Epigenetic mechanisms play important roles in the maladaptive transcriptional and behavioral responses to drugs of abuse. Inhibition of bromodomain and extra-terminal domain (BET) proteins, a class of histone acetylation reader proteins, has been shown to reduce cocaine-seeking behaviors in animal models of addiction. To date, the role of BET protein in animal models of substance use disorder (SUD) has only been evaluated using pan-BET inhibitors, small molecules that bind to both bromodomains (BD1 and BD2) in all BET proteins. Although these initial studies are encouraging, side effects associated with pan-BET inhibitors may limit their clinical utility as a SUD treatment. In order to evaluate safer and more selective approaches, we utilized a clinically tested BD2 selective BET inhibitor, RVX-208. We show that RVX-208 dose-dependently reduced cocaine conditioned place preference in male mice, similar to the pan-BET inhibitor JQ1. Additionally, RVX-208 did not alter other behaviors, such as: locomotor activity, elevated zero maze, or novel object recognition memory. At the transcriptional level, RVX-208 attenuated the expression of multiple cocaine-induced genes in the nucleus accumbens. RVX-208 also produced a distinct transcriptional response in stimulated primary neurons compared to JQ1 but had little effect on gene expression in non-stimulated neurons. Together, these data indicate that targeting domain-specific BET mechanisms may be an effective and safer strategy to reduce cocaine-induced neurobehavioral adaptations.
Support or Funding Information
This work was supported by National Institute on Drug Abuse grant R00DA040744.
