Role of BRD4 phosphorylation in the nucleus accumbens in relapse to cocaine-seeking behavior in mice.

Cocaine addiction is a chronic relapsing brain disorder characterized by compulsive drug seeking. Preliminary study suggested that bromodomain-containing protein 4 (BRD4), an epigenetic reader protein, participates in cocaine-induced reward and neuroplasticity. However, the exact role of BRD4 in cocaine addiction, particularly cocaine relapse, remains elusive. In this study, we found that BRD4 phosphorylation in the nucleus accumbens (NAc) was closely related to the maintenance of cocaine reinforcement and relapse in different cocaine exposure paradigms. Cocaine significantly increased the binding of phosphorylated BRD4 (pBRD4) at the promoter of Gria2 and Bdnf genes in the NAc. (+)JQ1, a selective BRD4 inhibitor, markedly reduced the reinforcement and reinstatement of cocaine-seeking behaviors, which was accompanied by the decreased expressions of GRIA2 and BDNF. Furthermore, chromatin immunoprecipitation assay showed that (+)JQ1 clearly attenuated cocaine-enhanced binding of pBRD4 at the promotor of Gria2 and Bdnf genes. Blockade of casein kinase II significantly attenuated BRD4 phosphorylation and cocaine relapse-like behaviors, suggesting the important role of pBRD4 in modulating cocaine effect. Together, our findings suggest that BRD4 phosphorylation in the NAc modulates multiple addiction-related behaviors of cocaine and particularly relapse to cocaine-seeking behaviors. Inhibition of BRD4 activity may be a novel target against cocaine addiction and relapse.