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

Abstract

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.

Inhibiting Brd4 alleviated PTSD‐like behaviors and fear memory through regulating immediate early genes expression and neuroinflammation in rats

“…In addition, a previous study showed that JQ1 could inhibit the expression of a key set of neuroplasticity‐related genes (i.e., Egr‐2, insulin‐like growth factor 2) in the anterior cingulate cortex of medial PFC and remote fear memory and fear generalization and response in a model of PTSD (Duan et al., 2020). JQ1 administration significantly decreased the expressions of Arc mRNA in the nucleus accumbens induced by cocaine (Guo et al., 2020). The chronic inhibition of Brd4 prevented the increased expression of Arc, c‐fos, FosB, and ΔFosB observed in a dyskinesia model of animals after levodopa administration (Figge & Standaert, 2017).…”

The Functions of BET Proteins in Gene Transcription of Biology and Diseases

“…Importantly, CK2-mediated phosphorylation of a conserved acidic region in BRD4 dictates whether this region contacts with juxtaposed bromodomain (BD2) or an adjacent basic region, therefore determining if BD2 is free to bind acetylated-TF p53 (Wu et al, 2013). The same mechanism also applies in cocaine-seeking behavior and memory function in mice, as cocaine or neuronal stimulation induces the activation and binding of pBRD4 to the key gene promoter, which can be attenuated by CK2 blockade (Korb et al, 2015;Guo, 2020). Therefore, apart from modulating BRD4 bromodomains' interactions with chromatin, strategies targeting activated pBRD4 may represent an alternative and promising approach.…”

Opposing Functions of BRD4 Isoforms in Breast Cancer

“…Increased phosphorylation of BRD4 in this acidic region because of decreased protein phosphatase 2A (PP2A) activity has been linked to triple-negative breast cancer (TNBC) progression (Shu et al, 2016). This phosphorylation event is also important for learning and memory, as well as normal brain functioning and drug addiction, as illustrated in mouse behavioral studies (Korb et al, 2015;Guo et al, 2019).…”