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The Journal of Neuroscience, November 15, 1999, 19(22):10107-10115
Null Mutation of c-fos Causes Exacerbation of Methamphetamine-Induced Neurotoxicity
Xiaolin Deng, Bruce Ladenheim, Li-I Tsao, and Jean Lud Cadet Molecular Neuropsychiatry Section, National Institute on Drug Abuse Intramural Research Program, Baltimore, Maryland 21224
Methamphetamine neurotoxicity has been demonstrated in rodents and nonhuman primates. These neurotoxic effects may be associated with mechanisms involved in oxidative stress and the activation of immediate early genes (IEG). It is not clear, however, whether these IEG responses are involved in a methamphetamine-induced toxic cascade or in protective mechanisms against the deleterious effects of the drug. As a first step toward clarifying this issue further, the present study was thus undertaken to assess the toxic effects of methamphetamine in heterozygous and homozygous c-fos knock-out as well as wild-type mice. Administration of methamphetamine caused significant reduction in [125I]RTI-121-labeled dopamine uptake sites, dopamine transporter protein, and tyrosine hydroxylase-like immunohistochemistry in the striata of wild-type mice. These decreases were significantly exacerbated in heterozygous and homozygous c-fos knock-out mice, with the homozygous showing greater loss of striatal dopaminergic markers. Moreover, in comparison with wild-type animals, both genotypes of c-fos knock-out mice showed more DNA fragmentation, measured by the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeled nondopaminergic cells in their cortices and striata. In contrast, wild-type mice treated with methamphetamine demonstrated a greater number of glial fibrillary acidic protein-positive cells than did c-fos knock-out mice. These data suggest that c-fos induction in response to toxic doses of methamphetamine might be involved in protective mechanisms against this drug-induced neurotoxicity.
Key words: methamphetamine; neurotoxicity; c-fos mutant; glial fibrillary acidic protein; DNA fragmentation; cell death; apoptosis
Copyright © 1999 Society for Neuroscience 0270-6474/99/192210107-09$05.00/0
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