The Role of Dynorphin / Kappa-Opioid Systems in Alcohol Dependence

描述(由申请人提供)：过度饮酒的一个基本特征是酒精依赖和情感障碍的共病。这些消极情绪状态的自我治疗可能会导致过度饮酒和复发。慢性酒精暴露所产生的消极情绪状态是由尚不清楚的动机和情感神经回路中的神经适应引起的。主要研究人员的长期目标是确定治疗酒精中毒的有效药物治疗靶点。这项应用的目标是了解强啡肽/kappa阿片系统中对慢性酒精暴露的反应并有助于减弱动机和情感状态的神经适应，这是追求这一目标的下一步。中心假设是强啡肽/kappa阿片系统中的代偿性神经适应对抗酒精的急性影响，并通过改变负面情感行为促进过度饮酒。这项拟议研究的基本原理是，确定强啡肽靶标将有助于开发旨在缓解酒精依赖所产生的动机和情感症状的药物疗法。这一假设将通过追求以下具体目标来检验：Aim#1将评估急性戒断期间杏仁核延伸区域特定部位的kappa阿片受体拮抗作用。目的#2将现场评估扩展的杏仁核强啡肽系统在抑郁和焦虑样行为中的作用。具体目标#3将在急性和长期戒断期间最大限度地改变依赖诱导的负面情感行为。这三个目标都将利用酒精强化和情感行为的动物模型，对神经递质系统和神经回路进行系统研究，这些系统有助于改变长期接触酒精所产生的动机和情感状态。这三个具体目标将共同帮助确定慢性酒精暴露导致的重要神经适应，并提供有关改变的动机和情感系统所涉及的神经回路的迫切需要的信息。这一贡献意义重大，因为它将有助于制定治疗酒精中毒的药物治疗目标，重点是消除减弱的动机和负面情绪状态；这一战略应该会极大地提高服药依从性，降低复发率。

DESCRIPTION (provided by applicant): A fundamental characteristic of excessive alcohol use is the comorbidity of alcohol dependence and disorders of affect. Self-medication of these negative affective states likely contributes to excessive alcohol use and relapse. Negative affective states produced by chronic alcohol exposure result from neuroadaptations in motivational and affective neurocircuitry that are not yet understood. The principal investigator's long-term goal is to identify effective pharmacotherapeutic targets for the treatment of alcoholism. The objective of this application, which is the next step in pursuit of that goal, is to understand the neuroadaptations in dynorphin / kappa-opioid systems that occur in response to chronic alcohol exposure and contribute to attenuated motivational and affective states. The central hypothesis is that compensatory neuroadaptations in dynorphin / kappa-opioid systems oppose the acute effects of alcohol, and promote excessive alcohol intake by altering negative affective behaviors. The rationale for the proposed studies is that identification of dynorphin targets will enable the development of pharmacotherapies designed to alleviate motivational and affective symptoms produced by alcohol dependence. The hypothesis will be tested by pursuing the following specific aims: Aim #1 will evaluate kappa opioid receptor antagonism within specific sites of the extended amygdala during acute withdrawal. Aim #2 will site-specifically evaluate the role of extended amygdala dynorphin systems in depressive- and anxiety-like behavior. Specific Aim #3 will maximize dependence-induced alterations in negative affective behaviors during acute and protracted withdrawal. All three aims will utilize animal models of ethanol reinforcement and affective behavior to allow for the systematic investigation of neurotransmitter systems and neurocircuitry that contribute to altered motivational and affective states produced by chronic ethanol exposure. These three specific aims will collectively help to identify important neuroadaptations that result from chronic alcohol exposure and provide much needed information regarding the neurocircuitry involved in altered motivational and affective systems. Such a contribution is significant because it will help to develop pharmacotherapeutic targets for the treatment of alcoholism that focus on the removal of attenuated motivational and negative affective states; a strategy that should greatly increase medication compliance and decrease rates of relapse.