因A和G,三种基因型AA,AG,GG．三种基因型在对照组中频率分别是38．5％,55．8％,5．8％;在病例组中的频率分别是30％,63．6％,6．4％。结论：在云彝族人群中,HTR2A基因rs6311（A－1438G）位点与酒精依赖无显著关联,HTR2A基因rs6311（A-1438G）位点在云南汉族和云南彝族酒精依赖组中无显著差异,但是在健康对照组中存在关联性．     

A Naturally Occurring Amino Acid Substitution of the Human Serotonin 5-HT2A Receptor Influences Amplitude and Timing of Intracellular Calcium Mobilization

Abstract: Recently, two naturally occurring amino acid substitutions were identified in the C-terminal region of the serotonin 5-HT_2A receptor. One of these, His ⁴⁵²Tyr, has a rarer allele Tyr frequency of 9%. If ⁴⁵²Tyr alters 5-HT_2A function, it would thus be a candidate allele for human neurobehavioral variation. The present study was designed to evaluate the potential influence of the ⁴⁵²His and ⁴⁵²Tyr alleles on cellular 5-HT_2A functions. Platelet 5-HT_2A binding and 5-HT-induced Ca²⁺ response were compared in eight ⁴⁵²His/⁴⁵²His homozygous and eight ⁴⁵²His/⁴⁵²Tyr heterozygous individuals matched for sex, age, and diagnosis (all were patients with seasonal affective disorder). There was no difference in 5-HT_2A binding measured using ¹²⁵I-lysergic acid diethylamide. Nor were levels of G-protein subunits or PKC α, δ, ε, or ζ significantly altered. However, when Ca²⁺ response was stimulated by 2, 5, 10, or 25 µM 5-HT, significant differences were found. In ⁴⁵²His/⁴⁵²Tyr heterozygotes, ⁴⁵²Tyr was associated with both smaller peak amplitude in Ca²⁺ mobilization and a different time course of response, with slower peak latency and longer half-time in ⁴⁵²His/⁴⁵²Tyr heterozygotes compared with ⁴⁵²His/⁴⁵²His homozygotes. The overall difference in the response of the 5-HT_2A receptor in individuals with ⁴⁵²Tyr was a blunting of the shape of the Ca²⁺ mobilization peak. The data reported here suggest that the primary sequence of this intracellular domain is important in function of the receptor and that the ⁴⁵²His and ⁴⁵²Tyr 5-HT_2A alleles should be carefully evaluated for effects on human neurobehavioral variation.     

Hippocampal Serotonin 5-HT1A Receptor Enhances Acetylcholine Release in Conscious Rats

Abstract: We investigated changes in the extracellular levels of acetylcholine (ACh) following local application of serotonergic agents to the dorsal hippocampus of freely moving rats by means of perfusion using a microdialysis technique. Perfusion of serotonin (5-HT; 10 μM, for 30 min at a rate of 3 μl/min), dissolved in Ringer's solution containing 10 μM eserine, showed no marked effect on the extracellular levels of ACh. 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 20 μM), a 5-HT_1A agonist, increased ACh levels, whereas 7-trifluoromethyl-4-(4-methyl-1 -piperazinyl)-pymoto[1,2-a]quinoxaline (CGS-12066B; 100 μM), a 5-HT_1B agonist, decreased it. Clomipramine (2 μM), an uptake inhibitor of 5-HT, had no effect on ACh levels. Following perfusion of 1-(2-methoxyphenyl)-4-[4- (2-phthalimido)butyl]piperazine (NAN-190; 10 μM), which is a selective 5-HT_1A antagonist, the effect of 8-OH-DPAT was totally abolished, whereas CGS-12066B decreased extracellular ACh levels. 5-HT, as well as Clomipramine, had a decreasing effect on ACh levels after pretreatment with NAN-190. These results indicate that the 5-HT_1A receptor, which exists in the dorsal hippocampus, enhances the spontaneous ACh release, and that the mechanism of serotonergic modulation of ACh release partly depends on both the stimulatory control via the 5-HT_1A receptor and the suppressive one via the 5-HT_1B receptor in the dorsal hippocampus of rats.     

