Decoding Cocaine-Induced Proteomic Adaptations in the Mouse Nucleus Accumbens

Cocaine use disorder (CUD) is a chronic neuropsychiatric condition characterized by a compulsion to use cocaine, resulting from enduring cellular and molecular adaptations. Among substance use disorders (SUDs), CUD is notable for its rising prevalence and the lack of approved pharmacotherapies. The nucleus accumbens (NAc), integral to the brain's reward circuitry, plays a crucial role in the initiation and continuation of maladaptive behaviors intrinsic to CUD. Leveraging advancements in neuroproteomics, we undertook an in-depth proteomic analysis of the NAc in a mouse model that spans membrane, cytosolic, nuclear, and chromatin compartments. Our study unveils immediate and sustained proteomic modifications post-cocaine exposure and during prolonged withdrawal. We identify congruent protein regulatory patterns during initial cocaine exposure and re-exposure post-withdrawal, contrasted against distinct patterns during withdrawal. Pronounced proteomic shifts within the membrane compartment indicate adaptive and long-lasting molecular responses prompted by cocaine withdrawal. Additionally, we describe protein translocation events between soluble-nuclear and chromatin-bound compartments, providing novel insight into intracellular protein dynamics post-cocaine exposure. Together, our findings illuminate the intricate proteomic landscape altered in the NAc by cocaine and provide a comprehensive dataset for future research toward potential therapeutics.