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，从而导致乙醇依赖的发展仍有待确定。本申请中提出的研究对RFA（AA-08-009）有响应，因为它们检验了一种与乙醇依赖背景下乙醇厌恶特性耐受性作用相关的新假设。更具体地说，我们提出，耐受性发展到乙醇的厌恶性质，这种耐受性，反过来，保持过度饮酒依赖的动物。此外，我们假设，一个潜在的机制，耐受乙醇的厌恶性质涉及到神经适应在基底外侧杏仁核（BLA）的神经递质。我们的整体研究策略和方法涉及采用一个良好表征的乙醇依赖小鼠模型，可靠地产生过量的自愿乙醇消费。使用该模型，将进行以下研究：（a）检查对乙醇的厌恶性质的耐受性，如通过对乙醇诱导的条件味觉厌恶的敏感性降低所定义的（特定目的I）;（B）测量基础水平和乙醇刺激BLA中谷氨酸的细胞外水平的能力（具体目标二）;以及（c）检查直接操纵BLA介导的神经传递对乙醇诱导的条件性味觉厌恶和饮酒行为的影响（特定目标III）在乙醇依赖性和非依赖性小鼠中。这些发现将填补文献中关于谷氨酸盐在BLA中对乙醇不良后果耐受性的作用的一般空白，并应描述与过量乙醇消耗风险增加和依赖性复发增加的潜在联系。 公共卫生相关性：对酒精的厌恶特性的耐受性可能会促进消费的增加，这反过来又会导致依赖性的发展沿着持续的过度饮酒。使用酒精依赖和饮酒的动物模型，我们的目标是推进与促进过度饮酒行为的耐受性和依赖性相关的因素和机制的知识。进一步发现动物对酒精厌恶特性的耐受性机制可能会更好地理解人类的酒精耐受性和依赖性，并最终为酒精依赖患者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.