多巴胺D2受体TaqIA多态性与海洛因依赖行为相关性

目的 :探讨多巴胺 (DA)受体D2 亚型基因TaqIA多态性与海洛因依赖者行为之间的相关性。方法 :应用PCR -RFLP法对 6 6例海洛因依赖病人与 132例正常人D2 R基因的TaqIA多态性特征进行对照研究。以A型行为问卷 (TABPQ) [1] 测评海洛因依赖者的行为类型 ,与其TaqIA多态性特征进行相关分析。结果 :海洛因依赖组与正常对照组DRD2 基因的TaqIA多态性基因型及等位基因频率有显著性差异 (前者携带A1等位基因的频率为 0 6 1,后者携带A1等位基因的频率为 0 31,P <0 0 5 ) ,携带A1等位基因更易形成海洛因依赖者 (比值比OR :3 47,P <0 0 5 )。各种行为类型的海洛因依赖者之间 ,基因型 (TaqIA多态性 )无显著性差异 (P >0 0 5 )。结论 :多巴胺D2 受体基因的TaqIA多态性与海洛因依赖相关连。多巴胺D2 受体基因TaqIA多态性与海洛因依赖者成瘾性的形成可能相关。这种基因位点特征可能与其他候选基因及环境因素共同作用 ,影响着海洛因依赖者的行为     

多巴胺D2受体基因启动子多态性与帕金森病的关联研究

目的 探讨中国汉族人群多巴胺D2受体基因启动子多态性在帕金森病（Parkinson's disease,PD)遗传易感性中的作用。方法 采用病例－对照关联分析，聚合酶链反应－限制性片段长度多态性方法分析了123例PD患者（PD组）与124名健康成人（对照组）多巴胺D2受体基因启动子多态性。结果 PD组－141△C等位基因频率为8．5％，对照组为11．7％；两组差异无显著性（P＞0．05）；中国汉族人PD组组和对照组－141△C等位基因频率明显高于意大利南部人群，差异有显著性（P＜0．05）。结论中国汉族人群多巴胺D2受体基因启动子多态性与PD的遗传易感性无关，该多态性有明显的种族差异。     

SD大鼠海洛因CPP易感性差异的伏隔核壳区D2受体及DAT机制

目的:建立大鼠海洛因成瘾易感性差异的条件性位置偏爱模型,检测海洛因CPP易感性差异大鼠伏隔核壳区(AcbSH)D2受体(dopamine D2 receptor,D2R)及多巴胺转运体(dopamine transportor,DAT)蛋白表达的动态变化,探讨海洛因精神依赖易感性差异可能机制.方法:130只雄性SD大鼠随机抽取30为生理盐水对照组(SC),其余100只大鼠为海洛因处理组进行条件性位置偏爱(CPP)训练,海洛因处理组根据海洛因诱导的CPP强度不同再分为高CPP组(HP)和低CPP组(LP),各占总数的30%,利用免疫组化方法对高、低偏爱组及生理盐水对照组大鼠末次海洛因注射后30分钟、戒断第1、3、7、14天AcbSH D2R和DAT蛋白表达进行检测.结果:①海洛因处理后大鼠AcbSH区D2R和DAT蛋白表达均显著下降,而在戒断后逐渐回升;②海洛因高偏爱组大鼠在所有检测时点AcbSH区D2R下凋比低偏爱组大鼠更为明显;③海洛因高偏爱组大鼠各脑区所有检测时点DAT表达与低偏爱组大鼠均无明显差别.结论:①海洛因慢性处理后,大鼠AcbSH区D2R和DAT均出现适应性下调;②不同个体D2R敏感性或受体水平存在差异,低D2R可能与海洛因成瘾的高易感性与有关;③未发现不同易感性的大鼠DAT蛋白水平存在差异,海洛因成瘾易感性与DAT的表达可能没有直接的相关性.     

