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

甲基苯丙胺(MAP)是一种有效的儿茶酚胺能激动剂，也是一种滥用药物，可导致类似精神分裂症的精神状态。据推测，基因表达的长期变化是由MAP诱导的，在MAP处理的动物的大脑中。DNA上二核苷酸序列5‘-CG-3’胞嘧啶残基的甲基化可强烈抑制下游基因的表达。我们先前在MAP处理的大鼠脑内发现了DNA甲基转移酶I(DnmtI)mRNA表达的变化。根据这些结果，我们在本项目中进行了如下研究：(1)MAP降低了对MAP高度敏感的Fischer 344大鼠海马区皮质酮受体的mRNA表达。而Lewis大鼠海马区皮质酮受体rnRNA无明显变化，对MAP敏感性较低。据报道，MAP的作用部分是通过皮质酮实现的，皮质酮受体可通过DNA甲基化抑制基因表达。我们的结果表明，Fischer 344和Lewis对MAP的敏感性差异与DNA甲基化对转录的调控有关(Kabbaj，M.，Yoshida，S.，Nuinachi，Y.，等人)。(2)MAP不改变Wistar大鼠脑内DNMT2基因的表达。而Wistar大鼠额叶皮质的Reelin mRNA在MAP后3h开始下降，随后恢复到正常水平。最近，在精神分裂症患者的额叶皮质中，发现了reelin mRNA的减少和Dnmt I的mRNA的增加(Veldic，2004)。因此，MAP诱导的大鼠额叶皮质reelin基因表达下降可能与MAP(Numachi，Y.，Yoshida，S.，Yamashita，M.等人)的拟精神行为有关。在新闻发布会上)。

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).