Proteomic Approaches to Alcoholism

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导致从非依赖酒精使用向酒精中毒的转变，以及什么持续变化调节复发。本提案的目标是开始探索导致酒精升高的神经生物学机制，并开始确定复发的机制。 为了实现这些目标，我们将检验以下假设： 1)足够的酒精暴露会导致杏仁核延伸部分的特定元素发生变化，这些元素会在享乐设定点产生升高。反过来，这会导致酒精摄入量逐渐增加，并在禁欲期间复发的倾向。 2)乙醇自身给药与被动给药相结合会引起蛋白质表达水平和功能的变化，这比单独被动给药更具成瘾过程的特征。 为了验证这些假设，我们提出了以下具体目标的研究： 1)研究酒精依赖对蛋白质表达和修饰的影响，重点研究与酒精强化相关的变化。 2)确定与再次接触乙醇时易复发相关的蛋白质表达和修饰的长期变化。 我们提议的尖端行为、神经解剖学和蛋白质组学方法的组合将允许识别重要的分子靶点，这些分子靶点应该能够开发出更具体和有效的药物治疗方法，帮助阻止酒精成瘾的过程，并防止酒精中毒患者的复发。

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 begin to explore the neurobiological mechanisms responsible for alcohol escalation and to begin to define the mechanisms responsible for 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 molecular targets 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.