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

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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.