The Selective Bromodomain and Extra‐Terminal Domain (BET) Inhibitor RVX‐208 Reduces Cocaine‐Seeking Behaviour and Alters Proteomic Pathways in the Nucleus Accumbens

Bromodomain and extra terminal domain (BET) epigenetic 'reader' proteins are key regulators of both behavioural and molecular responses to cocaine. 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-BET inhibition may restrict translational applications. Recently, RVX-208, a clinically tested and domain-selective BET inhibitor, was found to reduce cocaine conditioned responses and cocaine-induced gene expression in the nucleus accumbens (NAc), while avoiding the learning and memory impairments associated with pan-BET inhibitors. However, the effectiveness of RVX-208 in cocaine self-administration procedures remains unclear. Here, we investigated whether repeated RVX-208 treatment during abstinence altered cocaine-seeking behaviour in rats trained to self-administer cocaine. Male and female Sprague Dawley rats underwent 17 days of cocaine or sucrose self-administration, followed by daily treatment with vehicle or RVX-208 (25 mg/kg, ip) during a 14-day abstinence period. Rats in the RVX-208-treated group showed reduced lever pressing compared to vehicle controls. Sucrose-seeking and open field behaviour (distance travelled and time in the centre zone) were not significantly affected by RVX-208 treatment. Proteomic analysis of the NAc revealed that RVX-208 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-dependent. Collectively, these findings indicate that domain-selective BET inhibition is effective at reducing cocaine-seeking behaviour and point to novel mechanisms that may contribute to its therapeutic effect.