Reversal of Cocaine-Conditioned Place Preference through Methyl Supplementation in Mice: Altering Global DNA Methylation in the Prefrontal Cortex

Weiping Tian,Mei Zhao,Min Li,Shengbin Li,Zhong Sheng Sun,Min Zhang,Li Quan,Tianbao Song,Judith Homberg

doi:10.1371/journal.pone.0033435

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.

Highlights

Drug addiction is defined as a compulsive pattern of drugseeking and drug-taking behavior that craving continues despite adverse physical or psychosocial consequences [1]
In the current study, using conditioned place preference (CPP) procedure, we examined the role of the global DNA methylation level in the nucleus accumbens (NAc) and the prefrontal cortex (PFC) in regulating drug rewarding effect
To determine the role of DNA methylation in cocaine, morphine and food CPP, we examined the global DNA methylation in the PFC and the NAc 2 h after CPP testing

Summary

Introduction

Drug addiction is defined as a compulsive pattern of drugseeking and drug-taking behavior that craving continues despite adverse physical or psychosocial consequences [1]. These behavioral abnormalities develop gradually and progressively following repeated exposure to drugs of abuse, and can persist for months or years after discontinuation of drug use [2]. It is suggested that drug-induced neural plasticity drives these longterm behavioral abnormalities and changes of gene expression in brain reward regions playing important roles in this process [1,2,3]. Repeated cocaine exposures increase histone H3 acetylation on the gene promoters of both

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Conclusion