Null mutation of c-fos causes exacerbation of methamphetamine-induced neurotoxicity

Methamphetamine neurotoxicity has been demonstrated in rodents and nonhuman primates. These neurotoxic effects may be associated with mechanisms invol ved in oxidative stress and the activation of immediate early genes (IEG). It is not clear, however, whether these IEG responses are involved in a met hamphetamine-induced toxic cascade or in protective mechanisms against the deleterious effects of the drug. As a first step toward clarifying this iss ue further, the present study was thus undertaken to assess the toxic effec ts of methamphetamine in heterozygous and homozygous c-fos knock-out as wel l as wild-type mice. Administration of methamphetamine caused significant r eduction in [I-125] RTI-121-labeled dopamine uptake sites, dopamine transpo rter protein, and tyrosine hydroxylase-like immunohistochemistry in the str iata of wild-type mice. These decreases were significantly exacerbated in h eterozygous and homozygous c-fos knock-out mice, with the homozygous showin g greater loss of striatal dopaminergic markers. Moreover, in comparison wi th wild-type animals, both genotypes of c-fos knock-out mice showed more DN A fragmentation, measured by the number of terminal deoxynucleotidyl transf erase-mediated dUTPnick-end-labeled nondopaminergic cells in their cortices and striata. In contrast, wild-type mice treated with methamphetamine demo nstrated 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.