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

强啡肽/κ-阿片类药物系统在酒精依赖中的作用

• 批准号: 8442394
• 负责人: Brendan M Walker
• 金额: $ 30.7万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8442394
• 关键词: Acute; Address; Adult; Affect; Affective; Affective Symptoms; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcoholism; Alcohols; Amygdaloid structure; Animal Model; Animals; Anxiety; Anxiety Disorders; Attenuated; Behavior; Cell Nucleus; Characteristics; Chronic; Comorbidity; Data; Dependence; Development; Diagnosis; Disease; Dynorphins; Emotional; Excision; Goals; Heavy Drinking; Individual; Infusion procedures; Investigation; Knowledge; Ligands; Measures; Mental Depression; Moods; Neurotransmitters; Opioid; Opioid Receptor; Outcome; Pathogenesis; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacotherapy; Phenotype; Principal Investigator; Process; Psychological reinforcement; Public Health; Rattus; Recovery; Relapse; Role; Self Administration; Self Medication; Site; Swimming; System; Testing; Withdrawal; Work; alcohol effect; alcohol exposure; alcohol reinforcement; alcohol relapse; alcohol use disorder; alcoholism therapy; base; compliance behavior; cost; depressive symptoms; design; kappa opioid receptors; medication compliance; neuroadaptation; neurotransmission; public health relevance; research study; response; success; therapy development; treatment adherence; treatment strategy; vapor

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.

描述（由申请人提供）：过量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旧病复发。长期接触酒精所产生的负面情感状态是由动机和情感神经回路中的神经适应引起的，但目前尚不清楚。主要研究者的长期目标是确定治疗酒精中毒的有效药物治疗靶点。该应用程序的目标是实现该目标的下一步，是了解强啡肽/卡帕阿片类药物系统中因长期酒精暴露而发生的神经适应，并导致动机和情感状态减弱。核心假设是强啡肽/κ-阿片类药物系统中的代偿性神经适应可以抵抗酒精的急性作用，并通过改变负面情感行为促进过量饮酒。拟议研究的基本原理是，强啡肽靶点的识别将有助于开发旨在减轻酒精依赖产生的动机和情感症状的药物疗法。该假设将通过追求以下具体目标进行检验：目标#1将评估急性戒断期间扩展杏仁核特定位点内的κ阿片受体拮抗作用。目标#2 将针对特定部位评估扩展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将最大限度地提高急性和长期戒断期间依赖性引起的负面情感行为的改变。所有三个目标都将利用乙醇强化和情感行为的动物模型，以便对神经递质系统和神经回路进行系统研究，这些神经递质系统和神经回路有助于改变慢性乙醇暴露所产生的动机和情感状态。这三个具体目标将共同帮助识别因长期酒精暴露而产生的重要神经适应，并提供有关改变动机和情感系统的神经回路的急需信息。这样的贡献意义重大，因为它将有助于开发治疗酗酒的药物治疗目标，重点是消除减弱的动机和消极情感状态；这一策略将大大提高药物依从性并降低复发率。