环境线索诱导海洛因依赖者心理渴求的SPECT研究

目的 :研究与海洛因相关的环境线索诱导急性脱毒后海洛因依赖者的心理渴求及其局部脑血流灌注的变化特征。方法 :选择脱毒治疗一个月后海洛因依赖者 ,给于与海洛因相关的环境刺激 (暴露 ) 15分钟 ,在海洛因环境暴露前后分别评定心理渴求量表和汉米尔顿焦虑量表 ,同时采用单光子发射计算机断层扫描 (SPECT)测量局部脑血流灌注 (rBCF)的变化。结果 :暴露海洛因相关的环境可增加病人对药物的心理渴求 :1)使脱毒海洛因依赖者的心理渴求量表评分增加 ,与暴露前相比差异有显著性 (t =3 2 1P <0 0 5 ) ;2 )海洛因相关的环境刺激可以增加病人的焦虑情绪 ,表现为汉米尔顿焦虑量表总评分增高 ,(t =3 1,P <0 0 1)特别是躯体焦虑因子评分增高更为明显 (t =2 98,P <0 0 1) ;3 )海洛因的环境刺激明显增加额叶 ,颞叶皮层及杏仁核等脑区的局部脑血流 ,而其他脑区如顶叶、枕叶、扣带回及基底节等区域的脑血流灌注则无明显的变化。结论 :海洛因相关的环境可以诱导吸毒者对海洛因的心理渴求 ,是脱毒后发生复吸的主要因素之一 ,额叶、颞叶皮层及杏仁核等脑区参与了环境线索诱导复吸的神经生物过程。阻断药物相关的环境线索的刺激可以作为预防吸毒者脱毒后的再次复吸行为的手段之一。     

[123I]-IBZM SPECT显像检测帕金森病患者脑多巴胺D2受体

目的：观察帕金森病（ＰＤ）患者脑多巴胺Ｄ２受体的变化。方法：「＾１２３Ｉ」－（Ｓ）－（－）－３－碘－２－羟基－６－甲氧基－Ｎ－「（１－乙基－２－吡咯烷基）」苯酰胺为放射配体，对１３例未接受左旋多巴治疗的的发性ＰＤ（ＩＰＤ－Ａ组）、１８例接受左旋多巴治疗的原发性ＰＤ（ＩＰＤ－Ｂ组）、８例继发性帕金森氏综合征（ＳＰＳ组）和７例正常对照者进行了「＾１２３Ｉ」－ＩＢＺＭ脑多巴胺Ｄ２受体ＳＰＥＣＴ显像和半定     

多巴胺D2受体基因与精神分裂症和双相情感障碍关联研究的荟萃分析

遗传因素是精神分裂症(schizophrenia,SCZ)和双相情感障碍(bipolar disorder,BP)的重要致病因素,已有大量基因关联研究表明多巴胺D2受体基因与两种精神疾病可能存在风险关系,然而许多研究的结果并不一致.系统的荟萃分析可以弥补单个研究样本量小可能引起的结果偏差.经过严格筛选,本文纳入8个关于BP和49个关于SCZ的独立研究,荟萃分析多巴胺D2受体3个基因多态性(141C Del/Ins、TaqI-A、SCr311Cys)与这两种精神疾病的风险关系.结果 提示Ser311Cys的G/C多态性和SCZ发病显著关联,而TaqI-A的T/C多态性和BP发病存在显著关联(P<0.05).基因型分析结果揭示了多巴胺D2受体基因Ser311Cys携带G等位基因的基因型是SCZ的风险因素,TaqI-A的TT基因型可能是BP的风险因子而对于SCZ是保护因子.     

多巴胺受体D2型基因启动区多态性与精神分裂症关联研究

目的探讨湖北武汉地区汉族人群中多巴胺受体D2型基因(dopamine receptor D2, DRD2)启动区-141位点胞嘧啶插入/缺失多态性与精神分裂症的关联关系.方法应用聚合酶链反应-限制性片段长度多态性方法,对120例精神分裂症患者、100名健康对照者进行基因分型.对精神分裂症患者的 DRD2 -141位点胞嘧啶插入/缺失多态性进行了相关分析.结果 DRD2型基因启动区-141位点的等位基因、基因型频率在精神分裂症组与对照组之间的分布差异有统计学意义(P<0.05).在精神分裂症组中,-141C缺失的等位基因频率为0.11,对照组为0.18(比值比为0.55,95%可信区间为0.30～0.96,P <0.05).结论 -141位点胞嘧啶插入/缺失多态性非独立性地对精神分裂症与 DRD2基因的相关性产生修饰作用.-141位点胞嘧啶缺失可能是湖北武汉汉族精神分裂症患者的保护因素之一.     

