Regulation of delta opioid receptor function by cocaine

描述（由申请人提供）：药物成瘾的特征是药物中毒、戒断和复发的重复循环。成瘾治疗的最大挑战是预防复吸到进一步的寻药和吸毒行为。由药物戒断产生的负面情绪状态，包括焦虑和快感缺乏的加剧状态，是复发的主要原因。暴露于外部压力也会促进复发。这是我们研究项目的竞争性更新申请，该项目调查长期暴露于可卡因对δ阿片受体系统的影响。在之前的奖励期间，我们已经表明，从重复可卡因给药中急性戒断会导致大鼠模型中焦虑和抑郁样行为的增加，这些行为效应伴随着δ阿片受体信号转导的脱敏。δ阿片受体激动剂在基线条件下和可卡因戒断期间均显示为有效的抗焦虑药。δ阿片受体在焦虑中的重要作用进一步通过δ阿片受体激动剂在直接注射到杏仁核的中央核中时减弱应激诱导的焦虑的能力来证明。本申请中概述的研究将调查压力和焦虑样状态的相互作用 因吸食可卡因而产生的这些研究将使用大鼠可卡因位置偏好恢复模型来确定高度焦虑是否会导致对压力诱导的可卡因寻求行为复发的易感性增加。δ阿片受体激动剂在缓解戒断诱导的焦虑中的作用的解剖学部位将被确定，重点是扩展的杏仁核。由于可卡因戒断过程中出现的焦虑和消极情感状态可能会促使复发，因此拟议的研究将确定δ阿片受体激动剂是否可以预防压力诱导的复发。其他研究将开始，以阐明可卡因戒断产生的焦虑样状态所涉及的细胞和分子机制，以及δ阿片受体产生有益作用的机制。这些研究的重点将是三角洲的相互作用 阿片受体与促肾上腺皮质激素释放因子和去甲肾上腺素能传递。拟议的研究的总体目标是确定焦虑状态的作用，在压力诱导的复发可卡因寻求行为，并阐明神经基板的基础上产生的焦虑从反复服用可卡因。这项研究的意义在于建立了一个预防复发的新靶点，并阐明了杏仁核中δ阿片受体在调节可卡因戒断的负面影响中的功能作用。长期使用可卡因后δ阿片系统的调节异常可能在对压力的异常反应和长期易复发性中起关键作用。

DESCRIPTION (provided by applicant): Drug addiction is characterized by repeating cycles of drug intoxication, withdrawal, and relapse. The greatest challenge in the treatment of addiction is the prevention of relapse to further drug-seeking and drug-taking behaviors. The negative mood state produced by drug withdrawal, including heightened states of anxiety and anhedonia, is a major contributor to relapse. Relapse is also facilitated by exposure to external stressors. This is an application for a competitive renewal of our research project that investigates the impact of chronic exposure to cocaine on the delta opioid receptor system. During the prior award period, we have shown that acute withdrawal from repeated cocaine administration results in increases in anxiety- and depression-like behaviors in a rat model and these behavioral effects are accompanied by a desensitization of delta opioid receptor signaling. Delta opioid receptor agonists were shown to be effective anxiolytic agents under both baseline conditions and during cocaine withdrawal. The important role of delta opioid receptors in anxiety was further demonstrated by the ability of delta opioid receptor agonists to attenuate stress-induced anxiety when injected directly into the central nucleus of the amygdala. The research outlined in this application will investigate the interactions of stress and the anxiety-like state produced by withdrawal from cocaine. The studies will determine if heightened anxiety leads to increased susceptibility to stress-induced relapse to cocaine-seeking behaviors using the reinstatement to cocaine place preference model in the rat. The anatomical site of action of delta opioid receptor agonists in relieving withdrawal-induced anxiety will be determined with a focus on the extended amygdala. As anxiety and the negative affective state that occur during cocaine withdrawal can precipitate relapse, the proposed research will determine if delta opioid receptor agonists can prevent stress-induced reinstatement. Additional studies will begin to elucidate the cellular and molecular mechanisms that are involved in anxiety-like states produced by cocaine withdrawal and the mechanism through which delta opioid receptors are producing their beneficial actions. The focus of these studies will be on the interactions of delta opioid receptors with corticotrophin releasing factor and noradrenergic transmission. The overall objectives of the proposed research are to determine the role of anxiety states in stress-induced relapse to cocaine-seeking behaviors and to elucidate the neural substrates underlying anxiety produced by withdrawal from repeated administration of cocaine. The significance of the proposed research is the establishment of a novel target for the prevention of relapse and the elucidation of the functional role of delta opioid receptors in the extended amygdala in modulating the negative effects of cocaine withdrawal. Dysregulation of the delta opioid system following chronic cocaine use may play a critical role in abnormal responsiveness to stress and the long-lasting vulnerability to relapse.