Changes in gene expression linked to methamphetamine-induced dopaminergic neurotoxicity.
The purpose of these studies was to examine the role of gene expression in methamphetamine (METH)-induced dopamine (DA) neurotoxicity. First, the effects of the mRNA synthesis inhibitor, actinomycin-D, and the protein synthesis inhibitor, cycloheximide, were examined. Both agents afforded complete protection against METH-induced DA neurotoxicity and did so independently of effects on core temperature, DA transporter function, or METH brain levels, suggesting that gene transcription and mRNA translation play a role in METH neurotoxicity. Next, microarray technology, in combination with an experimental approach designed to facilitate recognition of relevant gene expression patterns, was used to identify gene products linked to METH-induced DA neurotoxicity. This led to the identification of several genes in the ventral midbrain associated with the neurotoxic process, including genes for energy metabolism [cytochrome c oxidase subunit 1 (COX1), reduced nicotinamide adenine dinucleotide ubiquinone oxidoreductase chain 2, and phosphoglycerate mutase B], ion regulation (members of sodium/hydrogen exchanger and sodium/bile acid cotransporter family), signal transduction (adenylyl cyclase III), and cell differentiation and degeneration (N-myc downstream-regulated gene 3 and tau protein). Of these differentially expressed genes, we elected to further examine the increase in COX1 expression, because of data implicating energy utilization in METH neurotoxicity and the known role of COX1 in energy metabolism. On the basis of time course studies, Northern blot analyses, in situ hybridization results, and temperature studies, we now report that increased COX1 expression in the ventral midbrain is linked to METH-induced DA neuronal injury. The precise role of COX1 and other genes in METH neurotoxicity remains to be elucidated.
Xie
Tao
T
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21224, USA.
Tong
Liqiong
L
Barrett
Tanya
T
Yuan
Jie
J
Hatzidimitriou
George
G
McCann
Una D
UD
Becker
Kevin G
KG
Donovan
David M
DM
Ricaurte
George A
GA
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D015152:Blotting, Northern; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D007036:Hypothermia, Induced; D017403:In Situ Hybridization; D008297:Male; D008562:Membrane Glycoproteins; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D008694:Methamphetamine / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D021122:Protein Subunits; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D013574:Synaptosomes / Q000378:metabolism; D014018:Tissue Distribution
D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D021122:Protein Subunits; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D015102:3,4-Dihydroxyphenylacetic Acid; D008694:Methamphetamine; D003576:Electron Transport Complex IV; D004298:Dopamine