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Articles, Behavioral/Cognitive

Arginine Methyltransferase 1 in the Nucleus Accumbens Regulates Behavioral Effects of Cocaine

Yan Li (李燕), Ruiming Zhu (朱睿明), Wenjing Wang (汪文静), Dengqi Fu (付登琦), Jing Hou (侯静), Sen Ji (纪森), Bo Chen (陈波), Zhengtao Hu (扈正桃), Xue Shao (邵雪), Xuri Yu (余旭日), Qian Zhao (赵倩), Baolai Zhang (张宝来), Changman Du (杜长蔓), Qian Bu (卜迁), Chunyan Hu (胡春燕), Yun Tang (唐芸), Lei Zhong (钟磊), Shengyong Yang (杨胜勇), Yinglan Zhao (赵瀛兰) and Xiaobo Cen (岑小波)
Journal of Neuroscience 16 September 2015, 35 (37) 12890-12902; DOI: https://doi.org/10.1523/JNEUROSCI.0246-15.2015
Yan Li (李燕)
1National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, People's Republic of China, and
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Ruiming Zhu (朱睿明)
1National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, People's Republic of China, and
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Wenjing Wang (汪文静)
2State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, People's Republic of China
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Dengqi Fu (付登琦)
1National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, People's Republic of China, and
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Jing Hou (侯静)
1National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, People's Republic of China, and
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Sen Ji (纪森)
1National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, People's Republic of China, and
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Bo Chen (陈波)
1National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, People's Republic of China, and
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Zhengtao Hu (扈正桃)
1National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, People's Republic of China, and
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Xue Shao (邵雪)
1National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, People's Republic of China, and
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Xuri Yu (余旭日)
2State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, People's Republic of China
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Qian Zhao (赵倩)
1National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, People's Republic of China, and
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Baolai Zhang (张宝来)
1National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, People's Republic of China, and
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Changman Du (杜长蔓)
1National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, People's Republic of China, and
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Qian Bu (卜迁)
1National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, People's Republic of China, and
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Chunyan Hu (胡春燕)
1National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, People's Republic of China, and
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Yun Tang (唐芸)
2State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, People's Republic of China
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Lei Zhong (钟磊)
2State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, People's Republic of China
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  • ORCID record for Lei Zhong (钟磊)
Shengyong Yang (杨胜勇)
2State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, People's Republic of China
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Yinglan Zhao (赵瀛兰)
2State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, People's Republic of China
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Xiaobo Cen (岑小波)
1National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, People's Republic of China, and
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Abstract

Recent evidence suggests that histone modifications play a role in the behavioral effects of cocaine in rodent models. Histone arginine is known to be methylated by protein arginine N-methyltransferases (PRMTs). Evidence shows that PRMT1 contributes to >90% 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 H4R3me2a is upregulated in NAc after repeated cocaine administration, and that H4R3me2a upregulation in turn controls the expression of Cdk5 and CaMKII. Additionally, the suppression of PRMT1 in NAc with lentiviral-short hairpin PMRT1 decreases 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.

SIGNIFICANCE STATEMENT This work demonstrated that repeated cocaine injections led to an increase of protein arginine N-methyltransferase (PRMT1) in nucleus accumbens (NAc). We then identified a selective inhibitor of PRMT1 (SKLB-639), which inhibited cocaine-induced conditioned place preference (CPP). Additionally, genetic downregulation of PRMT1 in NAc also attenuated cocaine-caused CPP and locomotion activity, which was associated with decreased expression of histone H4 arginine 3 asymmetric demethylation (H4R3me2a) and hypoacetylation of histone H3 lysine 9 and 14 (acH3K9/K14). This study also showed that H4R3me2a controlled transcriptions of Cdk5 and CaMKII, and that PRMT1 negatively affected the ability of cocaine to induce CaMKII and Cdk5 in NAc. Notably, increased H4R3me2a by repeated cocaine injection was relatively long-lived as increased expression was observed up to 7 d after withdrawal from cocaine. Together, this study suggests that PRMT1 inhibition may serve as a potential therapeutic strategy for cocaine addiction.

  • behavioral plasticity
  • cocaine
  • histone arginine methylation
  • PRMT inhibitor
  • protein arginine N-methyltransferase 1
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The Journal of Neuroscience: 35 (37)
Journal of Neuroscience
Vol. 35, Issue 37
16 Sep 2015
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Arginine Methyltransferase 1 in the Nucleus Accumbens Regulates Behavioral Effects of Cocaine
Journal of Neuroscience 16 September 2015, 35 (37) 12890-12902; DOI: 10.1523/JNEUROSCI.0246-15.2015

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Arginine Methyltransferase 1 in the Nucleus Accumbens Regulates Behavioral Effects of Cocaine
Journal of Neuroscience 16 September 2015, 35 (37) 12890-12902; DOI: 10.1523/JNEUROSCI.0246-15.2015
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Keywords

  • behavioral plasticity
  • cocaine
  • histone arginine methylation
  • PRMT inhibitor
  • protein arginine N-methyltransferase 1

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