1. Arginine Methyltransferase 1 in the Nucleus Accumbens Regulates Behavioral Effects of Cocaine.
- Author
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Yan Li, Ruiming Zhu, Wenjing Wang, Dengqi Fu, Jing Hou, Sen Ji, Bo Chen, Zhengtao Hu, Xue Shao, Xuri Yu, Qian Zhao, Baolai Zhang, Changman Du, Qian Bu, Chunyan Hu, Yun Tang, Lei Zhong, Shengyong Yang, Yinglan Zhao, and Xiaobo Cen
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COCAINE & psychology ,PROTEIN arginine methyltransferases ,NUCLEUS accumbens ,HISTONES ,DOWNREGULATION - Abstract
Recent evidence suggests that histone modifications play a role in the behavioral effects of cocaine in rodent models. Histone arginine is knownto be methylated by protein arginineN-methyltransferases (PRMTs). Evidence shows thatPRMT1contributes to90%of cellular PRMT activity, which regulates histone H4 arginine 3 asymmetric dimethylation (H4R3me2a). Though histone arginine methylation represents a chemical modification that is relatively stable compared with other histone alterations, it is less well studied in the setting of addiction. Here, we demonstrate that repeated noncontingent cocaine injections increase PRMT1 activity in the nucleus accumbens (NAc) of C57BL/6 mice. We, subsequently, identify a selective inhibitor of PRMT1, SKLB-639, and show that systemic injections of the drug decrease cocaine-induced conditioned place preference to levels observed with genetic knockdown of PRMT1. NAc-specific downregulation of PRMT1 leads to hypomethylation of H4R3me2a, and hypoacetylation of histone H3 lysine 9 and 14. We also found that H4R3me2ais upregulated inNAcafter repeated cocaine administration, and thatH4R3me2aupregulation in turn controls the expression of Cdk5 and CaMKII. Additionally, the suppression ofPRMT1in NAc with lentiviral-short hairpinPMRT1decreases levels of CaMKII and Cdk5 in the cocaine-treated group, demonstrating that PRMT1 affects the ability of cocaine to induce CaMKII and Cdk5 in NAc. Notably, increased H4R3me2a by repeated cocaine injections is relatively long-lived, as increased expression was observed for up to 7 d after the last cocaine injection. These results show the role of PRMT1 in the behavioral effects of cocaine. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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