GABRA2 & the Pharmacokinetics of Risk for Alcoholism Component

GABRA2与酒精中毒危险性的药代动力学 假设：一个人的GABRA2基因的基因型会影响人类大脑的初始和 对酒精的适应性反应。这种基因效应受酗酒家族史的影响，而且 这些影响共同导致了不同的酗酒风险。这个项目的长期目标是 阐明与大脑对酒精的反应有关的因素，这些因素会使一些人面临更大的风险 酗酒和与酒精有关的问题。在未来，可以开发检测方法来识别高风险 可以更早地启动个人和干预措施，以降低未来酒精依赖的风险。 在目前的资助周期中，我们规定呼气酒精浓度的时间进程的方法 (BRAC)被用来检测酒精依赖家族史与(A) 戒酒一周后大脑对酒精反应的变化，以及(B)大脑对酒精的敏感度 酒精暴露的变化。最近，GABRA2基因被证明是酒精的一个危险因素 依赖，研究表明，大脑对酒精的反应中存在GABRA2效应。因此，我们建议 用BRAC“钳制”方法研究GABRA2基因变异对大脑对 在有酗酒家族史和其他与更大风险相关的因素的背景下 酗酒。 阻断BRAC消除了与口服酒精给药相关的实验差异，并 为所有受试者实现相同的、持续的脑暴露。我们将使用夹持法来检查 大脑对潜在酒精的电生理、眼球运动、行为和主观反应 与酒精相关的风险内表型。为了探索基因影响的可能机制，我们将 在相同的受试者中使用功能磁共振成像来检查GABRA2基因和家族史的影响 酒精暴露被夹住时，酒精中毒对2个运动去抑制任务中额叶活动的影响。我们 将启动对所有受试者酒精使用障碍症状的纵向、定期评估，以便 最终验证基因与酒精相关的风险内表型之间的关联。总体而言，我们 预计GABRA2高危基因对酒精反应的影响将更加明显 在有阳性酗酒家族史的受试者中，会加速与酒精有关的发病 有问题。

GABRA2 and the Pharmacokinetics of Risk for Alcoholism Hypothesis: An individual's genotype at the GABRA2 gene influences the human brain's initial and adaptive responses to alcohol. This genotypic effect is modulated by a family history of alcoholism, and together these effects contribute to a differential risk for alcoholism. The long term goal of this project is to elucidate factors related to the brain's response to alcohol that place some individuals at greater risk for alcoholism and alcohol-related problems. In the future, assays could be developed to identify high-risk individuals and interventions could be initiated earlier to decrease the risk of future alcohol dependence. In the current grant cycle, our methods for prescribing the time-course of breath alcohol concentration (BrAC) were applied to detect an association between a family history of alcohol dependence and (a) changes in the brain's response to alcohol following a week of abstinence, and (b) brain sensitivity to the rate of change of alcohol exposure. Recently, GABRA2 genotype has been shown to be a risk factor for alcohol dependence, and research suggests a GABRA2 effect in the brain's response to alcohol. Thus, we propose to employ BrAC "clamping" methods to study the effects of variation in GABRA2 on the brain's responses to alcohol in the context of a family history of alcoholism and other factors associated with greater risk for alcoholism. BrAC clamping eliminates the experimental variance associated with oral alcohol administration and achieves the same, constant brain exposure for all subjects. We will use the clamping method to examine the brain's electrophysiological, eye-movement, behavioral, and subjective responses to alcohol as potential alcohol-related endophenotypes of risk. To explore a possible mechanism of genetic influence, we will employ fMRI in the same subjects to examine the effect of GABRA2 genotype and a family history of alcoholism on frontal lobe activity during 2 motor disinhibition tasks while alcohol exposure is clamped. We will initiate longitudinal, periodic assessment of all subjects for symptoms of alcohol use disorders in order to eventually validate the association of genotype with alcohol-related endophenotypes of risk. Overall, we expect that the influences of the GABRA2 high-risk genotype on responses to alcohol will be more apparent in subjects with a positive family history of alcoholism, and will accelerate the onset of alcohol-related problems.