Elucidating behavior and neural circuits underlying opioid addiction and dependence

项目总结/摘要 处方阿片类药物成瘾是一个重要的问题，其特征是强迫性药物寻求， 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， 一些临床前研究已经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延伸杏仁核中的神经回路调节情绪 行为，以及这些奖励和压力系统的失调是药物依赖的标志， 戒断静脉内药物自我给药的模型是用于研究 加强药物的作用，我已经开发了一个模型的羟考酮自我管理下延长 访问条件（12小时/天），产生强烈的寻求药物行为的升级，并提供一个 阿片类药物滥用的预防相关模型。我们假设羟考酮滥用的升级和 依赖是由戒断引起的神经信号机制的变化介导的， 操纵这些潜在的神经系统将减弱对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来检验这一假设 羟考酮的自我给药 我的研究培训将由我的导师迈克尔·塔菲、托马斯·卡什和坎迪斯博士监督 Contet，在Bryan Roth博士作为顾问和Marisa Roberto博士，Kim Janda和 迈克尔·福斯特是我职业发展的顾问。我们设计了一个多学科项目， 利用不同的实验方式，允许行为，生化和免疫组织化学， 羟考酮成瘾性和依赖性研究KOR激活的精确表征将是 通过使用化学遗传学技术实现，设计者受体仅由 设计师药物（DREADDs）。我们将采用神经回路操作，特别是抑制性的Gi-耦合 杏仁核中央核（CeA）中的κ阿片受体DREADD（KORD）GABA能投射到 下丘脑室旁核（PVN）了解阿片类药物诱导的 神经适应调节药物寻求行为。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学方面的经验。这些技能将在 在我的K99阶段在斯克里普斯研究所，并将进一步实施在我的新机构 在R00阶段。我的导师团队将帮助我在我的独立实验室建立这些技术 以确保实验的可重复性。总的来说，这项工作将提供深入了解卡帕的影响， 杏仁核通路中的阿片受体信号介导阿片成瘾和依赖诱导 行为

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.