Synaptic Correlates of Ethanol-Mediated Anxiolysis

描述(由申请人提供)：越来越多的证据表明，乙醇被使用和滥用是因为其积极和消极的强化作用，而乙醇介导的焦虑缓解是与饮酒相关的消极强化的重要因素。此外，最近的研究表明，酒精的负面强化作用随着反复接触和戒酒而变得突出，并可能在酗酒的发展和复发中发挥不可或缺的作用。尽管人们对酒精摄入引起的积极强化的神经生理学机制了解很多，但对导致乙醇许多负面强化作用的神经回路却知之甚少。这项提议的首要目标是整合电生理学和行为学方法，开始研究可能有助于乙醇抗焦虑作用的一些神经生理学机制。具体地说，这些实验将整合电生理和行为方法，以开始解决这一中心假设，即酒精增强杏仁基底外侧核(BLA)中的GABA能抑制有助于乙醇介导的焦虑缓解的特定措施。初步和已发表的数据表明，在BLA内有两个主要的GABA能回路，它们将包囊旁、前馈和局部反馈抑制介导到该核的主要输出细胞上。目标1和目标2将测试乙醇增强这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品系，该品系对乙醇的一些急性缓解焦虑作用具有更高的敏感度。通过结合这些基因工程小鼠(AIM 3)和杂交大鼠(AIM 4)的行为和体外电生理学研究，我们将检验工作假设，即在BLA中局部和/或包囊旁GABA能抑制的乙醇增强与乙醇介导的焦虑缓解的具体措施之间存在正相关关系。总之，这些研究将确定介导和调节乙醇增强BLA中局部和囊旁GABA能抑制的机制，并为可能有助于乙醇抗焦虑作用的一些突触机制提供初步的见解。与公共健康相关：这项提案的前两个目标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，杏仁基底外侧核是大脑的一个区域，长期以来一直被认为在调节类焦虑行为方面发挥着不可或缺的作用。目标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，以开始评估乙醇增强BLA GABA能抑制和乙醇介导的焦虑缓解措施之间的关系。这些研究的结果可能有助于更好地理解乙醇缓解焦虑的一些神经生物学机制，并可能揭示新的突触元件，这些突触元件可以作为开发更有效的酒精中毒治疗方法的靶点。

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.