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In substance use disorder (SUD) models, BET function has primarily been investigated using small molecule inhibitors that prevent both bromodomains of BET proteins from interacting with acetylated histones. Although these inhibitors have been shown to be effective in SUD models, the potential adverse effects of pan\u2010BET inhibition may restrict translational applications. Recently, RVX\u2010208, a clinically tested and domain\u2010selective BET inhibitor, was found to reduce cocaine conditioned responses and cocaine\u2010induced gene expression in the nucleus accumbens (NAc), while avoiding the learning and memory impairments associated with pan\u2010BET inhibitors. However, the effectiveness of RVX\u2010208 in cocaine self\u2010administration procedures remains unclear. Here, we investigated whether repeated RVX\u2010208 treatment during abstinence altered cocaine\u2010seeking behaviour in rats trained to self\u2010administer cocaine. Male and female Sprague Dawley rats underwent 17\u2009days of cocaine or sucrose self\u2010administration, followed by daily treatment with vehicle or RVX\u2010208 (25\u2009mg\/kg, ip) during a 14\u2010day abstinence period. Rats in the RVX\u2010208\u2010treated group showed reduced lever pressing compared to vehicle controls. Sucrose\u2010seeking and open field behaviour (distance travelled and time in the centre zone) were not significantly affected by RVX\u2010208 treatment. Proteomic analysis of the NAc revealed that RVX\u2010208 modulated several proteins, including those associated with dopamine activity (DRD1 and SLC6A3), transcriptional regulation (NFKB1), glutamate transport (SLC1A2) and ion channel activity (KCNJ10), and many changes were sex\u2010dependent. Collectively, these findings indicate that domain\u2010selective BET inhibition is effective at reducing cocaine\u2010seeking behaviour and point to novel mechanisms that may contribute to its therapeutic effect.<\/jats:p>","DOI":"10.1111\/adb.70121","type":"journal-article","created":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T04:29:29Z","timestamp":1767932969000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The Selective Bromodomain and Extra\u2010Terminal Domain (BET) Inhibitor RVX\u2010208 Reduces Cocaine\u2010Seeking Behaviour and Alters Proteomic Pathways in the Nucleus Accumbens"],"prefix":"10.1111","volume":"31","author":[{"given":"Tyler\u00a0J.","family":"Sacko","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences University of Connecticut  Storrs Connecticut USA"},{"name":"Center for Addiction Sciences and Innovation (CASI) University of Connecticut  Storrs 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