GPR6: A Circuit-Level Druggable Target in Cocaine Use Disorder

ABSTRACT Cocaine use disorder (CUD) remains a significant threat to the health and welfare of millions of affected individuals. Despite advances in understanding the neurobiology of CUD, the impact of chronic cocaine use on the brain and the neuronal mechanisms underlying associated behavioral deficits are not fully understood, representing untapped opportunities for therapeutic intervention. Cocaine induces potent rewarding effects primarily through rapid dopamine (DA) release, with medium spiny neurons (MSNs) in the nucleus accumbens (NAc) being particularly responsive to this DA surge. Using a bioinformatics-informed approach, we identified high and selective expression of the G protein-coupled receptor (GPCR) GPR6 in MSNs. GPR6 is an orphan GPCR which lacks verified endogenous agonist(s) and exhibit high constitutive activation of Gs signaling which is proposed to regulate reward-specific behaviors. This proposal aims to address key cell-type and pathway- specific questions by investigating: 1) GPR6 expression on D1R- vs. D2R-MSNs within CUD neurobiology, 2) GPR6 status following intravenous self-administration (IVSA) of cocaine, and 3) the therapeutic potential of GPR6 ligands in CUD treatment using IVSA models. Overall, elucidating GPR6 circuitry, behavior, and signaling mechanisms in well-controlled conditions holds significant potential to inspire innovative approaches for CUD medications. GPR6 is a unique and compelling target for medications development with minimal likelihood of undesirable effects as only trace expression is observed in other tissues.