Drug-induced plasticity in mesolimbic dopamine circuits in opioid dependence

阿片类药物依赖中脑边缘多巴胺回路的药物诱导可塑性

• 批准号: 10470911
• 负责人: Sarah Warren Gooding
• 金额: $ 3.89万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10470911
• 关键词: Acute; Addictive Behavior; Address; Affect; Americas; Analgesics; Biological; Brain; Cell Nucleus; Cells; Characteristics; Chronic; Clinical; Collection; Color; Communities; Dependence; Development; Disease; Dopamine; Drug Addiction; Economics; Electrophysiology (science); Environment; Fellowship; Fiber; Goals; Healthcare; Individual; Intervention; Label; Lateral; Literature; Maps; Measures; Medial; Midbrain structure; Morphine; Mouse Strains; Mus; Neurons; Neurosciences; Nucleus Accumbens; Opiate Addiction; Opioid; Opioid Antagonist; Opioid Receptor; Optical Methods; Output; Pathway interactions; Pharmaceutical Preparations; Photometry; Physiologic tolerance; Physiological; Play; Population; Prevention strategy; Probability; Productivity; Public Health; Research; Rewards; Risk; Role; Slice; Specificity; Substance of Abuse; Synapses; Techniques; Testing; Time; Tracer; Training; Ventral Tegmental Area; Withdrawal; Work; addiction; dopaminergic neuron; drug abstinence; drug reward; druggable target; experimental study; gamma-Aminobutyric Acid; improved; in vivo; neural circuit; neuromechanism; opiate tolerance; opioid epidemic; opioid exposure; opioid use; opioid withdrawal; patch clamp; presynaptic; receptor; response; sensor; treatment strategy

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.

项目摘要 阿片类药物成瘾是一种毁灭性的疾病，对个人和公共健康产生深远的影响。的 重复阿片类药物治疗产生生理耐受性和依赖性是一种常见的前体 上瘾行为的原因这项提议旨在确定哪些中脑回路被长时间的 阿片类药物的使用，更具体地说，哪些神经元有助于阿片类药物依赖。当急性给予阿片类药物时， 作为GABA能神经元上的抑制性阿片受体，解除多巴胺从中脑神经元的释放 都被激活了这导致下游多巴胺张力增加。反复接触，一个受体- 一种独立的稳态机制增加了这些GABA能神经元的活性， 状态耐受性GABA能神经元是高度活跃的，并且在缺乏GABA能神经元的情况下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降低的原因。 这些GABA能和多巴胺能的变化主要发生在腹侧被盖区（VTA），即中脑 同时涉及奖赏和厌恶的区域。自从发现这些阿片类药物机制以来， 已经描述了腹侧被盖区多巴胺回路，并发现其在奖赏和兴奋方面具有不同的功能。 厌恶，这对已知阿片类药物作用的回路特异性提出了质疑。总体而言， 非常缺乏对中脑子回路中的急性和长期阿片样物质作用的表征。的 建议的研究使用带有逆行示踪剂的膜片钳电生理学来确定阿片类药物的作用 在不同的VTA输出通路，并确定哪些神经元表现出上述细胞 撤退的特点。他们还探讨了不同的中脑边缘亚区与阿片类药物的相关性。 依赖性，通过使用具有遗传编码的纤维光度法记录多巴胺释放变化， 多巴胺传感器我们以前的研究表明，阿片类药物暴露的奖励方面和 对阿片样物质依赖的厌恶反应（戒断）可以在机制上分开。通过分离 在回路水平上阿片类药物使用的急性和慢性成分，这项研究将填补我们理解的空白 大脑中的依赖性是如何发展的这项工作对改善阿片类药物的治疗有意义， 药物依赖的风险降低，开发更安全的镇痛剂。作为一项研究金项目， 还将提供一个框架，培训在几个基本的神经科学技术的帮助下， 在高度协作的研究环境中收集各种专家。