DUSP5 Downregulation in Nucleus Accumbens Core Correlates with Synaptic Plasticity and Cue-Induced Cocaine Reinstatement

ABSTRACT The United States is currently facing a drug overdose epidemic, with substance use disorder (SUD) characterized by cyclical phases of drug use, withdrawal, and relapse. The nucleus accumbens core (NAcore), a brain region critical for reward and aversion behaviors, undergoes structural and functional synaptic adaptations in response to chronic drug exposure. These changes, particularly in dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs), are implicated in drug-seeking behaviors and synaptic plasticity. However, the molecular mechanisms underlying these adaptations remain poorly understood. In this study, we investigate the role of dual-specificity phosphatase 5 (DUSP5), an phosphatase known to deactivate extracellular signal-regulated kinase (ERK), in cocaine-induced neuroplasticity. While prior research has linked other DUSP family members to various drugs of abuse, the specific role of DUSP5 in cocaine addiction remains unexplored. We hypothesized that lack of DUSP5 contributes to NAcore synaptic plasticity during cue-induced cocaine reinstatement. To test this, we employed a rat cocaine self-administration model, integrated molecular analyses, and mined publicly available single-cell RNA sequencing data from cocaine-treated NAcore. Our findings aim to elucidate the potential involvement of DUSP5 in cocaine-related synaptic adaptations and behavior, addressing a significant gap in the mechanistic understanding of SUD. Competing Interest Statement The authors have declared no competing interest.