Regulation of delta opioid receptor function by cocaine

描述（由申请人提供）：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、耐受性、敏化、戒断和渴望的过程来促进可卡因成瘾的延续。可卡因增强中皮质边缘通路多巴胺能神经传递的能力无疑在这种药物最初的强化特性中起着关键作用。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。其中一个系统是内源性阿片系统。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，慢性暴饮暴食模式的可卡因可以深刻地改变大脑中与可卡因成瘾有关的区域的阿片受体的表达和功能。对这一应用特别重要的是，长期服用可卡因会导致阿片受体信号通过伏隔核和尾状壳核中的腺苷酸环化酶脱敏。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δ受体功能减弱对行为的影响。具体目的如下：1)表征伏隔核和尾状壳核中多巴胺D1与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；3)通过运动活动、焦虑和抑郁模型，确定可卡因诱导的δ阿片受体脱敏在全动物中的功能意义。创新在于将几种强大的技术结合起来，在超微结构、解剖、分子和行为水平上解决这些问题。

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.