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- Title
Decoding cocaine-induced proteomic adaptations in the mouse nucleus accumbens.
- Authors
Mews, Philipp; Sosnick, Lucas; Gurung, Ashik; Sidoli, Simone; Nestler, Eric J.
- Abstract
Cocaine use disorder (CUD) is a chronic neuropsychiatric condition that results from enduring cellular and molecular adaptations. Among substance use disorders, CUD is notable for its rising prevalence and the lack of approved pharmacotherapies. The nucleus accumbens (NAc), a region that is integral to the brain's reward circuitry, plays a crucial role in the initiation and continuation of maladaptive behaviors that are intrinsic to CUD. Leveraging advancements in neuroproteomics, we undertook a proteomic analysis that spanned membrane, cytosolic, nuclear, and chromatin compartments of the NAc in a mouse model. The results unveiled immediate and sustained proteomic modifications after cocaine exposure and during prolonged withdrawal. We identified congruent protein regulatory patterns during initial cocaine exposure and reexposure after withdrawal, which contrasted with distinct patterns during withdrawal. Pronounced proteomic shifts within the membrane compartment indicated adaptive and long-lasting molecular responses prompted by cocaine withdrawal. In addition, we identified potential protein translocation events between soluble-nuclear and chromatin-bound compartments, thus providing insight into intracellular protein dynamics after cocaine exposure. Together, our findings illuminate the intricate proteomic landscape that is altered in the NAc by cocaine use and provide a dataset for future research toward potential therapeutics. Editor's summary: Cocaine use, addiction, and relapse are challenging to treat. Reward circuits in the brain activated by cocaine include the nucleus accumbens (NAc) in the CNS. Mews et al. performed subcellular proteomics of the NAc in mice to explore the spatiotemporal protein landscape during chronic cocaine use, withdrawal, and reuse. The findings implicated plasma membrane–associated proteins and intranuclear protein shuttling during withdrawal, providing insight into the intricate protein dynamics from which therapeutic strategies might be developed. —Leslie K. Ferrarelli
- Subjects
NUCLEUS accumbens; COCAINE-induced disorders; PROTEOMICS; REWARD (Psychology); DOPAMINE; BRAIN physiology; BLOOD proteins
- Publication
Science Signaling, 2024, Vol 17, Issue 832, p1
- ISSN
1945-0877
- Publication type
Article
- DOI
10.1126/scisignal.adl4738