Numachi Y, Yoshida S, Toda S, Matsuoka H, Sato M
Department of Psychiatry, Tohoku University Graduate School of Medicine, Sendai, Japan.
Ann N Y Acad Sci. 2000 Sep;914:33-45. doi: 10.1111/j.1749-6632.2000.tb05181.x.
Recently, a role of the hypothalamo-pituitary-adrenocortical (HPA) axis in facilitating the behavioral and neurochemical effects of psychostimulants has been proposed. Two inbred strains of rats, Fischer 344/N (F344) and Lewis/N (LEW), have markedly different HPA axes as well as behavioral responses to psychostimulants: F344 rats show hyperresponsive HPA axis and no significant sensitization to cocaine, whereas LEW rats display blunted response in HPA axis and develop cocaine-induced locomotor sensitization. Corticosterone exerts its biological effects via intracellular receptors, termed type I (mineralocorticoid receptor: MR) and type II (glucocorticoid receptor: GR). The present study examines the development of stereotypy sensitization and the brain expression of mRNAs for MR, GR, and heat shock protein 90 (HSP90) in methamphetamine (MAP)-treated F344 and LEW rats. Animals received i.p. injections with chronic saline (SAL: once daily for 21 days), chronic saline and acute MAP (AM: saline for 20 days and 4 mg/kg MAP on the 21st day), or chronic MAP (CM: 4 mg/kg MAP for 21 days) and were sacrificed three hours after the last injections. Striatum, hippocampus, and cerebellum were quickly dissected on ice and total RNA was isolated for northern analyses. LEW rats developed stereotypy sensitization significantly earlier than F344 rats. AM significantly decreased GR and MR mRNA expression in hippocampus of LEW, compared to SAL. CM significantly increased GR and MR mRNA expression in striatum of F344 compared to SAL and AM, while it decreased GR mRNA in striatum of LEW and MR mRNA in hippocampus, compared to SAL. AM significantly increased HSP90 mRNA in all brain regions examined, without the hippocampus in LEW. CM significantly increased the expression of HSP90 mRNA in the striatum and cerebellum of F344, but significantly decreased in the striatum and hippocampus of LEW. These contrasting differences between F344 and LEW, in their susceptibility to stereotypy sensitization and striatal expression of GR mRNA by chronic MAP, suggest that some striatal genes, whose transcription is regulated by GR, play a crucial role in the development of MAP-induced behavioral sensitization.
最近，有人提出下丘脑 - 垂体 - 肾上腺皮质（HPA）轴在促进精神兴奋剂的行为和神经化学效应方面发挥作用。两种近交系大鼠，Fischer 344/N（F344）和Lewis/N（LEW），具有明显不同的HPA轴以及对精神兴奋剂的行为反应：F344大鼠表现出HPA轴反应过度，对可卡因无明显的致敏作用，而LEW大鼠的HPA轴反应迟钝，并出现可卡因诱导的运动致敏。皮质酮通过细胞内受体发挥其生物学作用，这些受体被称为I型（盐皮质激素受体：MR）和II型（糖皮质激素受体：GR）。本研究考察了甲基苯丙胺（MAP）处理的F344和LEW大鼠中刻板行为致敏的发展以及MR、GR和热休克蛋白90（HSP90）mRNA在脑中的表达。动物接受腹腔注射，分别为慢性生理盐水（SAL：每日一次，共21天）、慢性生理盐水和急性MAP（AM：生理盐水注射20天，第21天注射4mg/kg MAP）或慢性MAP（CM：4mg/kg MAP注射21天），并在最后一次注射后3小时处死。在冰上迅速解剖纹状体、海马和小脑，分离总RNA用于Northern分析。LEW大鼠比F344大鼠更早出现明显的刻板行为致敏。与SAL相比，AM显著降低了LEW大鼠海马中GR和MR mRNA的表达。与SAL和AM相比，CM显著增加了F344大鼠纹状体中GR和MR mRNA的表达，而与SAL相比，它降低了LEW大鼠纹状体中GR mRNA的表达以及海马中MR mRNA的表达。AM显著增加了所有检测脑区中HSP90 mRNA的表达，但LEW大鼠的海马除外。CM显著增加了F344大鼠纹状体和小脑中HSP90 mRNA的表达，但在LEW大鼠的纹状体和海马中显著降低。F344和LEW大鼠在对刻板行为致敏的易感性以及慢性MAP对纹状体GR mRNA表达方面的这些对比差异表明，一些其转录受GR调节的纹状体基因在MAP诱导的行为致敏发展中起关键作用。
