Novel Addiction Neurocircuits in Cocaine Taking

PROJECT SUMMARY Cocaine use disorder (CUD) is a debilitating problem in the United States with no FDA approved medications to maximize success of treatment. This problem has been exacerbated by the COVID-19 pandemic, and over the past year, cocaine use has increased 10% and a 26.5% increase has been observed in overdose deaths involving cocaine. We endeavor to drive a fresh strategy to develop new pharmacotherapies for CUD. Using a bottom-up strategy, we initiated a focus on the ventral pallidum (VP) which encodes reward and motivation to represent a “final common pathway” for cocaine-taking. A gap in our understanding of the upstream neural circuits regulating the VP hampers our efficacy in predicting strategies to suppress relapse and extend abstinence from CUD. Our exciting new data suggest that a γ-aminobutyric acid (GABA) pathway arising in the dorsal raphe nucleus and targeting the nucleus accumbens converges into the VP to influence reward and motivation processes. This novel pathway is regulated by the G-protein coupled receptor neuromedin U Receptor 2 (NMUR2), a putative “druggable target” for CUD pharmacotherapy. Our goal is to establish this neurocircuitry as a central element in the upstream control of cocaine-driven behavior through the VP of the accumbal pathway. To accomplish this goal, we will employ contemporary strategies including behavioral economics, GABA-specific DREADDs and transsynaptic neuroanatomical tracing to detail connectivity through three integrated brain regions. Overall, these studies will impact the field by laying the foundation for developing therapeutics to treat individuals with CUD.