Regulation of delta opioid receptor function by cocaine

描述(申请人提供)：药物成瘾的特征是反复出现药物中毒、戒断和复发的循环。治疗成瘾的最大挑战是防止复发，进一步寻求毒品和吸毒行为。戒毒产生的负面情绪状态，包括高度焦虑和快感缺乏，是复发的主要原因。暴露于外部应激源也会促进复发。这是对我们的研究项目的竞争性更新的申请，该研究项目调查长期接触可卡因对增量阿片受体系统的影响。在之前的获奖期间，我们已经表明，在大鼠模型中，急性戒断反复服用可卡因会导致焦虑和抑郁样行为的增加，并且这些行为影响伴随着增量阿片受体信号的脱敏。Delta阿片受体激动剂被证明在两种基线条件下和可卡因戒断期间都是有效的抗焦虑药物。当三角洲阿片受体激动剂直接注射到杏仁中央核时，其减轻应激引起的焦虑的能力进一步证明了三角洲阿片受体在焦虑中的重要作用。在本申请中概述的研究将调查压力和类焦虑状态的相互作用 通过戒除可卡因而产生的。这些研究将使用恢复到可卡因的位置偏好模型来确定高度焦虑是否会导致压力诱导的可卡因寻找行为复发的易感性增加。三角洲阿片受体激动剂在缓解戒断诱导的焦虑中的作用部位将被确定，重点是扩大的杏仁核。由于在可卡因戒断过程中出现的焦虑和负面情绪状态会导致复发，拟议中的研究将确定增量阿片受体激动剂是否可以防止应激诱导的恢复。其他研究将开始阐明因可卡因戒断而产生的焦虑状态的细胞和分子机制，以及增量阿片受体产生有益作用的机制。这些研究的重点将放在三角洲的相互作用上。 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。这项拟议的研究的总体目标是确定焦虑状态在应激诱导的可卡因寻求行为复发中的作用，并阐明因反复服用可卡因而产生的焦虑的神经基础。这项研究的意义在于为预防复发建立了一个新的靶点，并阐明了扩展的杏仁核中的增量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，三角洲阿片系统的失调可能在对压力的异常反应和长期的复吸脆弱性中发挥关键作用。 公共卫生相关性：戒除反复使用可卡因产生的焦虑可能会促使人们重新开始寻求毒品和吸毒行为，而预防复发是治疗药物成瘾的核心。这项拟议的研究将调查可卡因戒断引起的焦虑的机制，压力与焦虑样状态的相互作用，以及增量阿片受体药物降低焦虑和预防复发的潜在效用。这项工作的总体目标是关键地建立增量阿片受体作为治疗可卡因戒断期间的焦虑和防止应激诱导的成瘾行为复发的NOEL靶点。

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. PUBLIC HEALTH RELEVANCE: Anxiety produced by withdrawal from repeated cocaine use can precipitate relapse to drug-seeking and drug-taking behaviors, and the prevention of relapse is at the core of efforts to treat drug addiction. The proposed research will investigate the mechanisms of cocaine withdrawal-induced anxiety, the interactions of stress with anxiety-like states, and the potential utility of a delta opioid receptor drug to reduce anxiety and preven relapse. The overall goal of this work is to critically establish the delta opioid receptor as a noel target to treat anxiety during cocaine withdrawal and to prevent stress-induced relapse to addictive behaviors.