Temporal profiling of methamphetamine-induced changes in gene expression in the mouse brain: evidence from cDNA array.
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.
Cadet
J L
JL
Molecular Neuropsychiatry Section, NIH/NIDA, Intramural Research Program, Baltimore, Maryland 21224, USA. jcadet@intra.nida.nih.gov
Jayanthi
S
S
McCoy
M T
MT
Vawter
M
M
Ladenheim
B
B
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000494:pharmacology* / Q000633:toxicity; D016000:Cluster Analysis; D015870:Gene Expression / Q000187:drug effects* / Q000502:physiology; D016147:Genes, Tumor Suppressor / Q000187:drug effects / Q000502:physiology; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology* / Q000633:toxicity; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D009857:Oncogenes / Q000187:drug effects / Q000502:physiology; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology
D000697:Central Nervous System Stimulants; D014157:Transcription Factors; D008694:Methamphetamine