Elucidating behavior and neural circuits underlying opioid addiction and dependence

阐明阿片类药物成瘾和依赖背后的行为和神经回路

• 批准号: 10658061
• 负责人: Jacques DucHuy Nguyen
• 金额: $ 24.9万
• 依托单位: BAYLOR UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658061
• 关键词: Elucidating; behavior; neural; circuits; underlying

Project Summary/Abstract Prescription opioid addiction is a significant problem characterized by compulsive drug seeking, withdrawal and chronic relapse. Despite the growing impact of prescription opioids on public health, relatively few pre-clinical studies have investigated the neurobiological mechanisms underlying self-administration of oxycodone, a commonly prescribed medication. Neural circuits in the extended amygdala mediate emotional behaviors, and dysregulation of these reward and stress systems is a hallmark of drug dependence and withdrawal. Models of intravenous drug self-administration are a standard paradigm for investigating the reinforcing effects of drugs, and I have developed a model of oxycodone self-administration under extended access conditions (12 hours/day) that produces robust escalation of drug-seeking behavior and provides a translationally relevant model of opioid abuse. We hypothesize that escalation of oxycodone abuse and dependence are mediated by withdrawal-induced changes in neural signaling mechanisms, and that the manipulation of these underlying neural systems will attenuate the promotion of drug-seeking behavior. We will test this hypothesis using behavioral pharmacology, chemogenetics, and immunohistochemistry in a rat model of oxycodone self-administration under extended access conditions. My research training will be supervised by my mentors, Drs. Michael Taffe, Thomas Kash and Candice Contet, with additional support from Dr. Bryan Roth as consultant and Drs. Marisa Roberto, Kim Janda and Michael Forster as advisors for my career development. We have designed a multidisciplinary project that utilizes different experimental modalities that allow for behavioral, biochemical, and immunohistochemical investigation of oxycodone addiction and dependence. Precise characterization of KOR activation will be achieved through the use of the chemogenetic technology, designer receptors exclusively activated by designer drugs (DREADDs). We will employ neural circuit manipulations, specifically the inhibitory Gi-coupled kappa opioid receptor DREADD (KORD) in the central nucleus of the amygdala (CeA) GABAergic projection to paraventricular nucleus of the hypothalamus (PVN) to understand the effect of opioid-induced neuroadaptations mediating drug-seeking behavior. I will train in DREADD-based and immunohistochemical techniques to complement my experience in behavioral opioid pharmacology. These skills will be acquired during my K99 phase at The Scripps Research Institute and will be further implemented at my new institution during the R00 phase. My mentor team will help me establish these techniques in my independent laboratory to ensure experimental reproducibility. Collectively, this work will provide insight into the influence of kappa opioid receptor signaling in amygdalar pathways mediating opioid addiction and dependence-induced behavior.

项目概要/摘要 处方阿片类药物成瘾是一个以强迫性药物寻求为特征的重大问题， 戒断和慢性复发。尽管处方阿片类药物对公共卫生的影响越来越大，但相对而言 很少有临床前研究调查了自我给药的神经生物学机制 羟考酮，一种常用处方药。扩展杏仁核中的神经回路调节情绪 行为以及这些奖赏和压力系统的失调是药物依赖和 撤回。静脉注射药物自我给药模型是研究药物的标准范例 加强药物的作用，我开发了一种在延长的情况下羟考酮自我给药的模型 准入条件（每天 12 小时）会导致寻求毒品的行为急剧升级，并提供 阿片类药物滥用的翻译相关模型。我们假设羟考酮滥用的升级和 依赖性是由戒断引起的神经信号机制变化介导的，并且 对这些潜在神经系统的操纵将削弱寻求药物行为的促进。我们将 在大鼠模型中使用行为药理学、化学遗传学和免疫组织化学检验这一假设 羟考酮在扩展使用条件下的自我管理。 我的研究培训将由我的导师 Drs 进行监督。迈克尔·塔夫、托马斯·卡什和坎迪斯 Contet，并得到顾问 Bryan Roth 博士和 Drs 的额外支持。玛丽莎·罗伯托、金·詹达和 迈克尔·福斯特 (Michael Forster) 担任我的职业发展顾问。我们设计了一个多学科项目 利用不同的实验方式进行行为、生化和免疫组织化学分析 羟考酮成瘾和依赖性的调查。 KOR 激活的精确表征将是 通过使用化学遗传学技术实现，设计受体专门由 设计药物（DREADD）。我们将采用神经回路操作，特别是抑制性 Gi 耦合 杏仁核中央核 (CeA) 的 kappa 阿片受体 DREADD (KORD) GABA 能投射至 下丘脑室旁核 (PVN) 了解阿片类药物诱导的作用 介导药物寻求行为的神经适应。我将接受基于 DREADD 和免疫组织化学的培训 技术来补充我在行为阿片类药物药理学方面的经验。将获得这些技能 我在斯克里普斯研究所的 K99 阶段期间，并将在我的新机构进一步实施 在R00阶段。我的导师团队将帮助我在我的独立实验室中建立这些技术 以确保实验的重现性。总的来说，这项工作将深入了解 kappa 的影响 杏仁核通路中的阿片受体信号传导介导阿片成瘾和依赖性诱导 行为。