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

## TL;DR

A drug called RVX-208 reduces cocaine-seeking behavior in rats without affecting normal behaviors, possibly by altering brain pathways linked to dopamine and glutamate.

## Contribution

RVX-208, a selective BET inhibitor, reduces cocaine-seeking without impairing memory, offering a safer therapeutic approach for substance use disorders.

## Key findings

- RVX-208 reduced cocaine-seeking behavior in rats during abstinence without affecting sucrose-seeking.
- Proteomic changes in the nucleus accumbens suggest dopamine and glutamate signaling are involved in the drug's effect.
- The effects of RVX-208 on proteins were sex-dependent, indicating potential differences in treatment response.

## Abstract

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.

Rats treated with the domain‐selective BET inhibitor RVX‐208 during a 2‐week forced abstinence period exhibited a reduction in cocaine‐seeking behaviour but not sucrose seeking or open field behaviour. This treatment effect was associated with proteomic changes in pathways relevant to dopaminergic and glutamatergic signalling in the nucleus accumbens. Together, these findings provide preliminary support for RVX‐208's therapeutic potential in cocaine self‐administration procedures and highlight potential mechanisms through which domain‐selective BET inhibition reduces cocaine‐seeking behaviour.