Drug-induced plasticity in mesolimbic dopamine circuits in opioid dependence

项目摘要 阿片成瘾是一种破坏性疾病，对个人和公共健康造成深远影响。这个 反复阿片类药物治疗所形成的生理耐受性和依赖性是常见的先兆 会上瘾的行为。这项提议旨在确定哪些中脑回路会因长时间延长而改变。 阿片类药物的使用，更具体地说，哪些神经元对阿片类药物依赖有贡献。当给予阿片类药物时， 抑制GABA能神经元上抑制阿片受体的中脑神经元释放多巴胺 被激活了。这会导致下游多巴胺紧张程度的增加。反复暴露，一种受体- 独立的动态平衡机制增加这些GABA能神经元对阿片类药物耐受的活性 州政府。耐受GABA能神经元高度活跃，在缺乏时强烈抑制多巴胺能神经元 阿片类药物。这可能是与阿片类药物戒断相关的多巴胺张力下降的一个原因。 这些GABA能和多巴胺能变化主要发生在腹侧被盖区(VTA)，即中脑 既涉及奖励又涉及厌恶的区域。自从这些阿片类药物的机制被发现以来，多个不同的 已经描述并发现VTA多巴胺回路具有关于奖赏和 厌恶，这使已知的阿片类药物效应的电路特异性受到质疑。总的来说，一个全面的 对中脑亚回路中阿片类药物的急性和长期影响的描述非常缺乏。这个 建议的研究使用膜片钳电生理学和逆行示踪剂来确定阿片类药物的作用 在不同的VTA输出通路上，并识别哪些神经元展示了前面描述的细胞 退缩特征。他们还探索了不同的中脑边缘亚区与阿片类药物的相关性。 用基因编码的纤维光度法记录体内多巴胺释放变化的依赖性 多巴胺传感器。我们之前的研究表明，阿片类药物暴露的回报方面和 对阿片依赖(戒断)的厌恶反应可能在机械上是可分离的。通过将 在急性和慢性阿片类药物使用的电路水平上，这项研究将填补我们认识上的一个空白 依赖是如何在大脑中发展的。这项工作对改善阿片类药物的治疗具有重要意义 这项研究将用于预防上瘾和开发更安全的止痛药，降低依赖的风险。作为一个联谊项目，它 还将提供几种基本神经科学技术的培训框架 在高度协作的研究环境中汇集不同的专家。

Project Summary Opioid addiction is a devastating illness with far-reaching personal and public health consequences. The physiological tolerance and dependence that develop with repeated opioid treatment are a common precursor to addictive behaviors. This proposal is aimed at determining which midbrain circuits are altered by prolonged opioid use and, more specifically, which neurons contribute to opioid dependence. When given acutely, opioids disinhibit the release of dopamine from midbrain neurons as inhibitory opioid receptors on GABAergic neurons are activated. This leads to increases of dopamine tone downstream. With repeated exposure, a receptor- independent, homeostatic mechanism increases the activity of these GABAergic neurons to an opioid tolerant state. Tolerant GABAergic neurons are hyper active and strongly inhibit dopaminergic neurons in the absence of opioids. This is a likely cause of the decrease in dopamine tone that is associated with opioid withdrawal. These GABAergic and dopaminergic changes occur primarily in the ventral tegmental area (VTA), a midbrain region involved in both reward and aversion. Since the discovery of these opioid mechanisms, multiple distinct VTA dopamine circuits have been described and found to have different functions with respect to reward and aversion which calls into question the circuit-specificity of known opioid effects. Overall, a comprehensive characterization of acute and long-term opioid effects in midbrain sub-circuits is very much lacking. The proposed studies use patch clamp electrophysiology with retrograde tracers to determine the effects of opioids on different VTA output pathways and identify which neurons demonstrate the previously described cellular withdrawal characteristics. They also explore the relevance of different mesolimbic sub-regions to opioid dependence by recording dopamine release changes in vivo using fiber photometry with a genetically encoded dopamine sensor. Our previous research suggests that the rewarding aspects of opioid exposure and the aversive responses to opioid dependence (withdrawal) may be mechanistically separable. By separating the acute and chronic components of opioid use at the circuit level, this research will fill a gap in our understanding of how dependence develops in the brain. This work has implications both for improved treatment of opioid addiction and for development of safer analgesics with reduced risk for dependence. As a fellowship project, it will also provide a framework for training in several essential neuroscience techniques with the help of a diverse collection of experts in a highly collaborative research environment.