ALCOHOL CHALLENGE

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 酒精滥用和依赖是重要的公共卫生问题。继承（即，遗传）风险因素被认为在酒精使用障碍的发展中是重要的。最近的酒精依赖的遗传因素的家庭为基础的病例对照研究表明，GABA-A基因，GABRA 2，变异与酒精依赖。我们对人类酒精挑战研究的初步结果表明，GABRA 2的变异也会影响酒精的主观效应，这表明该基因可能影响酒精依赖风险的潜在机制。基于这些初步数据，本研究的目的是：1）检查酒精对30名社交饮酒者对急性酒精给药反应的多个领域的影响; 2）检查GABRA 2基因型对急性酒精给药反应的这些主观测量的调节作用。我们假设，在BrAC的上升肢，酒精的刺激和奖励作用将由GABRA 2基因型调节，这样，在SNP rs 279858（GABRA 2的内含子标记）的A等位基因纯合的个体将显示出比酒精依赖相关的G等位基因携带者对酒精的影响更大的反应。相比之下，酒精的其他影响，如镇静，运动不协调和认知能力下降（后两者分别通过静态共济失调和工作记忆测量），将不受GABRA 2基因型的影响，因为这些影响更可能涉及含有GABA-A <$-1亚基的受体的调节。确定特定的遗传决定因素的变化的质量或规模的反应，酒精可能有助于我们理解为什么有些人是脆弱的，或保护，酒精依赖。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Alcohol abuse and dependence are important public health problems. Inherited (i.e., genetic) risk factors are thought to be important in the development of alcohol use disorders. Recent family-based and case-control studies of genetic factors in alcohol dependence indicate that variation in the GABA-A gene, GABRA2, is associated with alcohol dependence. Our preliminary results from alcohol challenge studies in humans suggest that variation in GABRA2 also influences the subjective effects of alcohol, suggesting a potential mechanism by which the gene may influence risk of alcohol dependence. Based on these preliminary data, the aims of this study are to: 1) examine the effect of alcohol on multiple domains of the response to acute alcohol administration in 30 social drinkers and to 2) examine the moderating effect of GABRA2 genotype on these subjective measures in response to acute alcohol administration. We hypothesize that, during the ascending limb of the BrAC, the stimulating and rewarding effects of alcohol will be moderated by GABRA2 genotype, such that individuals who are homozygous for the A-allele at SNP rs279858 (an intronic marker in GABRA2) will show a greater response to the effects of alcohol than will carriers of the alcohol-dependence-associated G-allele. In contrast, other effects of alcohol, such as sedation, motor incoordination, and decreased cognitive performance (the latter two measured by static ataxia and working memory, respectively), will not be influenced by GABRA2 genotype, as these effects are more likely to involve modulation of receptors containing the GABA-A ¿-1 subunit. The identification of specific genetic determinants for variation in the quality or magnitude of responses to alcohol may help in our understanding of why some individuals are vulnerable to, or protected from, alcohol dependence.