Role of dopamine D1 receptors in morphine withdrawal

描述（由申请人提供）： 人类阿片类药物依赖的特征是戒断综合征，包括烦躁不安和抑郁。减轻这些令人厌恶的戒断症状被认为是继续吸毒的主要动机。中脑边缘多巴胺系统，包括丘脑核（NAc），在阿片类药物如吗啡的奖赏和厌恶效应中起着重要作用。NRSA的这个提议的目的是研究NAc中多巴胺D1受体的激活如何影响吗啡依赖大鼠的分子过程和行为。NAc中的D1受体刺激激活转录因子cAMP反应元件结合蛋白（CREB），其与厌恶状态相关。这个建议的一个目的是确定在吗啡戒断过程中D1受体刺激对大鼠NAc中CREB激活的影响。NAc中的CREB调节可能有助于与吗啡戒断相关的厌恶状态。第二个目的是确定如何激活D1受体，特别是在NAC影响吗啡戒断诱导的大鼠条件性位置厌恶。最后一个目的是确定如何激活的D1受体在NAC吗啡依赖大鼠影响颅内自我刺激，一个操作性行为敏感的奖励和厌恶的状态。总之，这些研究可能会导致增加对阿片类药物依赖的机制的理解。这项工作可能会导致新的药物治疗，可以减轻与阿片类药物戒断相关的厌恶和烦躁状态，并可能减少吸毒复发。

DESCRIPTION (provided by applicant): Opiate dependence in humans is characterized by an abstinence syndrome that includes dysphoria and depression. Alleviation of these aversive withdrawal symptoms is thought to be a primary motivation for continued drug taking. The mesolimbic dopamine system, which includes the nucleus accumbens (NAc), plays an important role in both the rewarding and aversive effects of opiates such as morphine. The purpose of this NRSA proposal is to examine how activation of dopamine D1 receptors in the NAc affects molecular processes and behavior in morphine-dependent rats. D1 receptor stimulation in the NAc activates the transcription factor cAMP response element binding protein (CREB), which has been associated with aversive states. One aim of this proposal is to determine the effect of D1 receptor stimulation on CREB activation in the NAc of rats during morphine withdrawal. CREB regulation in the NAc may contribute to aversive states associated with morphine withdrawal. A second aim is to determine how activation of D1 receptors specifically in the NAc affects morphine withdrawal-induced conditioned place aversions in rats. A final aim is to determine how activation of D1 receptors in the NAc of morphine-dependent rats affects intracranial self-stimulation, an operant behavior sensitive to rewarding and aversive states. Together, these studies may lead to an increased understanding of the mechanisms underlying opiate dependence. This work may lead to new pharmacotherapies that can alleviate aversive and dysphoric states associated with opiate withdrawal and perhaps reduce relapse to drug taking.