Role of BRD4 phosphorylation in the nucleus accumbens in relapse to cocaine-seeking behavior in mice
Role of BRD4 phosphorylation in the nucleus accumbens in relapse to cocaine-seeking behavior in mice
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伏隔核中 BRD4 磷酸化在小鼠可卡因寻求行为复发中的作用
DOI：
10.1111/adb.12808
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发表时间：
2019-07-30
影响因子：
3.4
通讯作者：
Cen, Xiaobo
中科院分区：
文献类型：
--
作者：
Guo, Wei;Long, Hailei;Cen, Xiaobo
可卡因成瘾是一种以强迫性药物寻求为特征的慢性复发性大脑疾病。初步研究表明，含溴结构域蛋白4（BRD4），一种表观遗传阅读蛋白，参与可卡因诱导的奖赏和神经可塑性。然而，BRD4在可卡因成瘾，特别是可卡因复吸中的确切作用仍然难以捉摸。在这项研究中，我们发现，BRD4磷酸化的核神经元（NAc）是密切相关的可卡因强化和复发的维持在不同的可卡因暴露范式。在NAc中，辅酶Ⅱ显著增加了磷酸化BRD4（pBRD4）在Gria2和Bdnf基因启动子处的结合。（+）选择性BRD4抑制剂JQ1显著减少可卡因寻求行为的强化和恢复，伴随着GRIA2和BDNF表达的减少。此外，染色质免疫沉淀分析表明，（+）JQ1明显减弱可卡因增强的结合pBRD4在Gria2和Bdnf基因的启动子。阻断酪蛋白激酶II显著减弱BRD4磷酸化和可卡因复发样行为，表明pBRD4在调节可卡因效应中的重要作用。总之，我们的研究结果表明，NAc中的BRD4磷酸化调节可卡因的多种成瘾相关行为，特别是可卡因寻求行为的复发。抑制BRD4活性可能是对抗可卡因成瘾和复发的新靶点。
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.