DOPAMINE D2 RECEPTOR GENE MARKERS AND SUBSTANCE ABUSE VULNERABILITY

对基因标记的研究有助于阐明特定的基因 可能与易感性的个体间差异有关 滥用药物。一些研究人员研究酗酒者，但不是所有的调查人员， 表明人类多巴胺D2受体基因的一种特定形式， 在其3‘端有一个RFLP基因标记，可能与 更容易受到酒精中毒的伤害。在本财年，这 实验室已经开发出越来越有力的证据表明 多巴胺D2受体基因可能易受其他 还有令人上瘾的物质。 根据DSMIII-R标准对个人药物滥用的诊断，以及他们的 通过新验证的药物使用评估药物使用的最高生命周期 调查，与TaqI A和B多巴胺D2受体RFLP相关 按标准关联方法进行基因分型。这两个基因标记 在高加索人多物质滥用者中比 在对照种群中。这种关联似乎识别出了第一个 与药物滥用有关的特定基因变异。其他几个功能 可能支持或反对这一假说的DRD2基因座 都已经解决了。在这一年里，频率上的种族差异 DRD2 Taqi A和B RFLP中最初与药物滥用有关的 都得到了确认和延长。存在显著的连锁不平衡现象 发现了这些3‘和5’TaqI RFLP标记。最后，没有明确的目标 在物质滥用者中发现A1或B1频率增加 也是精神变态。 D2受体基因变异可能影响的行为通路 通过评估基因对药物滥用的影响来寻找药物滥用行为 急性心理刺激反应，检查特定的特征 那些具有适当基因型别的人表现出过度的毒瘾， 以及评估吸烟者，他们的环境影响很可能较小 相当可观。

Studies with gene markers can help to elucidate specific genes potentially involved in interindividual differences in vulnerability to substance abuse. Studies alcoholics by some, but not all investigators, indicate that a specific form of the human dopamine D2 receptor gene, marked by an RFLP gene marker at its 3' end, could be associated with increased vulnerability to alcoholism. During this fiscal year, this laboratory has developed increasingly-strong evidence that variants of the dopamine D2 receptor gene could predispose to vulnerability to other addictive substances as well. Individuals' substance abuse diagnoses by DSMIII-R criteria, and their peak lifetime substance use assessed by a newly-validated Drug Use Survey, were correlated with TaqI A and B dopamine D2 receptor RFLP genotypes by standard methods of association. Both of these gene markers were shown to be more prevalent in caucasian polysubstance abusers than in control populations. This association appears to identify the first specific gene variant associated with drug abuse. Several other features of the DRD2 locus that could support or weigh against this hypothesis were addressed. During this year, racial differences in the frequencies of the DRD2 TaqI A and B RFLPs initially associated with substance abuse were confirmed and extended. Substantial linkage disequilibrium between these 3' and 5' TaqI RFLP markers was found. Finally, no clearcut increase in the A1 or B1 frequencies were noted in substance abusers who also were psychopathic. Behavioral pathways whereby a D2 receptor gene variant might influence substance abuse behaviors are being sought by assessing gene effects on acute psychostimulant responses, examining the specific features of addiction displayed in excess by those with the appropriate genotypes, and assessing smokers, in whom environmental influences may well be less substantial.