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。酒精耐受在维持过度饮酒行为中的作用仍有待确定，过度饮酒行为可能导致酒精依赖的发展。本申请中提出的研究是对RFA(AA-08-009)的响应，因为它们测试了一个新的假说，该假说与在乙醇依赖的背景下对乙醇的厌恶特性的耐受性的作用有关。更具体地说，我们认为耐受性发展到乙醇的厌恶特性，而这种耐受性反过来又维持依赖动物的过度饮酒。此外，我们假设，对酒精厌恶特性的耐受的潜在机制与杏仁基底外侧核(BLA)谷氨酸能神经传递的神经适应有关。我们的整体研究策略和方法包括使用一个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。利用这一模型，将进行以下研究：(A)检测对乙醇的厌恶特性的耐受性，其定义是对酒精诱导的条件味觉厌恶的敏感度降低(特定目标一)；(B)测量酒精的基础水平和其刺激白血球细胞外谷氨酸水平的能力(特定目标二)；以及(C)检测直接操纵BLA谷氨酸能神经传递对酒精诱导的条件性味觉厌恶和饮酒行为的影响(特定目标三)。这些发现将填补文献中关于谷氨酸在BLA中对乙醇不良后果的耐受性所起作用的普遍空白，并应描绘出与过量摄入乙醇的风险增加和与依赖相关的复发增加的潜在联系。 与公共健康相关：对酒精令人厌恶的特性的容忍可能会促进消费的增加，而这反过来又可能导致依赖的发展以及持续的过度饮酒。利用酒精依赖和饮酒的动物模型，我们的目标是促进对促进过度饮酒行为的与耐受和依赖相关的因素和机制的了解。进一步发现动物对酒精厌恶特性的耐受机制可能会更好地理解人类对酒精的耐受和依赖，并最终为那些遭受酒精依赖的人提供更好的治疗策略和结果。

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.