Ventral Pallidum Circuits in Motivation, Risky Decision Making, and Opioid Addiction

腹侧苍白球回路在动机、危险决策和阿片类药物成瘾中的作用

基本信息

批准号：
10308001
负责人：
Mitchell Farrell
金额：
$ 4.3万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2022-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10308001
关键词：
Abstinence Acute Address Animal Model Attention Attenuated Award Behavior Behavior Control Behavioral Behavioral Model Brain Brain region Cells Cocaine Cognition Coupled Cues Data Decision Making Development Disease Doctor of Philosophy Drug Addiction Drug usage Educational process of instructing Educational workshop Electrophysiology (science)Environment Exhibits Faculty Fellowship Fentanyl Food Funding Gene Transfer Globus Pallidus Goals Grant Hand Health Image Individual Lead Learning Mediating Mental disorders Mentors Mentorship Modeling Monitor Motivation National Institute of Drug Abuse Neurons Neurosciences Neurotransmitters Opiate Addiction Opioid Outcome Palate Paper Pathologic Pathway interactions Pharmaceutical Preparations Pharmacology Phase Positioning Attribute Postdoctoral Fellow Preparation Problem Solving Procedures Process Protocols documentation Published Comment Publishing Punishment Rattus Relapse Research Resources Rest Rewards Risk Rodent Model Role Scientist Self Administration Shock Substance Use Disorder Sum Symptoms Techniques Testing Time Training Universities Ventral Tegmental Area Work addiction adverse outcome analog base career cell type cocaine exposure cocaine relapse cost designer receptors exclusively activated by designer drugs drug of abuse drug reward effective therapy footshock induced gamma-Aminobutyric Acid human model in vivo individual variation model design motivated behavior neural circuit opioid epidemic post-doctoral training pre-clinical pre-doctoral professor programs remifentanil skills tenure track therapeutic target training opportunity

项目摘要

Project Summary Substance use disorder poses a major health threat that costs billions of dollars and thousands of lives annually, and which is especially acute right now for opioid drugs and cocaine. In susceptible individuals, drugs of abuse hijack brain circuits that govern motivation and decision making, leading to continued seeking of drugs despite harmful consequences of using them. Even when people decide to cease their increasingly maladaptive drug use, in most cases they end up relapsing. In order to help those trying to quit using drugs to stay abstinent, we must understand how underlying neural circuits of motivation and decision making work in the brain, and for this we need translationally-relevant animal models. Here, I employ such models, coupled with cell-type and pathway-specific chemogenetic (DREADD) manipulation approaches to understand how they process decision making about cocaine and an opioid fentanyl analogue, as well as for natural rewards. I focus on the role of ventral pallidum (VP) circuits in addiction-relevant behaviors. To date, I have shown that VP neurons are Fos activated by cocaine-relapse-inducing cues, and that chemogenetic VP inhibition diminishes relapse-like behavior following voluntary abstinence, especially in the most compulsively cocaine- seeking individuals (Aim 1.1) I also showed that selective chemogenetic inhibition of VP GABA-expressing neurons attenuates risky decision making behavior in pursuit of palatable food, and decreases instrumental responding both in pursuit of valuable foods, and in avoidance of being shocked, indicating a fundamental role for these neurons in motivation regardless of valence (Aim 1.2). The F99 phase of this award will shift my focus to an ongoing health crisis: the opioid epidemic. I first confirm my preliminary finding of VP GABA neuron involvement in relapse to opioid seeking, using a new punishment-induced abstinence relapse procedure that models human relapse after voluntary abstinence (Aim 2.1). Aim 2.2 addresses the wider circuits in which VP is embedded to regulate addiction-related motivation. Specifically, we use a pathway-specific DREADD inhibition approach to test whether VP GABA projections to VTA in particular are involved in opioid addiction. The proposed training will facilitate my transition to a competitive postdoctoral position focused on in vivo circuit monitoring, which will dovetail with my expertise in addiction behavioral models, and chemogenetic circuit manipulations. Through establishment of the Irvine Center for Addiction Neuroscience, UCI offers a stimulating, collaborative research environment with faculty dedicated to solving the problem of addiction at the multiple levels with a host of technical resources, mentorship training opportunities, and professional development workshops. In sum, the F99/K00 will be invaluable for keeping me on a track to tenure and beyond as an addiction behavioral neuroscientist.

项目摘要药物使用障碍构成了主要的健康威胁，耗资数十亿美元和数千美元每年，对于阿片类药物和可卡因而言，这尤其是急性。在易感人群中，毒品虐待劫持动力和决策的劫持脑电路，导致继续寻求尽管使用它们有害后果，但毒品。即使人们决定停止越来越适应不良的药物使用，在大多数情况下，它们最终会复发。为了帮助那些试图戒烟的人保持戒酒，我们必须了解动机和决策的基本神经回路大脑，为此，我们需要与翻译相关的动物模型。在这里，我采用这样的模型，耦合采用细胞类型和途径特异性化学遗传（Dreadd）操纵方法，以了解如何了解他们处理有关可卡因和阿片类药物芬太尼类似物以及自然奖励的决策。我专注于腹侧颗粒（VP）电路在成瘾与相关行为中的作用。迄今为止，我已经表明 VP神经元通过可卡因 - 释放的诱导线索激活FO，并且化学遗传学VP抑制自愿戒酒后会减少复发样的行为，尤其是在最强迫性可卡因中寻求个体（AIM 1.1）我还表明，选择性化学发生抑制VP GABA表达神经元减弱了追求可口食品的风险决策行为，并降低了工具性为追求宝贵的食物以及避免被震惊而做出回应，表明了基本的角色对于这些神经元，无论价值如何（AIM 1.2）。该奖项的F99阶段将改变我的重点持续的健康危机：阿片类药物流行。我首先确认我对副总裁GABA神经元的初步发现使用新的惩罚引起的禁欲复发程序参与复发，模型自愿节制后的人类复发（AIM 2.1）。 AIM 2.2解决了VP的较宽电路被嵌入以调节与成瘾有关的动机。具体来说，我们使用特定于途径的恐惧测试VP GABA对VTA的预测是否尤其参与阿片类药物成瘾的抑制方法。拟议的培训将有助于我过渡到竞争性博士后位置，重点是体内电路监视，这将与我在成瘾行为模型方面的专业知识和化学遗传学相吻合电路操作。通过建立欧文成瘾神经科学中心，UCI提供了刺激，协作研究环境，专门用于解决成瘾问题拥有大量技术资源，指导培训机会和专业的多个级别开发研讨会。总而言之，F99/k00对于让我保持任期和超越成瘾行为神经科学家。