GABRA2 & the Pharmacokinetics of Risk for Alcoholism Component

GABRA2与酒精中毒风险的药代动力学 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型效应受到家族酗酒史的调节， 这些影响共同导致了酗酒风险的不同。该项目的长期目标是 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 可以更早地对个人和干预措施进行干预，以减少未来酒精依赖的风险。 在当前的资助周期中，我们用于规定呼吸酒精浓度时程的方法 （BrAC）应用于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）大脑对酒精的敏感性。 酒精暴露的变化。最近，GABRA2基因型已被证明是一个危险因素，酒精 研究表明，大脑对酒精的反应中存在GABRA2效应。因此，我们建议 采用BrAC“钳位”方法研究GABRA2变异对大脑反应的影响， 在有酗酒家族史的背景下饮酒以及其他与更大风险相关的因素 酒精中毒 BrAC钳夹消除了与口服酒精给药相关的实验差异， 对所有受试者来说都能达到相同的恒定的大脑暴露。我们将使用夹持法检查 大脑对酒精的电生理、眼球运动、行为和主观反应 酒精相关的内在表型风险。为了探索遗传影响的可能机制，我们将 在相同的受试者中使用fMRI检查GABRA2基因型和家族病史的影响。 酒精暴露对额叶活动的影响。我们 将对所有受试者的酒精使用障碍症状进行纵向定期评估， 最终验证基因型与酒精相关内表型风险的关联。总的来说，我们 预计GABRA2高风险基因型对酒精反应的影响将更加明显 在有酒精中毒家族史的受试者中， 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.