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。这些负面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负面情绪状态是动机和情感神经回路中的神经适应性的结果，这一点尚不清楚。主要研究者的长期目标是确定治疗酒精中毒的有效药物靶点。这个应用程序的目标，这是追求这一目标的下一步，是了解强啡肽/κ-阿片系统的神经适应性，发生在慢性酒精暴露，并有助于减弱动机和情感状态。核心假设是强啡肽/κ-阿片系统中的代偿性神经适应对抗酒精的急性效应，并通过改变负面情感行为促进过量酒精摄入。拟议研究的基本原理是，强啡肽靶点的确定将使旨在减轻酒精依赖产生的动机和情感症状的药物疗法的发展成为可能。将通过追求以下特定目标来检验该假设：目标1将评价急性戒断期间扩展杏仁核特定部位内的κ阿片受体拮抗作用。目标#2将现场具体评估的作用，扩展杏仁核强啡肽系统在抑郁和焦虑样行为。具体目标#3将在急性和长期戒断期间最大化依赖诱导的负面情感行为改变。所有这三个目标将利用乙醇强化和情感行为的动物模型，以系统地研究神经递质系统和神经回路，这些系统和神经回路有助于改变慢性乙醇暴露产生的动机和情感状态。这三个具体的目标将共同帮助确定重要的神经适应，导致慢性酒精暴露，并提供急需的信息，有关神经回路参与改变动机和情感系统。这样的贡献是重要的，因为它将有助于开发药物治疗酒精中毒的目标，重点是消除衰减的动机和消极的情感状态;一个策略，应该大大提高药物治疗的依从性和降低复发率。 公共卫生相关性：这一建议与公共卫生有关，将产生重要的积极影响，因为目前还没有药物疗法旨在减轻酒精戒断和依赖的负面情感和减弱的动机方面。除了在强化范例中对强啡肽/κ-阿片系统进行特定部位的研究外，该建议的益处是评估与酒精依赖相关的抑郁和焦虑样行为中的强啡肽/κ-阿片系统。拟议的实验将有助于开发基于减轻负面影响的酒精中毒药理学靶点，并提高个体的依从性和治疗成功率，减少与酒精中毒相关的社会成本。

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. PUBLIC HEALTH RELEVANCE: This proposal is relevant to public health and will have an important positive impact because there are currently no pharmacotherapies designed to alleviate the negative affective and attenuated motivational aspects of alcohol withdrawal and dependence. In addition to the site-specific investigation of dynorphin / kappa-opioid systems in reinforcement paradigms, the benefits of this proposal are the assessment of dynorphin / kappa-opioid systems in depressive- and anxiety-like behaviors associated with alcohol dependence. The proposed experiments will assist with the development of pharmacological targets for alcoholism based on the alleviation of negative affect and result in increased compliance and treatment success for the individual and less alcoholism-associated societal costs.