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Reversal of cocaine-conditioned place preference through methyl supplementation in mice: altering global DNA methylation in the prefrontal cortex.

Tian W, Zhao M, Li M, Song T, Zhang M, Quan L, Li S, Sun ZS - PLoS ONE (2012)

Bottom Line: We found that cocaine-, but not morphine- or food-CPP training decreased global DNA methylation in the PFC.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Forensic Science, School of Medicine, Xi'an Jiaotong University, Xi'an, Shan'xi, China.

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.

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Effects of methionine on the mRNA and protein expression of DNMTs.(a) The effects of methionine on the mRNA expressional alteration of Dnmts and Mbd2 induced by cocaine-CPP. Data depicted as the relative gene expression level. (b) The effects of methionine on the alteration of DNMT3a and 3b induced by cocaine-CPP. Data depicted as the relative protein expression level. *p<0.05 in comparison with S-S group. Data are expressed as mean±SEM. [S-S: n = 8(Fig. a), n = 10(Fig. b); M-S: n = 7(Fig. a), n = 9(Fig. b); S-C: n = 10(Fig. a), n = 9(Fig. b); M-C: n = 10(Fig. a), n = 8(Fig. b)].
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pone-0033435-g004: Effects of methionine on the mRNA and protein expression of DNMTs.(a) The effects of methionine on the mRNA expressional alteration of Dnmts and Mbd2 induced by cocaine-CPP. Data depicted as the relative gene expression level. (b) The effects of methionine on the alteration of DNMT3a and 3b induced by cocaine-CPP. Data depicted as the relative protein expression level. *p<0.05 in comparison with S-S group. Data are expressed as mean±SEM. [S-S: n = 8(Fig. a), n = 10(Fig. b); M-S: n = 7(Fig. a), n = 9(Fig. b); S-C: n = 10(Fig. a), n = 9(Fig. b); M-C: n = 10(Fig. a), n = 8(Fig. b)].

Mentions: To date, increasing data proposed that DNA methylation is a reversible reaction. The steady state of DNA methylation status of a gene reflects a balance of methylation and demethylation [21]. Thus, we speculated that cocaine exposures could disturb this balance through the stimulation of demethylation or inhibition of methylation. Both processes may further result in global DNA hypomethylation. It is generally accepted that DNA methylation occurs through catalysis of DNMTs such as DNMT1, DNMT3a and DNMT3b [21]. Recently, methylated DNA-binding protein 2 (MBD2) was shown to directly remove the methyl group from methylated cytosine in methylated CpGs [22]. Moreover, it was proposed that the DNA methyltransferase DNMT3a acts as a demethylase, possibly through a mechanism that involves deamination [23]. To understand the mechanisms of methionine treatment underlying the behavioral response to cocaine, we compared the mRNA expression of DNMTs and Mbd2 with methionine treatment to the one without methionine treatment. As shown in Figure 4a, Dnmt1 and Mbd2 were not significantly changed in response to methionine treatment. There were significant differences for mRNA expression of Dnmt3a and 3b among S-S, M-S, S-C and M-C groups (F(3, 8) = 30.54, p<0.001 for Dnmt3a and F(3, 8) = 8.23, p = 0.04 for Dnmt 3b). Post hoc analysis revealed that mRNA expression of Dnmt3b (S-S vs. S-C p<0.05) was downregulated following cocaine CPP training at 20 mg/kg cocaine. The downregulation of Dnmt3b (S-C vs. M-C p<0.05) was also reversed by methionine administration. Although Dmnt3a mRNA [S-C vs. M-C p<0.001] was upregulated following cocaine CPP training, the upregulation of Dnmt3a [S-C vs. M-C p = 0.548] was not reversed by subsequent methionine administration.


Reversal of cocaine-conditioned place preference through methyl supplementation in mice: altering global DNA methylation in the prefrontal cortex.

Tian W, Zhao M, Li M, Song T, Zhang M, Quan L, Li S, Sun ZS - PLoS ONE (2012)

Effects of methionine on the mRNA and protein expression of DNMTs.(a) The effects of methionine on the mRNA expressional alteration of Dnmts and Mbd2 induced by cocaine-CPP. Data depicted as the relative gene expression level. (b) The effects of methionine on the alteration of DNMT3a and 3b induced by cocaine-CPP. Data depicted as the relative protein expression level. *p<0.05 in comparison with S-S group. Data are expressed as mean±SEM. [S-S: n = 8(Fig. a), n = 10(Fig. b); M-S: n = 7(Fig. a), n = 9(Fig. b); S-C: n = 10(Fig. a), n = 9(Fig. b); M-C: n = 10(Fig. a), n = 8(Fig. b)].
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pone-0033435-g004: Effects of methionine on the mRNA and protein expression of DNMTs.(a) The effects of methionine on the mRNA expressional alteration of Dnmts and Mbd2 induced by cocaine-CPP. Data depicted as the relative gene expression level. (b) The effects of methionine on the alteration of DNMT3a and 3b induced by cocaine-CPP. Data depicted as the relative protein expression level. *p<0.05 in comparison with S-S group. Data are expressed as mean±SEM. [S-S: n = 8(Fig. a), n = 10(Fig. b); M-S: n = 7(Fig. a), n = 9(Fig. b); S-C: n = 10(Fig. a), n = 9(Fig. b); M-C: n = 10(Fig. a), n = 8(Fig. b)].
Mentions: To date, increasing data proposed that DNA methylation is a reversible reaction. The steady state of DNA methylation status of a gene reflects a balance of methylation and demethylation [21]. Thus, we speculated that cocaine exposures could disturb this balance through the stimulation of demethylation or inhibition of methylation. Both processes may further result in global DNA hypomethylation. It is generally accepted that DNA methylation occurs through catalysis of DNMTs such as DNMT1, DNMT3a and DNMT3b [21]. Recently, methylated DNA-binding protein 2 (MBD2) was shown to directly remove the methyl group from methylated cytosine in methylated CpGs [22]. Moreover, it was proposed that the DNA methyltransferase DNMT3a acts as a demethylase, possibly through a mechanism that involves deamination [23]. To understand the mechanisms of methionine treatment underlying the behavioral response to cocaine, we compared the mRNA expression of DNMTs and Mbd2 with methionine treatment to the one without methionine treatment. As shown in Figure 4a, Dnmt1 and Mbd2 were not significantly changed in response to methionine treatment. There were significant differences for mRNA expression of Dnmt3a and 3b among S-S, M-S, S-C and M-C groups (F(3, 8) = 30.54, p<0.001 for Dnmt3a and F(3, 8) = 8.23, p = 0.04 for Dnmt 3b). Post hoc analysis revealed that mRNA expression of Dnmt3b (S-S vs. S-C p<0.05) was downregulated following cocaine CPP training at 20 mg/kg cocaine. The downregulation of Dnmt3b (S-C vs. M-C p<0.05) was also reversed by methionine administration. Although Dmnt3a mRNA [S-C vs. M-C p<0.001] was upregulated following cocaine CPP training, the upregulation of Dnmt3a [S-C vs. M-C p = 0.548] was not reversed by subsequent methionine administration.

Bottom Line: We found that cocaine-, but not morphine- or food-CPP training decreased global DNA methylation in the PFC.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Forensic Science, School of Medicine, Xi'an Jiaotong University, Xi'an, Shan'xi, China.

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.

Show MeSH
Related in: MedlinePlus