Clinical-Genetic Variation in GABA /Alcohol Sensitivity

描述（由申请人提供）：NIAAA致力于了解增加酒精中毒易感性的遗传因素。先前的研究表明，父亲酗酒的孩子患病风险更高，这可能是因为父亲对酒精的敏感性降低或改变了。GABA-A受体a6基因的功能多态性已被确定为酒精或苯二氮卓类药物对运动损伤敏感性降低的合理原因。多态性是385号位置（即Pro385Ser）的脯氨酸到丝氨酸氨基酸取代。这是一份修订后的R21申请，作为对先前评论的回应，缩小了本探索性研究的重点，以更确定地解决Pro385Ser a6多态性在赋予尚未表现出酒精滥用或依赖的酗酒父亲的孩子对GABA-A复合物阳性调节剂的药物反应改变中的作用。该建议采用人类药物遗传学方法，通过实验验证以下假设：在21-25岁的男性和女性社交饮酒者人群中，由于父亲有酗酒家族史而被认为有酗酒风险，他们对酒精和苯二氮卓类药物引起的运动损伤的敏感性仍然存在差异，这可以通过Pro385Ser多态性的存在来解释。此外，我们将探讨这种减少的损伤是否也可能与减少的中毒自我报告或增强的欣快或强化效应有关。没有DSM- IV，轴i诊断的社交饮酒者将根据a6亚基的丝氨酸取代等位基因（Pro385Ser）的纯合（Pro/Pro）或杂合（Pro/Ser）被选择为两组。在2x5析因混合模型方差分析设计中，每一组的参与者将在交叉研究中进行测试，在实验室环境中给予安慰剂、乙醇和三唑仑的挑战剂量，在实验室环境中，可以使用调查者具有丰富经验的标准技术反复评估主观、运动和行为反应。这项研究将大大扩展我们对GABA-A阳性调节剂的药效学作用的功能差异的认识，这可能是由于a6多态性或在同一染色体簇内共同发生的其他相关基因。

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.