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

儿茶酚胺能激动剂是否通过 DNA 甲基化调节大脑中的基因表达？

• 批准号: 14570906
• 负责人: NUMACHI Yohtaro
• 金额: $ 1.6万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570906/
• 关键词: Psychostimulant; Drug Abuse; Schizophrenia; gene expression; Methylation; Synaptic proteins; reversibility

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).

甲基苯丙胺（methamphetamine，MAP）是一种强有力的儿茶酚胺能激动剂，可引起类似精神分裂症的精神状态。据推测，长期的基因表达的变化是由MAP诱导的，在MAP处理的动物的大脑中。DNA上5 '-CG-3'二核苷酸序列胞嘧啶残基的甲基化可强烈抑制下游基因的表达。我们先前发现MAP处理的大鼠脑中DNA甲基转移酶I（Dnmt I）mRNA表达的改变。根据这些结果，我们在本项目中研究了以下（1）和（2）。（1）MAP降低Fischer 344大鼠海马皮质酮受体mRNA的表达，表明该大鼠对MAP高度敏感。刘易斯大鼠海马皮质酮受体mRNA无变化，对MAP敏感性低。研究表明MAP的作用部分是通过皮质酮实现的，皮质酮受体通过DNA甲基化抑制基因表达。我们的结果表明Fischer 344和刘易斯对MAP敏感性的差异与DNA甲基化的转录调节有关（kabbaj，M.，吉田，S.，Nuinachi，Y.，等人，2003）。（2）MAP对Wister大鼠脑内Dnmt 2 mRNA表达无明显影响。而Wister大鼠额叶皮质reelin mRNA在MAP后3 h下降，3 h后恢复到正常水平。最近，在精神分裂症患者的额叶皮层中，发现了reelin mRNA的减少和Dnmt I mRNA的增加（Veldic，2004）。因此，MAP诱导的大鼠额叶皮层中的reelin mRNA的减少可能与MAP的拟精神病作用有关（Numachi，Y.，吉田，S.，Yamashita，M.，等出版）。

项目成果

佐藤光源, 梶尾靖, 菊池周一, 沼知陽太郎, 西川徹: "脳科学研究の現状と課題(杉田秀夫,高橋清久編)"(株)じほう,東京. 324 (2003)

Hikaru Sato、Yasushi Kajio、Shuichi Kikuchi、Yotaro Numachi、Toru Nishikawa：“脑科学研究的现状和挑战（杉田秀夫和高桥清久编辑）”Jihou Co., Ltd.，东京 324 (2003)。

藤山航, 堀内健太郎, 本多奈美, 沼知陽太郎, 他: "clobazam投与によって強制正常化を呈した前頭葉てんかんの一例"脳と精神の医学. 13. 427-431 (2002)

Wataru Fujiyama、Kentaro Horiuchi、Nami Honda、Yotaro Numachi 等人：“通过服用氯巴占而被迫恢复正常的额叶癫痫病例”《脑与精神病学医学》13. 427-431 (2002)。

Shen H, Numachi Y, Yoshida S, et al.: "Electroconvulsive shock increases serotonin transporter in the rat frontal cortex"Neurosci. 341(2). 170-172 (2003)

Shen H、Numachi Y、Yoshida S 等人：“电惊厥增加大鼠额叶皮层中的血清素转运蛋白”Neurosci。

Numachi Y, Yoshida S, Sora I.: "Common aspects between depression and anxiety (in Japanese)"Bulettin of Depression and Anxiety. 1. 8-11 (2003)

Numachi Y、Yoshida S、Sora I.：“抑郁和焦虑之间的共同点（日语）”抑郁和焦虑公告。

Shen, H., Numachi, Y, et al.: "Electroconvulsive shock increases serotonin transporter in the rat frontal cortex"Neuroscience Letters. (in press). (2003)

Shen, H., Numachi, Y 等人：“电惊厥增加大鼠额叶皮层中的血清素转运蛋白”神经科学快报。