Clinical-Genetic Variation in GABA /Alcohol Sensitivity

描述(由申请者提供)：NIAAA致力于了解增加酒精中毒易感性的遗传因素。之前的研究表明，父亲酗酒的孩子面临更高的风险，可能是因为对酒精影响的敏感度降低或改变。GABA-A受体a6基因的功能多态性被认为是酒精或苯二氮类药物引起的运动损伤敏感性降低的可能原因。该多态是位于#385位(即Pro385Ser)的Pro到Serine氨基酸的替代。这是一项修订的R21申请，针对之前的审查批评，缩小了这项探索性研究的重点，以更明确地解决Pro385Sera6多态在赋予尚未表现出酗酒或依赖的酗酒父亲的子女对GABA-A复合体的积极调节器的改变药物反应中的作用。该提案应用人类药物遗传学方法对这一假设进行了实验测试，即在21-25岁的男性和女性社交饮酒者中，由于父亲酗酒的家族史而被推定有酗酒风险的人群中，对酒精和苯二氮卓类药物造成的运动损伤的敏感度仍然存在差异，这可以由Pro385Ser多态的存在来解释。此外，我们将探索这种损害的减少是否也可能与醉酒自我报告的减少或增强欣快感或强化效果有关。没有DSM-IV，Axis-I诊断的社交饮酒者，将被选为两组，根据他们是A6亚单位丝氨酸替代等位基因(Pro385Ser)纯合子(Pro/Pro)还是杂合子(Pro/Ser)。在2x5析因混合模型单因素方差分析设计中，来自每一组的参与者将在实验室环境中接受交叉研究，接受安慰剂、乙醇和三唑仑的挑战剂量，在实验室环境中，可以使用研究人员拥有丰富经验的标准技术重复评估主观、运动和行为反应。这项研究将极大地扩展我们对GABA-A阳性调节剂药效作用的功能差异的了解，这些差异可能与同一染色体簇中的a6多态或其他相关基因有关。

DESCRIPTION (provided by applicant): NIAAA is dedicated to understanding the genetic factors that increase vulnerabilIty to alcoholism. Previous research has suggested that children of alcoholic fathers are at increased risk, perhaps because of a reduced or altered sensitivity to the effects of alcohol. A functional polymorphism of the GABA-A receptor a6 gene has been identified as a plausible cause for reduced sensitivity to motor impairment by alcohol or benzodiazepines. The polymorphism is a Proline to Serine amino acid substitution at position #385 (i.e., Pro385Ser). This is a revised R21 application that, in response to previous review critiques, has narrowed the focus of this exploratory study to more certainly address the role of the Pro385Ser a6 polvmorphism in conferring an altered drug response to positive modulators of the GABA-A complex in the children of alcoholic fathers who have not yet exhibited alcohol abuse or dependence. The proposal applies a human pharmacogenetic approach to experimentally test the hypothesis that within the population of male and female social drinkers aged 21-25 years who are presumed at risk for alcoholism because of a Family History of paternal alcoholism, there remain differences in sensitivity to motor impairment from alcohol and benzodiazepines that can be accounted for by the presence of the Pro385Ser polymorphism. Furthermore, we will explore whether this reduced impairment also may be associated with reduced self-reports of intoxication or enhanced euphoric or reinforcing effects. Participants who are social drinkers without a DSM- IV, Axis-I diagnosis, will be selected into two groups based upon whether they are homozygous (Pro/Pro) or heterozygous (Pro/Ser) for the serine-substituted allele (Pro385Ser) of the a6 subunit. In a 2x5 factorial mixed-model ANOVA design, participants from each of these groups will be tested in a crossover study administering challenge doses of placebo, ethanol, and triazolam in a laboratory environment where subjective, motor, and behavioral responses can be repeatedly assessed using standard techniques with which the investigators have a great deal of experience. This study will substantially extend our knowledge of functional differences in the pharmacodynamic effects of GABA-A positive modulators that may be attributable to the a6 polymorphism or other associated genes co-occurring within the same chromosomal cluster.