Role of Amygdala Glutamate in Tolerance to the Aversive Effects of Ethanol

描述（由申请人提供）：乙醇耐受性是一种复杂的现象，包括广泛的乙醇诱导过程。乙醇耐受性在维持过度饮酒行为中的作用，从而可能导致乙醇依赖的发展仍有待确定。本申请中提出的研究响应了RFA (AA-08-009)，因为它们测试了一个新的假设，该假设与乙醇依赖背景下对乙醇厌恶特性的耐受性的作用有关。更具体地说，我们认为对乙醇的厌恶特性产生了耐受性，而这种耐受性反过来又维持了依赖动物的过度饮酒。此外，我们假设对乙醇厌恶特性耐受的潜在机制与基底外侧杏仁核（BLA）中谷氨酸能神经传递的神经适应有关。我们的总体研究策略和方法包括采用一种具有良好特征的乙醇依赖小鼠模型，该模型可靠地产生过多的自愿乙醇消费。使用该模型，研究将进行：(a)检查对乙醇厌恶特性的耐受性，定义为对乙醇诱导的条件味觉厌恶的敏感性降低（具体目标1）；(b)测量基础水平和乙醇刺激BLA细胞外谷氨酸水平的能力（特异性目的II）；(c)研究直接操纵BLA谷氨酸能神经传递对乙醇依赖和非乙醇依赖小鼠酒精诱导的条件性味觉厌恶和饮酒行为的影响（Specific Aim III）。这一发现将填补文献中关于谷氨酸在BLA对乙醇不良后果耐受中的作用的空白，并应该描绘出过量乙醇消费风险增加和依赖相关复发增加的潜在联系。

DESCRIPTION (provided by applicant): Ethanol tolerance is a complex phenomenon that encompasses a wide range of ethanol-induced processes. The role of ethanol tolerance in sustaining excessive drinking behavior that consequently can lead to the development of ethanol dependence remains to be determined. Studies proposed in this application are responsive to the RFA (AA-08-009) in that they test a novel hypothesis related to the role of tolerance to the aversive properties of ethanol in the context of ethanol dependence. More specifically, we propose that tolerance develops to the aversive properties of ethanol and that this tolerance, in turn, maintains excessive drinking in dependent animals. Moreover, we hypothesize that an underlying mechanism for tolerance to the aversive properties of ethanol relates to neuroadaptation in glutamatergic neurotransmission in the basolateral amygdala (BLA). Our overall research strategy and approach involves employing a well-characterized mouse model of ethanol dependence that reliably produces excessive voluntary ethanol consumption. Using this model, studies will be conducted to: (a) examine tolerance to the aversive properties of ethanol, as defined by reduced sensitivity to ethanol-induced condition taste aversion (Specific Aim I); (b) measure basal levels and the capacity for ethanol to stimulate extracellular levels of glutamate in the BLA (Specific Aim II); and (c) examine the effects of direct manipulation of BLA glutamatergic neurotransmission on ethanol-induced conditioned taste aversion and drinking behavior (Specific Aim III) in ethanol dependent and non-dependent mice. The findings will fill a general void in the literature regarding the role of glutamate in the BLA for tolerance to the aversive consequences of ethanol, and should delineate a potential link to increased risk for excessive ethanol consumption and increased relapse associated with dependence. PUBLIC HEALTH RELEVANCE: Tolerance to the aversive properties of alcohol may facilitate increased consumption that, in turn, can lead to the development of dependence along with sustained excessive drinking. Using an animal model of alcohol dependence and drinking, we aim to advance knowledge regarding factors and mechanisms associated with tolerance and dependence that promote excessive drinking behavior. Further discovery about mechanisms underlying tolerance to the aversive properties of alcohol in animals may lead to a better understanding of alcohol tolerance and dependence in humans and, ultimately, better treatment strategies and outcomes for those suffering with alcohol dependence.