Mechanistic Role of NMUR2 in Cue-Induced Reinstatement to Cocaine

Mechanistic Role of NMUR2 in Cue-Induced Reinstatement to Cocaine We are proposing a mechanistic strategy to understand the neural circuits that drive cocaine use disorder (CUD). Our work centers on the nucleus accumbens (NAc) to ventral pallidum (VP) projection which represents a critical component in reinforcement and motivated behavior1,2 that may represent a key projection for responses to cocaine- associated cues. Our group identified a previously underexplored ?-aminobutyric acid (GABA) pathway, originating in the dorsal raphe nucleus (DRN) and projecting to the NAc shell (NAcSh), which converges specifically on the ventromedial VP (VPvm) to regulate motivational processing 3- 5 This circuit is tightly regulated by neuromedin U receptor 2 (NMUR2), a G-protein coupled receptor expressed on presynaptic GABA terminals in the NAcSh 3-5 (Fig. 1). Using advanced circuit-mapping approaches, we delineated the GABAergic DRN ? NAcSh ? VPvm pathway and found that neuromedin U (NMU) suppresses GABA release in the NAcSh 3 , thereby attenuating cocaine sensitization 3 , a core neuroadaptation underlying compulsive drug use. Conversely, NMUR2 knockdown in DRN-derived GABA terminals potentiates cocaine sensitization, highlighting this receptor as a key molecular regulator of drug-induced plasticity. In vivo calcium imaging, transsynaptic neuroanatomical tracing 3 , and behavioral responses to cocaine-associated cues are being integrated to dissect the causal role of this pathway in reward and motivation. To further probe this mechanism, we employ NY0128, a small-molecule NMUR2 agonist, as an experimental tool to modulate receptor function in vivo 6. Our preliminary studies demonstrate that NY0128 reduces cue-induced reinstatement to cocaine (Fig. 2). By leveraging NY0128 as a pharmacological probe, we can causally test how NMUR2 signaling shapes DRN?NAcSh?VPvm activity and downstream motivational states. This approach allows us to identify how receptor- level regulation of inhibitory signaling contributes to the maladaptive plasticity underlying cocaine-seeking behavior. Taken together, this work will define how NMUR2-dependent regulation of DRN-derived GABAergic inputs alters mesolimbic circuit dynamics, providing mechanistic insight into one of the root causes of pathological motivation for cues in CUD. By integrating molecular, synaptic, and circuit-level analyses, we seek to uncover fundamental mechanisms that drive behavioral responses to cocaine.