Regulation of delta opioid receptor function by cocaine

可卡因调节 δ 阿片受体功能

• 批准号: 7217481
• 负责人: ELLEN M UNTERWALD
• 金额: $ 23.7万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7217481
• 关键词: Abbreviations; Address; Adenylate Cyclase; Affinity; Agonist; Animals; Anxiety; Appendix; Attenuated; Behavior; Behavioral; Binding; Biological Assay; Brain region; Chinese Hamster Ovary Cell; Chronic; Cocaine; Cocaine Dependence; Corpus striatum structure; Data; Dopamine; Dopamine D1 Receptor; Down-Regulation; Drug Addiction; Emotional; Enkephalins; Exposure to; G-Protein-Coupled Receptors; Goals; Individual; Label; Localized; Locomotion; Manuscripts; Measures; Mediating; Mental Depression; Modeling; Molecular; Motor Activity; Neurotransmitters; Nucleus Accumbens; Opioid; Opioid Receptor; Pathway interactions; Pattern; Pharmaceutical Preparations; Phenotype; Phosphorylation; Phosphotransferases; Play; Process; Property; Proteins; Rattus; Receptor Activation; Receptor Signaling; Regulation; Research Personnel; Role; Score; Swimming; System; Techniques; Testing; Withdrawal; addiction; craving; delta opioid receptor; desensitization; endogenous opioids; innovation; intraperitoneal; neuroadaptation; neurochemistry; neurotransmission; putamen; receptor; receptor function; reinforced behavior; response; subcutaneous

DESCRIPTION (provided by applicant): Cellular and molecular neuroadaptations that occur during exposure to cocaine likely contribute to the perpetuation of cocaine addiction by mediating the processes of drug dependence, tolerance, sensitization, withdrawal, and craving. The ability of cocaine to enhance dopaminergic neurotransmission in the mesocorticolimbic pathway undoubtedly plays a critical role in the initial reinforcing properties of this drug. However, other neurotransmitter systems are also integral to the addiction process. One such system is the endogenous opioid system. A large body of data indicates that opioidergic and dopaminergic neurotransmitter systems together regulate emotional, locomotor, and goal-directed behaviors. In addition, previous studies from our lab demonstrate that chronic binge-pattern cocaine can profoundly alter the expression and function of opioid receptors in brain regions critically involved in cocaine addiction. Of specific importance to this application, chronic cocaine administration results in the desensitization of delta opioid receptor signaling through adenylyl cyclase in the nucleus accumbens and caudate putamen. This functional desensitization is mediated by cocaine's actions on dopamine D1 receptors. Results from the studies proposed herein will determine the molecular mechanism(s) mediating cocaine-induced delta opioid receptor heterologous desensitization and the behavioral impact of attenuated delta receptor fuction. Specific Aims are as follows: 1) to characterize the cellular interactions of dopamine D1 and delta opioid receptors in the nucleus accumbens and caudate putamen, 2) to determine the molecular mechanisms by which cocaine caused the desensitization of delta opioid receptor function, and 3) to determine the functional significance of cocaine-induced delta receptor desensitization in the whole animal using models of locomotor activity, anxiety, and depression. The innovation lies in combining several powerful techniques to address these aims at ultrastructural, anatomical, molecular, and behavioral levels.

描述（由申请人提供）：接触可卡因期间发生的细胞和分子神经适应可能通过介导药物依赖性、耐受性、敏化、戒断和渴望过程而导致可卡因成瘾的持续。可卡因增强中皮质边缘通路中多巴胺能神经传递的能力无疑在该药物的初始增强特性中发挥着关键作用。然而，其他神经递质系统也是成瘾过程中不可或缺的一部分。内源性阿片系统就是这样的系统之一。大量数据表明阿片能和多巴胺能神经递质系统共同调节情绪、运动和目标导向行为。此外，我们实验室之前的研究表明，长期暴饮可卡因可以深刻改变与可卡因成瘾密切相关的大脑区域阿片受体的表达和功能。对于该应用特别重要的是，长期给予可卡因导致通过伏隔核和尾壳核中的腺苷酸环化酶的δ阿片受体信号转导脱敏。这种功能性脱敏是由可卡因对多巴胺 D1 受体的作用介导的。本文提出的研究结果将确定介导可卡因诱导的 δ 阿片受体异源脱敏的分子机制以及减弱 δ 受体功能的行为影响。具体目标如下：1) 表征伏隔核和尾壳核中多巴胺 D1 和 δ 阿片受体的细胞相互作用，2) 确定可卡因引起 δ 阿片受体功能脱敏的分子机制，以及 3)使用运动活动、焦虑和抑郁模型确定可卡因诱导的 δ 受体脱敏在整个动物中的功能意义。创新在于结合多种强大的技术来实现超微结构、解剖学、分子和行为水平上的这些目标。