Does catecholaminergic agonist modulate gene expression in the brain, via DNA methylation?

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Methamphetamine (MAP) is a potent catecholaminergic agonist as well as abused drug, which can cause psychotic state resembles schizophrenia. It is postulated that long-term alterations in gene expression is induced by MAP, in the brains of MAP-treated animals. Methylation on cytosine residues of dinucleotides sequence 5'-C G-3' on DNA can strongly inhibit expression of downstream gene. We previously found alterations in the expression of DNA methltransferase I (DnmtI) mRNA in the brain of MAP-treated rat. According to these results, we studied about (1) and (2) as below, in this project.(1)MAP decreased hippocampal mRNA for corticosterone receptor in Fischer 344 rat, which showed high sensitivity to MAP. On the other hand, there was no change in corticosterone receptor rnRNA in the hippocampus of Lewis rat, with low sensitivity to MAP. It is reported that actions of MAP is partially via corticosterone and corticosterone receptor can inhibit gene expression by DNA methylation. Our results suggest that differences between Fischer 344 and Lewis in their sensitivity to MAP is related to transcriptional regulation by DNA methylation (kabbaj, M., Yoshida, S., Nuinachi, Y., et al. 2003).(2)MAP did not alter expression of Dnmt2 mRNA in the brain of Wister rat. But reelin mRNA in the frontal cortex of Wister rat decreased 3 hrs after MAP, and thereafter returned to normal level. Recently, in the frontal cortex of schizophrenic patient, decrease in reelin mRNA and increase in Dnmt I mRNA were found (Veldic, 2004). So, MAP-induced decrease in reelin mRNA in the frontal cortex of rat might be related to psychotomimetic action of MAP (Numachi, Y., Yoshida, S., Yamashita, M., et al. in press).