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.