Authors: Caleb J. Browne, Rita Futamura, Angélica Minier-Toribio, Emily M. Hicks, Aarthi Ramakrishnan, Freddyson J. Martínez-Rivera, Molly Estill, Arthur Godino, Eric M. Parise, Angélica Torres-Berrío, Ashley M. Cunningham, Peter J. Hamilton, Deena M. Walker, Laura M. Huckins, Yasmin L. Hurd, Li Shen, Eric J. Nestler
Published: 2023-06-09
Source: Full article
Opioid use disorder (OUD) looms as one of the most severe medical crises facing society. More effective therapeutics will require a deeper understanding of molecular changes supporting drug-taking and relapse. Here, we develop a brain reward circuit-wide atlas of opioid-induced transcriptional regulation by combining RNA sequencing (RNA-seq) and heroin self-administration in male mice modeling multiple OUD-relevant conditions: acute heroin exposure, chronic heroin intake, context-induced drug-seeking following abstinence, and relapse. Bioinformatics analysis of this rich dataset identified numerous patterns of transcriptional regulation, with both region-specific and pan-circuit biological domains affected by heroin. Integration of RNA-seq data with OUD-relevant behavioral outcomes uncovered region-specific molecular changes and biological processes that predispose to OUD vulnerability. Comparisons with human OUD RNA-seq and genome-wide association study data revealed convergent molecular abnormalities and gene candidates with high therapeutic potential. These studies outline molecular reprogramming underlying OUD and provide a foundational resource for future investigations into mechanisms and treatment strategies.