Reelin可增强海马神经元的多巴胺D1受体表达

目的研究Reelin对小鼠海马神经元多巴胺D1受体的调控及其是否依赖Reelin受体（ApoER2／VLDLR）发挥调控作用。方法原代分离培养新生C57BL／6J小鼠海马神经元,将培养5d后的神经元随机分为6组：空白对照组、CR．50组（CR．50）,EDTA组（EDTA）,Reelin组（Reelin）,Reelin拮抗组（Reelin＋CR50）和Reelin受体拮抗组（Reelin＋EDTA）。分别加入Reelin、CR．50、EDTA进行共培：养,其后利用免疫荧光的方法观察Reelin受体ApoER2、VLDLR和多巴胺Dl受体在海马神经元上的定位以及各组多巴胺Dl受体的变化。结果（1）Reelin受体ApoER2、VLDLR均与多巴胺D1受体在海马神经元上共定位;（2）Redin拮抗组的多巴胺D1受体荧光强度（0．215±O．09）较Reelin组（O．663±0．15）减弱（P〈0．01）;（3）Reelin受体拮抗组的多巴胺D1受体荧光强度（0．687±0．11）与Reelin组（0．666±0．15）无明显差异（P〉0．05）。结论Reelin可增强小鼠海马神经元上的多巴胺D1受体的表达,Reelin上调多巴胺Dl受体的作用并不是依赖Reelin的经典受体ADoER2、VLDLR．其调控机制有待进一步研究。     

抽动秽语综合征汉族患者的执行功能及与多巴胺D4受体第3外显子48bp可重复序列多态性

目的:了解多巴胺D4受体基因第3外显子48bp可重复序列多态性(DRD4 exonIII NTR)与抽动秽语综合征(Gillesdela Tourette syndrome,GTS)患者执行功能缺陷之间的关系。方法:对86例GTS患者进行威斯康星卡片测验(Modified Wisconsin Card sortingtest,WCST)、Stroop色词测验(Strooptest)和连线测验,并和51例正常对照组进行比较;利用PCR技术对GTS患者进行了DRD4exonIII48bpVNTR分析。结果:与正常对照组比较,GTS组在Stroop测验中的C错误数[(44.39±65.3)vs.(20.50±10.85),P0.01]等(包括C纠错数、C时间、CW正确数、CW错误数、CW纠错数和CW时间)、连线测验A时间[(69.80±25.84)vs.(35.69±8.25),P0.01](包括连线B时间、错误数、犯规数)、WCST正确数[(44.39±65.37)vs.(27.49±10.85),P0.01](错误数、持续错误数、非持续错误数和分类数)等测验项目上成绩较差,从共病情况来看,注意缺陷多动综合征共病组在Stroop测验部分项目上比单纯GTS组要差;从GTS组内分析来看,DRD4exonIII48bpVNTR和各神经心理学测验成绩没有关联。结论:抽动秽语综合征患者存在执行功能缺陷,DRD4exonIII48bpVNTR和抽动秽语综合征执行功能缺陷之间可能没有关联。     

多巴胺D4受体和COMT基因多态性在精神分裂症患者攻击行为中的交互作用

目的:讨论多巴胺D4受体(DRD4)基因第3外显子48bp可重复序列多态性(exon Ⅲ 48 bp VNTR)和COMT val158met基因多态性及其交互作用对精神分裂症患者攻击行为的影响.方法:采用修改版外显攻击行为量表(MOAS)对301例精神分裂症患者进行分组,分为伴攻击行为组(研究组)和不伴攻击行为组(对...     

