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.

Methamphetamine (METH) abuse has become a major public health concern worldwide without approved pharmacotherapies. The brain renin-angiotensin system (RAS) is involved in the regulation of neuronal function as well as neurological disorders. Angiotensin II (Ang II), which interacts with Ang II type 1 receptor (AT-R) in the brain, plays an important role as a neuromodulator in dopaminergic transmission. However, the role of brain RAS in METH-induced behavior is largely unknown. Here, we revealed that repeated METH administration significantly upregulated the expression of AT-R in the striatum of mice, but downregulated dopamine D3 receptor (D3R) expression. A specific AT-R blocker telmisartan, which can penetrate the brain-blood barrier (BBB), or genetic deletion of AT-R was sufficient to attenuate METH-triggered hyperlocomotion in mice. However, intraperitoneal injection of AT-R blocker losartan, which cannot penetrate BBB, failed to attenuate METH-induced behavior. Moreover, intra-striatum re-expression of AT with lentiviral virus expressing AT reversed the weakened locomotor activity of AT mice treated with METH. Losartan alleviated METH-induced cytotoxicity in SH-SY5Y cells in vitro, which was accompanied by upregulated expressions of D3R and dopamine transporter. In addition, intraperitoneal injection of perindopril, which is a specific ACE inhibitor and can penetrate BBB, significantly attenuated METH-induced hyperlocomotor activity. Collectively, our results show that blockade of brain RAS attenuates METH-induced hyperlocomotion and neurotoxicity possibly through modulation of D3R expression. Our findings reveal a novel role of Ang II-AT-R in METH-induced hyperlocomotion.

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Circular RNA (circRNA), a novel type of endogenous non-coding RNA, plays natural miRNA sponge effect that represses the activities of corresponding miRNAs through binding with them, thus modulating transcriptional expression of genes. Recent studies indicate that circRNAs are significantly enriched in the brain and some of them are derived from synaptic protein-coding genes. In addition, miRNAs are involved in synaptic plasticity, memory formation, and cocaine addiction. However, the role of circRNAs in cocaine reward is unclear. This study aimed to investigate the expression profile of striatal circRNAs in the mice after cocaine self-administration. By using circRNA microarray analysis, we observed that 90 striatal circRNAs were differentially expressed in cocaine self-administering mice, of which 18 circRNAs were up-regulated and 72 down-regulated. Six circRNAs were selected randomly for validation by using quantitative reverse transcription-PCR, and their expression levels showed consistency with microarray analysis. We backward predicted the circRNAs and their binding sites of miRNAs associated with neuroplasticity. In functional validation test, mmu_circRNA_002381 may modulate the transcription of certain genes associated with neuroplasticity, such as limk1 and bdnf . Taken together, circRNAs may participate in cocaine behavioral effect via interacting with miRNAs. Our findings reveal a potential role of circRNAs in cocaine effect.