HUMAN DOPAMINERGIC GENES AND SUBSTANCE ABUSE VULNERABILITY

人类和动物之间存在很大的个体差异， 对滥用药物的行为、生理和毒理反应。 人类对药物行为反应的个体差异似乎 显示出巨大的遗传影响，尽管这些影响可能是 由几个基因提供。家庭研究表明，一些严重的 药物滥用中基于谱系的联系方法的局限性， 这表明关联研究可能更有成效。 使用 等位基因关联方法也要求仔细检查 群体的种族差异和特定条件下的连锁不平衡 可以混淆这些方法的位点。 在几个不同的多态性标记的关联研究 多巴胺能基因座可以检验个体间的假设 多巴胺能神经传递基因的差异 药物滥用易感性的个体间差异。 在本财政年度，该实验室继续发展 有证据表明，多巴胺D2受体基因的变异， 特异性TaqI RFLP多态性标记，易受 吸毒 这项工作是伴随着工作记录种族和 这些标记频率的种族差异，以及惊人的， 三个标记之间的连锁不平衡的特定模式， D2受体基因座。有趣的是，精神变态的药物滥用者 显示基因标记频率不高于那些表现为 精神正常的吸毒者 多巴胺转运蛋白RFLP或VNTR多态性标记的研究 突触囊泡单胺转运体位点未能揭示 在许多相同的研究对象中的等位基因关联。 然而，在这方面， 在D2受体基因位点发现的显著连锁不平衡 至少有几个多巴胺转运蛋白位点不存在 标记，使得它们对于可能的等位基因的报道不那么有效。 这些多巴胺能基因的变异。

There are large individual differences among humans and animals in behavioral, physiological and toxicological responses to drugs of abuse. Individual differences in human behavioral responses to drugs appear to display substantial genetic influences, although these influences may be provided by several genes. Family studies suggest several severe limitations to pedigree-based linkage approaches in drug abuse, suggesting that association studies might be more fruitful. Use of allelic association approaches also mandated careful examination of ethnic differences in populations and linkage disequilibrium at specific loci that can confound these approaches. Association studies with polymorphic markers at several different dopaminergic gene loci can test the hypothesis that interindividual differences in genes of dopaminergic neurotransmission could contribute to interindividual differences in vulnerability to substance abuse. During this fiscal year, this laboratory has continued to develop evidence that variants of the dopamine D2 receptor gene, marked by specific TaqI RFLP polymorphic markers, predispose to vulnerability to drug abuse. This work is accompanied by work documenting racial and ethnic differences in these marker frequencies, as well as striking and specific patterns of linkage disequilibrium across three markers at the D2 receptor gene locus. Interestingly, psychopathic substance abusers display gene marker frequencies no higher than those manifest by nonpsychopathic drug abusers. Studies of RFLP or VNTR polymorphic markers at the dopamine transporter and synaptic vesicular monoamine transporter loci failed to reveal allelic association in a number of the same research subjects. However, the striking linkage disequilibrium found at the D2 receptor gene locus does not exist for at least several of the dopamine transporter locus markers, rendering them less effective reporters for possible allelic variants in these dopaminergic genes.