Potential association of DRD2 and DAT1 genetic variation with heroin dependence

The aim of our study was to investigate the potential association of dopamine receptor D2 gene (DRD2) TaqI RFLP A (rs1800497) and dopamine transporter gene (DAT) 3′untranslated region VNTR genetic variations with heroin addiction. Genotyping was performed using PCR-based techniques in 530 heroin abusers and 500 controls. Our results showed that DRD2 TaqI A1 allele carriers (genotypes A1A1 and A1A2) were prone to heroin abuse in models of dominance or co-dominance. We detected a 12 repeat allele and 6/6, 7/9, 9/11, 10/12 genotype in a Chinese/eastern Asian population for the first time. However, no significant differences in the DAT1 VNTR were found between the two groups in either genotypic or allelic distributions and there was no gene interaction between the two genetic loci.     

DRD2/ANKK1 TaqIA and SLC6A3 VNTR polymorphisms in alcohol dependence: association and gene-gene interaction study in a population of Central Italy

Dopamine is a neurotransmitter whose functions are mediated by five receptors expressed in several organs and tissues. Dopaminergic system dysfunctions are involved in the etiology or treatment of several pathological conditions, including drug addiction. Alcohol dependence (AD) is a widespread psychiatric disorder, affecting 5.4% of the general population lifetime. Family and twins studies support the role of a genetic component in AD. Since dopamine neurotransmission has been shown to be involved in drug reward, related genes are plausible candidates for susceptibility to AD. Here, we evaluated both the DRD2/ANKK1 TaqIA (rs1800497) and SLC6A3 40 bp-VNTR SNP and gene-gene interaction analysis in AD patients from a population of Central Italy. The study design was a case-control. In total, 280 alcoholic subjects (213 men and 67 woman) and 280 age- and sex-matched control subjects were recruited for this study. Case subjects met the DSM-IV criteria for AD and they are free from any psychiatric co-morbidities. Controls were subjects who had non-alcohol problem either never drank; those who have smoked at least one pack of cigarettes per day for at least 1 year were excluded. Genotyping was performed by allele-specific PCR and RFLP-PCR. SLC6A3 40 bp 3'UTR-VNTR displays no association with AD. DRD2/ANKK1 TaqIA genotype distribution is significantly associated to AD (O.R.=1.551, p=0.023), with A1* allele displaying an O.R.=1.403 (p=0.029). Gene-gene interaction analysis using three-way contingency table analysis by a log-linear model yielded no significant result. Our study in a population of Central Italy extends and confirms previous results and, for the first time, tested the gene-gene interaction between SLC6A3 and DRD2 in AD.     

Interaction Between DRD2 C957T Polymorphism and An Acute Psychosocial Stressor on Reward-Related Behavioral Impulsivity

The dopamine D2 receptor (DRD2) C957T polymorphism CC genotype is associated with decreased striatal binding of DRD2 and executive function and working memory impairments in healthy adults. We investigated the relationships between C957T and acute stress with behavioral phenotypes of impulsivity in 72 young adults randomly allocated to either an acute psychosocial stress or relaxation induction condition. Homozygotes for 957C showed increased reward responsiveness after stress induction. They were also quicker when making immediate choices on the delay discounting task when stressed, compared with homozygotes who were not stressed. No effects were found for response inhibition, a dimension of impulsivity not related to extrinsic rewards. These data suggest that C957T is associated with a reward-related impulsivity endophenotype in response to acute psychosocial stress. Future studies should examine whether the greater sensitivity of 957C homozygotes to the effects of stress is mediated through dopamine release. Edited by Deborah Finkel.     

Association analysis of polymorphisms in the upstream region of the human dopamine D4 receptor gene (DRD4) with schizophrenia and personality traits

The human dopamine D4 receptor (DRD4) is of major interest in molecular studies of schizophrenia and personality traits. We examined the association of schizophrenia and polymorphisms in the upstream region of the DRD4 gene (−768G>A in the negative modulator region; −521C>T, −376C>T, and −291C>T in the cell type-specific promoter region; and −616C>G between the two regions) in 208 schizophrenic patients and 210 normal controls. No significant difference in genotype and allele frequencies was observed between the two groups, indicating that these polymorphisms do not make a major contribution to the pathogenesis of schizophrenia. We also studied the association of polymorphisms in the upstream region and a 48-bp repeat polymorphism in exon III of the DRD4 gene with personality traits in 173 Japanese individuals who completed the temperament and character inventory (TCI). The −768G>A polymorphism was significantly associated with reward dependence (P = 0.044), while no significant association was observed between novelty seeking and polymorphisms in the upstream region or the exon III repeat polymorphism of the DRD4 gene. Received: August 28, 2000 / Accepted: October 25, 2000     

Association of the -141C Del variant of the dopamine D2 receptor (DRD2) with positive family history and suicidality in German alcoholics.

