Brain Biomarkers of Alcoholism and Abstinence

描述（由申请人提供）：改善酒精中毒治疗的关键问题是什么神经生物学变化负责从非依赖性酒精使用到酒精中毒的过渡，以及什么持续的变化介导复发。本提案的目标是描绘大脑生物标志物，指示负责酒精升级的神经生物学机制，并定义与复发相关的大脑生物标志物。为了实现这些目标，我们将测试以下假设：1）充分接触酒精会导致扩展杏仁核特定元素的变化，从而提高享乐设定点。反过来，这会导致酒精摄入量的逐步增加和禁欲期间复发的倾向。2)自我管理的乙醇加上被动管理导致蛋白质的表达水平和功能的变化比被动管理单独的成瘾过程的特征。为了验证这些假设，我们提出了以下具体目的的研究：1）研究乙醇依赖对蛋白质表达和修饰的影响，重点是与乙醇强化相关的变化。2)确定与再次暴露于乙醇后复发的脆弱性相关的蛋白质表达和修饰的长期变化。我们提出的尖端行为，神经解剖学和蛋白质组学方法的组合将允许识别重要的生物标志物，这些生物标志物应该能够开发更具体和有效的药物治疗，以帮助阻止酒精成瘾的过程并防止酒精中毒患者复发。

DESCRIPTION (provided by applicant): Critical issues for improving the treatment of alcoholism are what neurobiological changes are responsible for the transition from non-dependent alcohol use to alcoholism, and what persistent changes mediate relapse. The goals of the present proposal are to delineate brain biomarkers that indicate the neurobiological mechanisms responsible for alcohol escalation and to define brain biomarkers associated with relapse. To achieve these goals, we will test the following hypotheses: 1) Sufficient exposure to alcohol leads to changes in specific elements of the extended amygdala that produce elevations in the hedonic set point. In turn, this leads to progressive elevation in ethanol intake and a propensity to relapse during abstinence. 2) Self-administration of ethanol coupled with passive administration causes changes in protein expression levels and function more characteristic of the addictive process than passive administration alone. To test these hypotheses, we propose studies with the following Specific Aims: 1) To examine the effects of ethanol dependence on protein expression and modification with a focus on changes associated with ethanol reinforcement. 2) To determine long-lasting changes in protein expression and modification associated with vulnerability to relapse upon re-exposure to ethanol. Our proposed combination of cutting-edge behavioral, neuroanatomical, and proteomic approaches will permit the identification of important biomarkers that should enable the development of more specific and effective pharmacotherapy both to help block the process of alcohol addiction and prevent relapse in those suffering from alcoholism.