Cadet J L, Jayanthi S, McCoy M T, Vawter M, Ladenheim B
Molecular Neuropsychiatry Section, NIH/NIDA, Intramural Research Program, Baltimore, Maryland 21224, USA.
Synapse. 2001 Jul;41(1):40-8. doi: 10.1002/syn.1058.
Methamphetamine (METH) is a neurodegenerative drug of abuse. Its toxicity is characterized by destruction of monoaminergic terminals and by apoptosis in cortical and striatal cell bodies. Multiple factors appear to control METH neurotoxicity, including free radicals and transcription factors. Here, using cDNA arrays, we show the temporal profile of gene expression patterns in the cortex of mice treated with this drug. We obtained two patterns of changes from 588 genes surveyed. First, an early pattern is characterized by upregulation of transcription factors, including members of the jun family. Second, a delayed pattern includes genes related to cell death and to DNA repair. A number of trophic factors were also activated at the later timepoint. These observations suggest that METH can activate a multigene machinery that participates in the production of its toxic effects. The resulting degenerative effects of the drug are thus the result of a balance between protoxic and antiapoptotic mechanisms triggered by its administration to these animals. These observations are of clinical relevance because of the recent identification of degenerative changes in the brains of METH abusers.
甲基苯丙胺（METH）是一种具有神经退行性毒性的滥用药物。其毒性表现为单胺能终末的破坏以及皮质和纹状体细胞体的凋亡。多种因素似乎参与调控METH的神经毒性，包括自由基和转录因子。在此，我们利用cDNA阵列展示了用该药物处理的小鼠皮质中基因表达模式的时间概况。从所检测的588个基因中，我们获得了两种变化模式。第一种，早期模式的特征是转录因子上调，包括jun家族成员。第二种，延迟模式包括与细胞死亡和DNA修复相关的基因。一些营养因子在较晚时间点也被激活。这些观察结果表明，METH可激活一个多基因机制，该机制参与其毒性作用的产生。因此，该药物产生的退行性效应是在给这些动物用药后引发的原毒性和抗凋亡机制之间平衡的结果。鉴于最近在METH滥用者大脑中发现了退行性变化，这些观察结果具有临床相关性。
