Effects of exercise on dopaminergic mechanisms of cocaine relapse

运动对可卡因复吸的多巴胺能机制的影响

• 批准号: 10573236
• 负责人: Natalie Zlebnik
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10573236
• 关键词: Aerobic Exercise; Animals; Attenuated; Behavior; Behavior Therapy; Brain; Chronic; Cocaine; Corpus striatum structure; Cues; Data; Development; Dopamine; Dopamine D1 Receptor; Dopamine D2 Receptor; Dopamine Receptor; Dorsal; Drug Addiction; Drug abuse; Drug usage; Effectiveness; Electrophysiology (science); Environment; Event; Exercise; Exposure to; Extinction; Genetic; Goals; Human; Intake; Intervention; Kinetics; Maintenance; Mediating; Methods; Molecular; Mus; Neurobiology; Neurons; Optics; Periodicity; Pharmaceutical Preparations; Pharmacotherapy; Phase; Process; Public Health; Recording of previous events; Relapse; Reporting; Rodent; Role; Running; Scanning; Signal Transduction; Slice; Technology; Therapeutic; Therapeutic Effect; Titrations; Treatment Efficacy; Ventral Striatum; Withdrawal; addiction; cell type; cocaine relapse; cocaine related behaviors; cocaine reward; cocaine seeking; cocaine self-administration; craving; drug craving; drug of abuse; drug relapse; effective therapy; examination questions; experimental study; extracellular; in vivo; insight; motivated behavior; mouse model; neural; neurochemistry; neurophysiology; novel; optogenetics; paired stimuli; prevent; prolonged abstinence; receptor expression; recruit; relapse prevention; response; restoration; reward circuitry; sedentary; spatiotemporal; uptake

PROJECT SUMMARY Relapse to drug abuse is the single greatest challenge in addiction treatment. Relapse can occur even after prolonged abstinence and is often preceded by robust drug craving precipitated by exposure to drug-paired stimuli and environments. Aerobic exercise is a novel and promising behavioral treatment for drug addiction and relapse. However, the precise mechanism of its therapeutic effects is unknown. The long-term goal of this project is to characterize the striatal network dynamics that mediate the effects of exercise on addiction and relapse. The current aims of this proposal are to examine the impact of chronic wheel running on rapid subsecond dopamine release dynamics and dopamine terminal function as well as on the longitudinal development of phasic dopamine signals that promote cocaine-seeking behavior and on the recruitment of cell- type specific neural processing of cocaine seeking and cocaine-paired cues. It is hypothesized that chronic wheel running will (1) attenuate cocaine-evoked subsecond dopamine release in the striatum, (2) decrease striatal phasic dopaminergic signals accompanying cocaine-paired cues and cocaine seeking, and (3) attenuate D1-MSN and potentiate D2-MSN encoding of cocaine-paired cues and cocaine seeking. These experiments will employ a sophisticated mouse model of cocaine relapse, state-of-the-art in vivo fast-scan cyclic voltammetry recordings, in vivo multiple single-unit electrophysiological recordings, and chemogenetic and optogenetic technologies to examine these questions in behaving animals. The proposed experiments aim to increase our understanding of the neurobiological substrates that mediate drug craving and relapse and identify the neurochemical and neurophysiological mechanisms of the beneficial effects of exercise.

项目摘要 药物滥用的复发是成瘾治疗的最大挑战。复发可能发生在 长期禁欲，并且通常在暴露于药物配对的 刺激和环境。有氧运动是一种新颖的、有前途的药物成瘾行为治疗方法 和复发然而，其治疗作用的确切机制尚不清楚。长期目标是 该项目是为了表征纹状体网络动态，介导运动对成瘾的影响， 复发本提案的当前目标是研究慢性车轮运行对快速 亚秒多巴胺释放动力学和多巴胺终末功能以及纵向 促进可卡因寻求行为的阶段性多巴胺信号的发展，以及对细胞募集的影响， 可卡因寻求和可卡因配对线索的类型特异性神经处理。据推测，慢性 跑轮子会（1）减弱可卡因诱发的纹状体多巴胺亚秒释放，（2）减少 伴随可卡因配对线索和可卡因寻求的纹状体阶段性多巴胺能信号，和（3） 减弱可卡因配对线索和可卡因寻求的D1-MSN和增强D2-MSN编码。这些 实验将采用复杂的可卡因复发小鼠模型，最先进的体内快速扫描， 循环伏安法记录，体内多个单单位电生理记录，和化学遗传学 和光遗传学技术来研究动物行为中的这些问题。实验目的 增加我们对介导药物渴望和复发的神经生物学底物的理解， 确定运动有益效果的神经化学和神经生理机制。