title: Reversal of cocaine-conditioned place preference through methyl supplementation in mice: altering global DNA methylation in the prefrontal cortex.
abstract: Analysis of global methylation in cells has revealed correlations between overall DNA methylation status and some biological states. Recent studies suggest that epigenetic regulation through DNA methylation could be responsible for neuroadaptations induced by addictive drugs. However, there is no investigation to determine global DNA methylation status following repeated exposure to addictive drugs. Using mice conditioned place preference (CPP) procedure, we measured global DNA methylation level in the nucleus accumbens (NAc) and the prefrontal cortex (PFC) associated with drug rewarding effects. We found that cocaine-, but not morphine- or food-CPP training decreased global DNA methylation in the PFC. Chronic treatment with methionine, a methyl donor, for 25 consecutive days prior to and during CPP training inhibited the establishment of cocaine, but not morphine or food CPP. We also found that both mRNA and protein level of DNMT (DNA methytransferase) 3b in the PFC were downregulated following the establishment of cocaine CPP, and the downregulation could be reversed by repeated administration of methionine. Our study indicates a crucial role of global PFC DNA hypomethylation in the rewarding effects of cocaine. Reversal of global DNA hypomethylation could significantly attenuate the rewarding effects induced by cocaine. Our results suggest that methionine may have become a potential therapeutic target to treat cocaine addiction.
authors.affiliation: Department of Forensic Science, School of Medicine, Xi'an Jiaotong University, Xi'an, Shan'xi, China.
authors.forename: Weiping
authors.initials: W
authors.lastname: Tian
authors.forename: Mei
authors.initials: M
authors.lastname: Zhao
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Tianbao
authors.initials: T
authors.lastname: Song
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Quan
authors.forename: Shengbin
authors.initials: S
authors.lastname: Li
authors.forename: Zhong Sheng
authors.initials: ZS
authors.lastname: Sun
mesh_terms: D000818:Animals; D001483:Base Sequence; D019970:Cocaine-Related Disorders / Q000188:drug therapy* / Q000378:metabolism* / Q000523:psychology; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005502:Food; D008297:Male; D008715:Methionine / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009021:Morphine Dependence / Q000188:drug therapy / Q000378:metabolism / Q000523:psychology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012201:Reward
chemical_list: D004268:DNA-Binding Proteins; C489326:Mbd2 protein, mouse; D012333:RNA, Messenger; D008715:Methionine; D004248:DNA (Cytosine-5-)-Methyltransferases