胆囊收缩素及受体基因多态性与精神分裂症的相关性研究

目的：探讨胆囊收缩素（cholecystokinin,CCK）基因、胆囊收缩素A受体（cholecystokininAreceptor。CCKAR）基因和胆囊收缩素B受体（cholecystokinin A recepmr,CCKBR）基因多态性与精神分裂症之间的相关性。方法：采用聚合酶链式反应．限制性片段长度多态性方法,对420例精神分裂症患者（病例组）和455例健康个体（对照组）三个基因的6个单核苷酸多态性（single nucleotide polymorphism,SNPs）位点（rs11571842、rs13069836、rs1800908、rs1800857、rs1042047、rs4758092）的多态性进行检测。并比较两组人群中基因型和等位基因频率分布的差异。结果：对照组6个SNPs位点的基因型频率分布均符合Hardy-Weinbere平衡（P〉0．05）;CCKAR基因rs1800857位点基因型频率分布在精神分裂症组与正常对照组间存在显著性差异（P〈0．000）,病例组T等位基因频率显著高于对照组（P〈0．01）。结论：CCKAR基因多态性与精神分裂症相关,携带T等位基因的个体可能更容易患精神分裂症。     

Identification of Serotonin Receptors Recognized by Anti-Idiotypic Antibodies

Anti-idiotypic antibodies were generated by immunizing rabbits with affinity-purified antibodies to serotonin (5-hydroxytryptamine; 5-HT). Anti-5-HT activity was removed from the resulting antisera by chromatography through a 5-HT affinity column. The anti-idiotypic antibodies were demonstrated by enzyme-linked immunosorbent assay to bind to affinity-purified whole anti-5-HT antibodies and their Fab fragments. Anti-idiotypic antibodies, purified by affinity chromatography on columns to which antibodies to 5-HT were coupled, competed with 5-HT (covalently bound to protein) for the binding sites on anti-5-HT antibodies and serotonin binding protein. The anti-idiotypic antibodies antagonized the binding of [3H]5-HT to membranes isolated from the cerebral cortex, striatum, and raphe area more than to membranes from hippocampus or cerebellum. The anti-idiotypic antibodies also blocked the binding of the 5-HT1B-selective ligand (-)-[125I]iodocyanopindolol (in the presence of 30 microM isoproterenol) to cortical membranes. In contrast, anti-idiotypic antibodies failed to inhibit binding of the 5-HT1A-selective ligand 8-hydroxy-2-(di-n-[3H]propylamino)-tetralin [( 3H]8-OH-DPAT) to raphe area membranes or hippocampal membranes. These observations suggested that the anti-idiotypic antibodies may recognize some 5-HT receptor subtypes but not others. This hypothesis was tested by ascertaining the ability of anti-idiotypic antibodies to immunostain cells transfected in vitro with cDNA encoding the 5-HT1C or 5-HT2 receptor or with a genomic clone encoding the 5-HT1A receptor. Punctate sites of immunofluorescence were found on the surfaces of fibroblasts that expressed 5-HT1C and 5-HT2 receptors, but not on the surfaces of HeLa cells that expressed 5-HT1A receptors. Immunostaining of cells by the anti-idiotypic antibodies was inhibited by appropriate pharmacological agents: immunostaining of cells expressing 5-HT1C receptors was blocked by mesulergine (but not ketanserin, 8-OH-DPAT, or spiperone), whereas that of cells expressing 5-HT2 receptors was blocked by ketanserin or spiperone (but not mesulergine or 8-OH-DPAT). The anti-idiotypic antibodies failed to inhibit the uptake of [3H]5-HT by serotonergic neurons. It is concluded that the anti-idiotypic antibodies generated with anti-5-HT serum recognize the 5-HT1B, 5-HT1C, and 5-HT2 receptor subtypes; however, neither 5-HT1A receptors nor 5-HT uptake sites appear to react with these antibodies.     

