Serial analysis of gene expression in the rat striatum following methamphetamine administration.
Methamphetamine (METH), a highly addictive drug, can cause degeneration of monoaminergic terminals and neuronal apoptosis in the mammalian brain. In the present article, we have used serial analysis of gene expression (SAGE) to investigate patterns of gene expression in the striata of rats that were given a neurotoxic dose of the drug. SAGE libraries were generated from animals treated with either saline or METH (40 mg/kg) and sacrificed 2 h later. A total of 315 transcripts were differentially expressed between the two libraries (P < 0.05), with 179 (56%) being upregulated and 136 (44%) being downregulated by the METH injection. Of these, CAATT enhancer-binding protein homologous protein (CHOP)/GADD153 (growth arrest- and DNA damage-inducible gene 153) was found to be upregulated by about threefold. Analysis of the expression of genes downstream of CHOP (DOCs) revealed significant METH-induced increases in their expression. Because DOC1 is an analog of carbonic anhydrase (CA) which is involved in the interconversion between carbon dioxide and the bicarbonate ion, we also measured the effects of METH on the expression of several CAs. These were significantly upregulated by METH in a time-dependent fashion. These results indicate that METH toxicity is mediated, in part, by drug-induced perturbations of physiological processes that are dependent on normal pH and CO(2) homeostasis.
Cai
Ning Sheng
NS
Molecular Neuropsychiatry Branch, National Institute on Drug Abuse, National Institute of Health, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA. jcadet@intra.nida.nih.gov
McCoy
Michael T
MT
Ladenheim
Bruce
B
Lyles
Johnalyn
J
Ali
Syed F
SF
Cadet
Jean Lud
JL
D000818:Animals; D001483:Base Sequence; D002135:Calcium-Binding Proteins / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology*; D015536:Down-Regulation; D020869:Gene Expression Profiling; D008694:Methamphetamine / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D051742:Transcription Factor CHOP / Q000378:metabolism; D015854:Up-Regulation
D002135:Calcium-Binding Proteins; C497251:Ddit3 protein, rat; D015259:Dopamine Agents; D009419:Nerve Tissue Proteins; D051742:Transcription Factor CHOP; D008694:Methamphetamine