Elucidating behavior and neural circuits underlying opioid addiction and dependence

项目摘要/摘要 处方类阿片成瘾是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健康的影响越来越大，但相对 很少有临床前研究探讨自我给药的神经生物学机制。 羟考酮，一种常见的处方药。杏仁核延长区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和 戒烟。静脉给药模型是研究药物自身给药的标准范式。 增强药物的作用，我开发了一个羟考酮自我给药模型，在扩展的 接触条件(每天12小时)，使寻求毒品行为强劲升级，并提供 阿片类药物滥用的翻译相关模式。我们假设羟考酮滥用的升级和 依赖是通过戒断诱导的神经信号机制的变化来调节的，而且 操纵这些潜在的神经系统将减弱对寻求毒品行为的促进。我们会 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验证这一假说 在延长访问条件下的羟考酮自我给药。 我的研究培训将由我的导师迈克尔·塔菲、托马斯·卡什和坎迪斯博士指导 Contet，由Bryan Roth博士担任顾问，Marisa Roberto博士，Kim Janda和 迈克尔·福斯特担任我职业发展的顾问。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 羟考酮成瘾和依赖的调查。KOR激活的准确特征将是 通过使用化学发生技术，设计者受体被独家激活 特制药(DREADD)。我们将使用神经电路操作，特别是抑制性胃肠道耦合 杏仁中央核内Kappa阿片受体DREADD(Kord)GABA能投射到 了解阿片类药物对下丘脑室旁核(PVN)的影响 神经适应调节寻药行为。我将接受基于DREADD和免疫组织化学的培训 补充我在阿片类药物行为学方面的经验的技巧。这些技能将会被获得 在我在斯克里普斯研究所的K99阶段，并将在我的新机构进一步实施 在R00阶段。我的导师团队将在我的独立实验室帮助我建立这些技术 以确保实验的重复性。总而言之，这项工作将提供对卡帕影响的洞察 杏仁核通路中阿片受体信号转导阿片成瘾和依赖 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.