Amphetamine is an addictive psychostimulant whose chronic abuse can cause impairments in cognitive functions and neurodegenerative changes in the brain. These include loss of dopaminergic axons and death of non-dopaminergic neurons in the striatum. The present study was undertaken to examine the extent to which amphetamine can cause axonal degeneration in the mouse cortex and to assess the potential role of superoxide radicals in mediating the toxic effects of the drug in that brain region. Administration of amphetamine (10 mg/kg, 4 times, 2 h apart) caused significant depletion of dopamine and its metabolite 3, 4-dihydroxyphenylacetic acid in the cortices of wild-type mice. In addition, superoxide dismutase transgenic mice were partially protected against amphetamine-induced toxic effects. Microarray studies conducted to test if amphetamine induced differential gene expression revealed that the same dose of the drug caused changes in the expression of 153 genes in the cortices of wild-type and superoxide dismutase transgenic mice. These genes are involved in several biological processes, such as transcription, translation, signal transduction, mitochondria-related functions, inflammatory response, cell cycle, cell adhesion, cytoskeletal activity, and apoptosis. Among the genes changed, we observed that amphetamine caused a differential expression of immediate early genes c-fos oncogene, junB oncogene, and activity-regulated cytoskeletal proteins, as well as those of dual specificity phosphatase 1, neuronal pentraxin II and caspase1 in a superoxide-dependent fashion. These results suggest that the long-term effects of the drug are dependent, in part, on the generation of reactive superoxides in the mouse cortex.