Clinical-Genetic Variation in GABA /Alcohol Sensitivity

GABA /酒精敏感性的临床遗传变异

• 批准号: 6544629
• 负责人: JOHN D ROACHE
• 金额: $ 13.34万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-05 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6544629
• 关键词: GABA receptor; alcoholic beverage consumption; alcoholism /alcohol abuse; behavior test; behavioral /social science research tag; behavioral habituation /sensitization; benzodiazepines; breath tests; caucasian American; clinical research; ethanol; euphoria; family genetics; gamma aminobutyrate; genetic polymorphism; genetic susceptibility; genotype; human subject; patient oriented research; pharmacogenetics; pharmacokinetics; questionnaires; reinforcer; triazolam; young adult human (21-34)

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.

描述（由申请人提供）：NIAAA致力于了解增加酒精中毒易发性的遗传因素。先前的研究表明，酗酒父亲的孩子风险增加，可能是因为对酒精影响的敏感性降低或改变。GABA-A受体α 6基因的功能多态性已被确定为对酒精或苯二氮卓类药物引起的运动损伤敏感性降低的合理原因。多态性是在位置#385处的脯氨酸至丝氨酸氨基酸取代（即，Pro385Ser）。这是一项修订的R21申请，为了响应先前的审查批评，缩小了这项探索性研究的重点，以更确定地解决Pro385 Ser α 6多态性在尚未表现出酒精滥用或依赖的酗酒父亲的子女中赋予对GABA-A复合物正调节剂的药物应答改变的作用。该提案采用人类药物遗传学方法，以实验方式检验假设，即在年龄为21-25岁的男性和女性社交饮酒者人群中，由于父亲酗酒家族史而被认为存在酗酒风险，对酒精和苯二氮卓类药物引起的运动障碍的敏感性仍然存在差异，这可以通过Pro385 Ser多态性的存在来解释。此外，我们将探讨这种减少的损害是否也可能与减少自我报告的中毒或增强欣快或强化效果。 没有DSM-IV、Axis-I诊断的社交饮酒者的参与者将基于他们对于α 6亚基的丝氨酸取代的等位基因（Pro 385 Ser）是纯合的（Pro/Pro）还是杂合的（Pro/Ser）被选择成两组。在2x 5析因混合模型ANOVA设计中，将在交叉研究中对每组受试者进行测试，在实验室环境中给予安慰剂、乙醇和三唑仑激发剂量，其中可以使用研究者具有丰富经验的标准技术重复评估主观、运动和行为反应。本研究将大大扩展我们对GABA-A阳性调节剂药效学作用的功能差异的认识，这些功能差异可能归因于α 6多态性或在同一染色体簇内共发生的其他相关基因。