Synaptic Correlates of Ethanol-Mediated Anxiolysis

描述（由申请人提供）：越来越多的证据表明，乙醇因其积极和消极的强化作用而被使用和滥用，乙醇介导的抗焦虑作用是与乙醇饮用相关的消极强化的重要因素。此外，最近的研究表明，乙醇的负面强化效应随着反复的乙醇暴露和戒断而变得突出，并可能在滥用饮酒的发展和复发中发挥不可或缺的作用。虽然我们对与酒精消耗相关的正强化的神经生理机制了解很多，但对导致许多酒精负强化效应的神经回路却知之甚少。这项建议的首要目标是整合电生理和行为的方法，开始检查一些神经生理机制，可能有助于乙醇的抗焦虑作用。具体而言，这些实验将整合电生理和行为的方法，开始，以解决中央的假设，即乙醇增强GABA能抑制基底外侧核的杏仁核（BLA）有助于特定的措施，乙醇介导的抗焦虑。初步和发表的数据表明，有两个主要的GABA能电路内的BLA介导的旁囊，前馈和本地，反馈抑制到这个核的主要输出细胞。目标1和2将测试乙醇增强两个回路的工作假设，尽管是通过不同的机制。我们还计划利用一种基因工程小鼠，这种小鼠对乙醇的某些急性抗焦虑作用的敏感性增加。通过结合这些基因工程小鼠（目的3）和远交系大鼠（目的4）的行为和离体电生理研究，我们将检验工作假设，即乙醇增强BLA中局部和/或囊旁GABA能抑制与乙醇介导的抗焦虑作用的具体措施之间存在正相关关系。总的来说，这些研究将确定的机制，介导和调节乙醇增强的局部和囊旁GABA能抑制BLA和提供初步了解一些突触机制，可能有助于乙醇的抗焦虑作用。公共卫生相关性：该提案的前两个目标旨在确定乙醇如何增强基底外侧杏仁核（BLA）中的两个不同抑制回路，该大脑区域长期以来被认为在焦虑样行为的调节中发挥不可或缺的作用。目的3和4概述了一种新的策略，该策略整合了行为和电生理方法，开始评估乙醇增强BLA GABA能抑制和乙醇介导的抗焦虑措施之间的关系。这些研究的结果可能会导致更好地了解一些神经生物学机制，有助于乙醇的抗焦虑作用，并可能揭示新的突触元件，可以有针对性地开发更有效的治疗酒精中毒。

DESCRIPTION (provided by applicant): There is a growing body of evidence suggesting that ethanol is used and abused for both its positive and negative reinforcing effects and that ethanol-mediated anxiolysis represents an important element of the negative reinforcement associated with ethanol drinking. Moreover, recent studies have suggested that ethanol's negative reinforcing effects gain salience with repeated ethanol exposure and withdrawal and may play an integral role in the development of, and relapse to, abusive drinking. Although much is known about the neurophysiological mechanisms responsible for the positive reinforcement associated with ethanol consumption, less is known about the neurocircuitry that contributes to many of ethanol's negative reinforcing effects. The overarching goal of this proposal is to integrate electrophysiological and behavioral approaches to begin to examine some of the neurophysiological mechanisms that may contribute to ethanol's anxiolytic effects. Specifically, these experiments will integrate electrophysiological and behavioral approaches to begin to address the central hypothesis that ethanol potentiation of GABAergic inhibition in the basolateral nucleus of the amygdala (BLA) contributes to specific measures of ethanol-mediated anxiolysis. Preliminary and published data suggest that there are two main GABAergic circuits within the BLA that mediate paracapsular, feedforward- and local, feedback-inhibition onto the principal output cells of this nucleus. Aims 1 and 2 will test the working hypothesis that ethanol potentiates both circuits, albeit via distinct mechanisms. We also plan to take advantage of a genetically engineered mouse line with increased sensitivity to some acute anxiolytic effects of ethanol. By combining behavioral and ex vivo electrophysiological studies in these genetically engineered mice (Aim 3) and outbred rats (Aim 4), we will test the working hypothesis that there is a positive relationship between ethanol potentiation of local and/or paracapsular GABAergic inhibition in the BLA and specific measures of ethanol-mediated anxiolysis. Collectively, these studies will identify the mechanisms that mediate and regulate ethanol potentiation of local and paracapsular GABAergic inhibition in the BLA and provide initial insight into some of the synaptic mechanisms that may contribute to ethanol's anxiolytic effects. PUBLIC HEALTH RELEVANCE: The first two aims of this proposal seek to determine how ethanol enhances two distinct inhibitory circuits in the basolateral amygdala (BLA), a brain region that has long been thought to play an integral role in the regulation of anxiety-like behaviors. Aims 3 and 4 outline a novel strategy that integrates behavioral and electrophysiological approaches to begin to assess the relationship between ethanol potentiation of BLA GABAergic inhibition and measures of ethanol-mediated anxiolysis. The results of these studies may lead to a better understanding of some of the neurobiological mechanisms that contribute to ethanol's anxiolytic effects and potentially reveal novel synaptic elements that can be targeted for the development of more effective treatments for alcoholism.