Several lines of evidence indicate an involvement of the dopaminergic system in alcoholism, withdrawal, suicidality, and attention-deficit hyperactivity disorder (ADHD). The functionally relevant -141C Ins/Del polymorphism located upstream to exon 1 in the 5'-region of the dopamine D2 receptor (DRD2) gene might be an interesting candidate gene. We investigated a sample of 1,126 well-characterized, primary chronic alcoholics of German descent according to a phenotype-genotype strategy, i.e., alcoholics suffering from severe withdrawal complications such as seizure or delirium, family history positive (FH+) alcoholics, alcoholics with an antisocial personality disorder (ASPD), alcoholics with an ADHD, and type 1 or type 2 alcoholics according to Cloninger's typology. Compared to the control subjects, there was a significant excess of the -141C Del allele in alcoholics with a paternal and grandpaternal history of alcoholism and in alcoholic subgroups with suicidality or without a history of withdrawal symptoms. There were no significant differences in allele frequency between the entire group or subgroups of alcoholics and healthy controls. Therefore, the -141C Del variant of the DRD2 might be a protective factor against the development of withdrawal symptoms. However, it might also be a risk factor in a highly burdened subgroup of alcoholics with a paternal and grandpaternal history of alcoholism and it might contribute to the substantially higher likelihood of suicide in alcoholics.     

Dopamine 2 receptor C957T and catechol-o-methyltransferase Val158Met polymorphisms are associated with treatment response in electroconvulsive therapy

Alterations in dopamine levels and dopamine receptors in brain are suggested to be associated with treatment response in electroconvulsive therapy (ECT). Dopamine 2 receptor gene (DRD2) polymorphism C957T (rs6277) and cathechol-o-methyltransferase (COMT) polymorphism Val158Met (rs4680) interaction was studied in 118 patients suffering from major depressive disorder (MDD) treated with ECT and 383 healthy controls. It was found that the combination of COMT Met allele and DRD2 T allele predicted more severe depression in those already affected but did not predict the risk of depression when compared to normal population. The genotype modified the response to ECT. The patients with TT genotype of D2 receptor gene C957T polymorphism combined with COMT gene polymorphism Met/Met genotype did not achieve remission as often as those with CC genotype of DRD2 C957T combined with COMT Val/Val genotype. Thus the interaction of these polymorphisms may be associated with response to ECT.     

Association and synergistic interaction between promoter variants of the DRD4 gene in Japanese schizophrenics

Recent association studies suggest that polymorphisms in the promoter and exon 1 upstream region of the dopamine D4 receptor (DRD4) gene play a functional role in the development of common psychiatric illnesses, although there are also conflicting results. In this study, we re-sequenced this region to identify all genomic variants, and tested them for association with schizophrenia. A total of 570 Japanese schizophrenic cases with matched controls were studied by genotyping all identified/validated common polymorphisms (−1106T>C, −906T>C, −809G>A, −616G>C, −521T>C, −376C>T, −291C>T and 12-bp repeat) and a known microsatellite (120-bp tandem duplication) in the upstream region. A single nucleotide polymorphism (SNP) −809G>A in the promoter region was found to be significantly associated with disease (P=0.018 and 0.032 for allelic and genotypic comparisons, respectively), although not surviving after Bonferroni correction. Logistic regression analysis showed that a combination of the four polymorphisms, −809G>A, −616G>C, −291C>T and the 12-bp repeat, conferred a susceptibility to schizophrenia. These results suggest that the upstream variants have a primary functional effect in the etiology of schizophrenia in the Japanese population. The nucleotide polymorphism data reported is available in the DDBJ/EMBL/GenBank databases under the accession number ss61570833.