DOPAMINE D2 RECEPTOR GENE MARKERS AND SUBSTANCE ABUSE VULNERABILITY

基因标记的研究有助于阐明特定的基因 可能涉及个体间的差异， 滥用药物 一些人研究酗酒者，但不是所有的研究者， 表明人类多巴胺D2受体基因的一种特殊形式， 在其3'端有一个RFLP基因标记，可能与 更容易酗酒。 在本财政年度， 实验室已经开发出越来越强有力的证据， 多巴胺D2受体基因可能使人易受他人伤害， 成瘾物质也是。 根据DSMIII-R标准进行的个人物质滥用诊断， 通过新验证的药物使用评估的药物使用高峰期 调查中，均与TaqI A和B多巴胺D2受体RFLP相关 基因型的标准关联方法。 这两个基因标记 在白种人的多种物质滥用者中比在 在控制人群中。 这种关联似乎表明， 与药物滥用相关的特定基因变异。 其他一些功能 DRD 2基因座的位置，可以支持或反对这一假设， 都得到了解决。 在这一年里，种族差异的频率 最初与药物滥用相关的DRD 2 TaqI A和B RFLP 得到了确认和延长。 之间的实质性联系不平衡 这些3'和5' TaqI RFLP标记被发现。最后， A1或B1频率的增加在物质滥用者中被注意到， 也有精神病 D2受体基因变异可能影响的行为途径 药物滥用行为正在通过评估基因对 急性精神刺激反应，检查的具体特点， 具有适当基因型的人表现出过度的成瘾， 评估吸烟者，他们受环境影响可能较小， 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.