title: Arginine Methyltransferase 1 in the Nucleus Accumbens Regulates Behavioral Effects of Cocaine.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: National 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.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: National 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.
authors.forename: Ruiming
authors.initials: R
authors.lastname: Zhu
authors.affiliation: State 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.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Wang
authors.affiliation: National 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.
authors.forename: Dengqi
authors.initials: D
authors.lastname: Fu
authors.affiliation: National 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.
authors.forename: Jing
authors.initials: J
authors.lastname: Hou
authors.affiliation: National 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.
authors.forename: Sen
authors.initials: S
authors.lastname: Ji
authors.affiliation: National 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.
authors.forename: Bo
authors.initials: B
authors.lastname: Chen
authors.affiliation: National 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.
authors.forename: Zhengtao
authors.initials: Z
authors.lastname: Hu
authors.affiliation: National 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.
authors.forename: Xue
authors.initials: X
authors.lastname: Shao
authors.affiliation: State 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.
authors.forename: Xuri
authors.initials: X
authors.lastname: Yu
authors.affiliation: National 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.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: National 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.
authors.forename: Baolai
authors.initials: B
authors.lastname: Zhang
authors.affiliation: National 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.
authors.forename: Changman
authors.initials: C
authors.lastname: Du
authors.affiliation: National 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.
authors.forename: Qian
authors.initials: Q
authors.lastname: Bu
authors.affiliation: National 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.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Hu
authors.affiliation: State 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.
authors.forename: Yun
authors.initials: Y
authors.lastname: Tang
authors.affiliation: State 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.
authors.forename: Lei
authors.identifier: http://orcid.org/0000-0002-1901-9698
authors.initials: L
authors.lastname: Zhong
authors.affiliation: State 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.
authors.forename: Shengyong
authors.initials: S
authors.lastname: Yang
authors.affiliation: State 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 xbcen@scu.edu.cn alancenxb@sina.com.
authors.forename: Yinglan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: National 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 xbcen@scu.edu.cn alancenxb@sina.com.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Cen
mesh_terms: D000578:Amidines / Q000494:pharmacology*; D000818:Animals; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D003042:Cocaine / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D006657:Histones / Q000378:metabolism*; D008745:Methylation; D051379:Mice; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational; D011484:Protein-Arginine N-Methyltransferases / Q000037:antagonists & inhibitors / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology
chemical_list: D000578:Amidines; D006657:Histones; D009419:Nerve Tissue Proteins; D011743:Pyrimidines; D034741:RNA, Small Interfering; C000603965:SKLB-639; C546338:Prmt1 protein, mouse; D011484:Protein-Arginine N-Methyltransferases; D003042:Cocaine
keywords: PRMT inhibitor; behavioral plasticity; cocaine; histone arginine methylation; protein arginine N-methyltransferase 1