Methamphetamine alters expression of DNA methyltransferase 1 mRNA in rat brain.
Methamphetamine, a potent and indirect dopaminergic agonist, also increases glucocorticoid hormone secretion. Glucocorticoid hormones facilitate behavioral effects of methamphetamine in rodents. Several reports suggest that glucocorticoid hormones modulate expression of DNA (cytosine-5-)-methyltransferase 1 (Dnmt1). Dnmt1 was originally recognized as being involved in DNA replication, but a recent study found high levels of Dnmt1 in rodent brains, suggesting a neuron-specific unknown function of Dnmt1. In the present study, we found subchronic methamphetamine treatment (4 mg/kg, i.p., once daily for 21 days) to induce different patterns of Dnmt1 mRNA expression in the nucleus caudatus and nucleus accumbens of two inbred rat strains, Fischer 344/N (increased Dnmt1) and Lewis/N (decreased Dnmt1). These patterns paralleled methamphetamine-induced striatal glucocorticoid receptor mRNA in these two rat strains in our previous study. Because Fischer rats have a hyperresponsive negative feedback in their hypothalamic-pituitary-adrenocortical (HPA) axis and thus a shorter duration corticosterone response to subchronic methamphetamine treatment, they were resistant to sensitizing effects of methamphetamine and their glucocorticoid receptor mRNA levels were upregulated. Lewis rats which have a hyporesponsive feedback in their HPA axis and a longer duration of corticosterone secretion with subchronic methamphetamine were prone to methamphetamine sensitization and their striatal glucocorticoid receptor mRNA levels were downregulated. Our present data suggest that methamphetamine results in differential DNA methylation as well as gene expression in the nucleus caudatus and nucleus accumbens of F344 and Lewis rats. Methamphetamine-induced differences in gene expression might be related to the contrasting susceptibilities of these rats to behavioral and neurochemical effects of methamphetamine.
Numachi
Yohtaro
Y
Clinical Research Institute, National Hospital Organization Hanamaki Hospital, Hanamaki, and Department of Psychiatry, Tohoku University Graduate School of Medicine, Sendai, Japan. ynumachi@hanamaki.hosp.go.jp
Shen
Haowey
H
Yoshida
Sumiko
S
Fujiyama
Ko
K
Toda
Shigenobu
S
Matsuoka
Hiroo
H
Sora
Ichiro
I
Sato
Mitsumoto
M
D000818:Animals; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects* / Q000201:enzymology*; D001923:Brain Chemistry / Q000187:drug effects* / Q000502:physiology; D002421:Caudate Nucleus / Q000187:drug effects / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D019175:DNA Methylation / Q000187:drug effects; D004351:Drug Resistance / Q000235:genetics; D005246:Feedback / Q000187:drug effects / Q000502:physiology; D005938:Glucocorticoids / Q000378:metabolism*; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000378:metabolism; D050436:Regulatory Elements, Transcriptional / Q000187:drug effects / Q000502:physiology; D013045:Species Specificity
D000697:Central Nervous System Stimulants; D005938:Glucocorticoids; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D008694:Methamphetamine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619382:Dnmt1 protein, rat