Effects of exercise on dopaminergic mechanisms of cocaine relapse

项目总结 吸毒复发是成瘾治疗中最大的挑战。即使在以下情况下也可能复发 长期禁欲，在此之前通常有强烈的药物渴望，这是由于接触成对的毒品而引发的 刺激和环境。有氧运动是治疗药物成瘾的一种新颖而有前途的行为疗法 以及故态复萌。然而，其治疗效果的确切机制尚不清楚。这样做的长期目标是 项目是描述纹状体网络的动力学特征，它介导了运动对成瘾和 旧病复发。这项建议目前的目的是检查长期车轮运行对快速的影响 亚秒多巴胺释放动力学和多巴胺末端功能以及对纵向 促进可卡因寻找行为的时相性多巴胺信号的发展以及对细胞- 可卡因寻找和可卡因配对线索的类型特异性神经加工。据推测，慢性病 转轮运动将(1)减弱可卡因诱发的纹状体亚秒多巴胺释放，(2)减少 纹状体时相多巴胺能信号伴随着可卡因配对线索和可卡因寻找，以及(3) 减弱d1-msn和增强d2-msn对可卡因配对线索和寻找可卡因的编码。这些 实验将采用先进的可卡因复发小鼠模型，体内最先进的快速扫描 循环伏安记录、体内多个单单位电生理记录和化学发生 以及光基因技术来研究动物行为中的这些问题。建议的实验目的是 为了增加我们对调节药物渴望和复发的神经生物学底物的了解，以及 确定锻炼有益效果的神经化学和神经生理学机制。

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.