GENETIC APPROACHES TO CHARACTERIZING DRUG RESPONSES AND VULNERABILITIES

药物滥用脆弱性存在很大的个体差异 在人类中，可能会显示遗传以及 环境组成部分。 在本财年，这些调查人员 继续探索等位基因变异在候选人中的可能作用， 基因位点可能导致人类个体差异， 药物滥用的脆弱性，并建立基因组 扫描方法来识别以前未预料到的基因 赋予了滥用药物的脆弱性。 这项工作揭示了 多巴胺转运蛋白和D2多巴胺的连锁不平衡 受体基因座和侧翼基因标记，允许改善 对初始阳性关联结果的实质性解释 滥用，与可卡因使用相关的偏执狂，以及注意力 缺陷/多动障碍，这是一种严重的药物滥用 科摩罗。 它使人们更加关注以前的特征- 据报道，寻求新奇和DRD 4多态性之间存在关联。 它鉴定了一种与以下疾病高度相关的COMT功能变体： 药物滥用的脆弱性。 它没有显示任何关联， DRD 3基因座的候选标记。 这些工人帮助研究 药物滥用的诊断标准， 大量遗传和那些显示大量环境 影响，并建立了受影响的同胞对策略， 允许定位鉴定等位基因的方法， 人的药物滥用脆弱性。 我们已经从一项持续的研究中得出了结果， 作为药物滥用的候选基因参与多巴胺功能 相关行为。除了一个非常显著的差异外， 表现出大量吸毒的药物滥用者与 儿茶酚-O-甲基转移酶（COMT）药物使用率低的患者 轨迹，我们发现物质之间也存在差异， 滥用者和对照个体的多巴胺受体等位基因 D4。 D4基因的等位基因编码的受体在以下方面表现出差异： 它们与cAMP第二信使系统偶联的能力， 提供多巴胺能基因的第二种功能多态性。 我们发现长形式的频率显著增加 与对照组相比，药物滥用者的D4 VNTR。 进一步 分析表明，COMT和D4等位基因的相互作用， 至少是加性的，这表明具有高COMT和 长型D4受体可能有更大的风险， 虐待 与保罗·科斯塔博士的另一次合作， 国家老龄研究所老年学研究中心 研究了D4基因与 追求新奇 我们没能复制一个 这种关联最初是由以色列和NIH的报告提出的。 这项工作补充了我们对潜在遗传学的研究， 药物滥用易感性的个体间差异。

There are large individual differences in drug abuse vulnerabilities among humans that are likely to display genetic as well as environmental components. During this FY, these investigators continued to explore possible roles of allelic variants at candidate gene loci in possibly contributing to human individual differences in drug abuse vulnerability, and to establish groundwork for genome scanning approaches to identifying previously-un-anticipated genes conferring drug abuse vulnerabilities. This work revealed patterns of linkage disequilibrium at the dopamine transporter and D2 dopamine receptor gene loci and with flanking gene markers that allows improved interpretation of initially-positive association findings in substance abuse, the paranoia associated with cocaine use, and in attention deficit/hyperactivity disorder, which is a significant drug-abuse comorbidity. It sharpened attention to features of a previously- reported association between novelty-seeking and DRD4 polymorphisms. It identified a COMT functional variant highly associated with substance abuse vulnerability. It revealed no association with candidate markers at the DRD3 locus. These workers aided studies of the diagnostic criteria for drug abuse that appear to display substantial genetic and those that display substantial environmental influences, and established affected-sib pair strategies that would allow approaches to positional identification of alleles that enhance drug abuse vulnerability in man. We have generated results from a continuing study to analyze genes involved in dopamine function as candidates genes for substance abuse related behavior. In addition to a highly significant difference between substance abusers exhibiting high quantities of drug use and those with low drug use at the Catechol-O-Methyltransferase (COMT) locus, we find that a difference also exists between the substance abusers and control individuals for alleles of the dopamine receptor D4. Alleles at the D4 gene encode receptors that show differences in their ability to couple to the cAMP second messenger system, and thus provide a second functional polymorphism in the dopaminergic genes. We have found a significant increase in the frequency of the long forms of the D4 VNTR in substance abusers compared to controls. Further analysis showed that the interaction of the COMT and D4 alleles that is at least additive, suggesting that individuals with high COMT and the long form of the D4 receptor may be at greater risk of substance abuse. An additional collaboration with Dr. Paul Costa, next door at the Gerontology Research Center, National Institute on Aging investigated the possibility of an association of the D4 gene and novelty seeking. We have failed to replicate the findings of an association that was first suggested by reports from Israel and NIH. This work compliments our studies of the underlying genetics of the inter-individual differences in susceptibility to substance abuse.