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、戒断和复发的反复循环。治疗成瘾的最大挑战是防止再次寻求药物和吸毒行为。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，是复发的主要原因。暴露于外部压力源也会促进复发。这是一个竞争性更新我们的研究项目的应用程序，研究慢性暴露于可卡因对三角洲阿片受体系统的影响。在之前的奖励期间，我们已经证明，在大鼠模型中，反复服用可卡因的急性戒断会导致焦虑和抑郁样行为的增加，这些行为效应伴随着δ阿片受体信号的脱敏。在基线条件下和可卡因戒断期间，δ阿片受体激动剂被证明是有效的抗焦虑剂。当将δ阿片受体激动剂直接注射到杏仁核中央核时，δ阿片受体激动剂能够减轻应激性焦虑，进一步证明了δ阿片受体在焦虑中的重要作用。本申请中概述的研究将调查压力和焦虑状态之间的相互作用

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.