Synaptic Correlates of Ethanol-Mediated Anxiolysis

描述（由申请人提供）：越来越多的证据表明，乙醇的使用和滥用既有积极的强化作用，也有消极的强化作用，乙醇介导的焦虑缓解是与酒精饮酒相关的消极强化的一个重要因素。此外，最近的研究表明，乙醇的负强化效应随着反复接触乙醇和戒断而变得突出，并可能在滥用饮酒的发展和复发中发挥不可或缺的作用。尽管我们对与乙醇消耗相关的正强化作用的神经生理机制了解甚多，但对导致许多乙醇负强化作用的神经回路了解甚少。本提案的首要目标是整合电生理和行为方法，开始研究一些可能有助于乙醇抗焦虑作用的神经生理机制。具体来说，这些实验将结合电生理和行为方法，开始解决核心假设，即乙醇增强杏仁核基底外侧核（BLA） gaba能抑制有助于酒精介导的焦虑缓解的具体措施。初步和已发表的数据表明，在BLA内有两种主要的gaba能回路，它们介导对该核主要输出细胞的囊旁前馈和局部反馈抑制。目标1和目标2将测试乙醇增强这两个回路的假设，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系，使其对乙醇的某些急性抗焦虑作用更加敏感。通过结合这些基因工程小鼠（Aim 3）和远交种大鼠（Aim 4）的行为和离体电生理研究，我们将验证乙醇增强BLA局部和/或包膜gaba能抑制与乙醇介导的焦虑缓解的具体措施之间存在正相关的工作假设。总的来说，这些研究将确定介导和调节乙醇增强BLA局部和囊旁gaba能抑制的机制，并初步了解一些可能有助于乙醇抗焦虑作用的突触机制。公共卫生相关性：该提案的前两个目的是试图确定乙醇如何增强基底外侧杏仁核（BLA）中的两个不同的抑制回路，这是一个长期以来被认为在调节焦虑样行为中起着不可或缺作用的大脑区域。目的3和4概述了一种整合行为和电生理方法的新策略，开始评估乙醇增强BLA - gaba能抑制与乙醇介导的焦虑缓解之间的关系。这些研究的结果可能会导致更好地理解一些神经生物学机制，这些机制有助于乙醇的抗焦虑作用，并可能揭示新的突触元件，这些元件可以作为开发更有效的酒精中毒治疗的目标。

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.