Regulation of delta opioid receptor function by cocaine

描述（由申请方提供）：暴露于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、耐受、致敏、戒断和渴望的过程而促成可卡因成瘾的持续。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这种药物的初始强化性质中起着关键作用。然而，其他神经递质系统也是成瘾过程的组成部分。一个这样的系统是内源性阿片系统。大量的数据表明，阿片类和多巴胺能神经递质系统共同调节情绪，运动和目标导向的行为。此外，我们实验室以前的研究表明，慢性暴食型可卡因可以深刻地改变与可卡因成瘾密切相关的大脑区域中阿片受体的表达和功能。对于该应用特别重要的是，慢性可卡因施用导致δ阿片样物质受体信号传导通过延髓核和尾状壳核中的腺苷酸环化酶脱敏。可卡因对多巴胺D1受体的作用介导了这种功能性脱敏。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和减弱的δ受体功能的行为影响。具体目标如下：1）描述多巴胺D1和δ阿片受体在中脑核和尾壳核中的细胞相互作用，2）确定可卡因引起δ阿片受体功能脱敏的分子机制，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。创新在于结合几种强大的技术，以解决这些目标在超微结构，解剖，分子和行为水平。

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.