5-HT_(1A)受体参与学习记忆的分子机制研究进展

5-HT(五羟色胺)能神经元是起源最早的神经元之一,在传统的神经元形成前,成长中的轴突就可释放5-HT,并且通过5-HT的各种亚型受体来实现不同的功能。近年来,随着5-HT、5-HTRs(五羟色胺受体)的基因克隆及5-HT受体选择性激动剂和拮抗剂的研究发展,5-HT系统在学习记忆中的作用越发明确,许多研究结果表明:5-HT系统在记忆的巩固、短时程记忆(STM)及长时程记忆(LTM)中起重要作用,5-HT1A受体更是在非脊椎动物及哺乳动物的脑中都高度表达,并通过相似的信号转导途径参与学习与记忆的形成和巩固。本文将介绍5-HT1A受体、5-HT1A受体激动剂、5-HT1A受体拮抗剂及其与学习记忆的联系,重点综述5-HT1A受体参与学习记忆的信号转导途径研究进展,讨论5-HT1A受体参与学习记忆的可能性分子神经生物学机制。     

Alterations in Serotonin Parameters in Brain of Thiamine-Deficient Rats Are Evident Prior to the Appearance of Neurological Symptoms

Abstract: Biochemical alterations of serotoninergic parameters have been demonstrated in experimental thiamine deficiency. In addition, hypophagia and hypothermia, two physiological processes associated with changes in the serotonin [5-hydroxytryptamine (5-HT)] system, are manifest early during the progression of thiamine deficiency. The binding of selected 5-HT radioligands was therefore investigated in discrete brain regions of pyrithiamine-induced thiamine-deficient rats. Using quantitative receptor autoradiography, the binding of 8-hydroxy-2-(di- n -[³H]propylamino)tetralin, a ligand used to label the somatodendritic 5-HT_1A autoreceptor of the dorsal raphe nucleus, was found to be unaffected in this region, suggesting that the structural integrity of the 5-HT cell bodies is maintained throughout the course of pyrithiamine treatment. Increased binding of [³H]-ketanserin was observed in regions considered vulnerable as well as in some considered to be nonvulnerable during the course of thiamine deficiency. These binding changes, which appear to represent changes in the density of the postsynaptic 5-HT_2A receptor population rather than the "tetrabenazine-sensitive" vesicular monoamine transporter, are evident before the appearance of histopathologic lesions and coincide with altered tissue concentrations of 5-HT. These data suggest that 5-HT neurons, although structurally intact, are functionally affected early during the progression of thiamine deficiency. These alterations, which are likely a part of adaptive neuronal change consequent to thiamine dysfunction, may be important in the physiological manifestations and the learning deficits commonly encountered in experimental thiamine deficiency.     

Primary Structure of the Human Platelet Serotonin 5-HT2A Receptor: Identity with Frontal Cortex Serotonin 5-HT2A Receptor

Abstract: Previous radioligand binding studies have demonstrated human platelet serotonin_2A (5-HT_2A) receptor binding sites. Pharmacological similarities between platelet and frontal cortex 5-HT_2A receptor binding parameters have been demonstrated. However, it is not clear whether the platelet 5-HT_2A receptor primary structure is identical to that of the brain receptor. Three overlapping cDNAs were obtained to span completely the coding region of the 5-HT_2A receptor. These clones were sequenced with external and internal primers. The nucleotide sequence of human platelet 5-HT_2A cDNA was identical to that reported for the human frontal cortex 5-HT_2A receptor, except for nucleotide 102 (T → C), which has been reported to represent a normal DNA polymorphism that does not alter the amino acid sequence. This finding may have implications in the study of neuropsychiatric disorders for which altered platelet 5-HT_2A receptor binding has been demonstrated.