Sensitivity to Intravenous Ethanol: Neuroimaging and Behavioral Phenotypes

描述（由申请人提供）：酒精敏感性的个体差异是酒精依赖最广泛研究的内表型之一。然而，人们对酒精敏感性的大脑机制知之甚少。人类酒精敏感性表型的研究通常依赖于自我报告测量和传统的口服酒精给药范式，这两种方法都可能引入相当大的测量误差，从而降低了检测遗传和神经相关因素的灵敏度。拟议的研究将在酒精挑战范式的背景下检查酒精敏感性的神经标志物，该范式包括高度控制的静脉乙醇输注。本提案的广泛目标包括a)发展我们整合fMRI和输液的方法；B)检查在这种情况下研究酒精敏感性的神经相关因素的可行性；c)估计效应大小，为未来研究的功率分析提供信息。酗酒的年轻人将参加两个输注阶段：基线“适应”阶段和功能磁共振成像阶段。基于生理的药代动力学（PBPK）模型将用于在15分钟内建立峰值目标血液酒精浓度（BAC）为0.06 1 0.005 g%。将BAC保持（夹紧）90分钟。酒精敏感性指数将包括传统的自我报告测量；输液时心率反应；在整个过程中对主观中毒（刺激/镇静）进行一系列测量。我们将在涉及激励动机和认知控制网络的任务中检查与BOLD反应相关的这些指标，并在BAC时间过程中进行重复评估。传统的和基于大脑的酒精敏感性测量方法将与自我报告的饮酒有关。通过检查急性酒精暴露背景下的神经表型，我们希望确定基于大脑的酒精敏感性表型，与传统测量相比，这种表型对遗传变异和行为结果可能更敏感。)

DESCRIPTION (provided by applicant): Individual variability in alcohol sensitivity is among the most widely studied endophenotypes for alcohol dependence. However, little is known about brain mechanisms relevant for alcohol sensitivity. Research on human alcohol sensitivity phenotypes has often relied on self-report measures and conventional oral alcohol administration paradigms, both of which may introduce considerable measurement error, thus decreasing sensitivity for detecting genetic and neural correlates. The proposed study will examine neural markers of alcohol sensitivity in the context of an alcohol challenge paradigm that incorporates highly controlled intravenous ethanol infusion. The broad aims of this proposal include a) developing our approach for integrating fMRI and infusion; b) examining feasibility of studying neural correlates of alcohol sensitivity in this context; and c) estimating effect sizes to inform power analyses for future studies. Heavy-drinking young adults will participate in two infusion sessions: a baseline "acclimation" session and an fMRI session. Physiologically- Based Pharmacokinetic (PBPK) modeling will be used to establish a peak target blood alcohol concentration (BAC) of 0.06 1 0.005 g% within 15 minutes. This BAC will be maintained (clamped) for 90 minutes. Alcohol sensitivity indices will include traditional self-report measures; heart rate response during infusion; and serial measures of subjective intoxication (stimulation/sedation) across the session. We will examine these indicators in relation to BOLD responses during tasks that engage incentive motivation and cognitive control networks, incorporating repeated assessments across the BAC time course. Both traditional and brain-based measures of alcohol sensitivity will be examined in relation to self-reported drinking. By examining neural phenotypes in the context of acute alcohol exposure, we hope to identify brain-based alcohol sensitivity phenotypes that are potentially more sensitive to genetic variation and to behavioral outcomes as compared to traditional measures. ) PUBLIC HEALTH RELEVANCE: Physiological sensitivity to alcohol is demonstrated to predict future risk for alcohol dependence. However, little is known about brain mechanisms relevant for alcohol sensitivity. This research aims to examine brain-based measures of alcohol sensitivity that could be useful as biomarkers for the risk for alcohol dependence.