Regulation of delta opioid receptor function by cocaine

可卡因调节 δ 阿片受体功能

• 批准号: 8446330
• 负责人: ELLEN M UNTERWALD
• 金额: $ 29.44万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8446330
• 关键词: Acute; Addictive Behavior; Adult; Affective; Agonist; Amygdaloid structure; Anhedonia; Anti-Anxiety Agents; Anxiety; Attenuated; Award; Behavior; Behavioral Model; Cell Nucleus; Chronic; Chronic stress; Cocaine; Corticotropin-Releasing Hormone; Diazepam; Drug Addiction; Drug Receptors; Exposure to; Goals; Intoxication; Investigation; Mediating; Mediator of activation protein; Mental Depression; Modeling; Molecular; Neurons; Norepinephrine; Norepinephrine Receptors; Nucleus Accumbens; Opioid; Pharmaceutical Preparations; Play; Post-Traumatic Stress Disorders; Predisposition; Rattus; Receptor Signaling; Regulation; Relapse; Research; Research Project Grants; Role; Site; Stress; Stressful Event; Structure of terminal stria nuclei of preoptic region; Substrate Interaction; System; Testing; Therapeutic; Therapeutic Effect; Withdrawal; Work; addiction; cocaine exposure; cocaine use; defined contribution; delta opioid receptor; desensitization; disorder later incidence prevention; drug withdrawal; male; negative mood; noradrenergic; novel; preference; prevent; receptor function; relating to nervous system; response; social; stressor; transmission process; treatment strategy

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.

描述（由申请人提供）：药物成瘾的特点是药物中毒、戒断和复发的重复循环。治疗成瘾的最大挑战是防止进一步寻求毒品和吸毒行为的复发。戒毒所产生的负面情绪状态，包括高度焦虑和快感缺乏，是导致复发的主要原因。暴露于外部压力源也会促进复发。这是我们研究项目竞争性更新的申请，该项目研究长期接触可卡因对 δ 阿片受体系统的影响。在之前的奖励期间，我们已经证明，重复给予可卡因的急性戒断会导致大鼠模型中焦虑和抑郁样行为的增加，并且这些行为效应伴随着 δ 阿片受体信号的脱敏。 Delta阿片受体激动剂在基线条件下和可卡因戒断期间均被证明是有效的抗焦虑剂。当直接注射到杏仁核中央核时，δ阿片受体激动剂能够减轻压力引起的焦虑，这进一步证明了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类焦虑状态的相互作用 由可卡因戒断产生。这些研究将利用老鼠恢复可卡因位置偏好模型来确定高度焦虑是否会导致压力诱发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引起的焦虑方面的作用解剖部位将重点关注扩展的杏仁核。由于可卡因戒断期间出现的焦虑和负面情感状态可能会导致复发，因此拟议的研究将确定 δ 阿片受体激动剂是否可以防止压力引起的复吸。其他研究将开始阐明可卡因戒断产生的焦虑样状态的细胞和分子机制，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。拟议研究的总体目标是确定焦虑状态在压力诱发的可卡因寻求行为复发中的作用，并阐明因重复服用可卡因戒断而产生焦虑的神经基础。这项研究的意义在于建立了预防复发的新靶点，并阐明了扩展杏仁核中 δ 阿片受体在调节可卡因戒断负面影响中的功能作用。长期使用可卡因后 δ 阿片系统的失调可能在对压力的异常反应和长期复发的脆弱性中发挥关键作用。