Either a single (acute) or repeated daily (chronic) injections (1 injection/day) of 20 mg/kg cocaine for 10 days to rats was found to increase reactive oxygen species production in two dopaminergic brain structures, the frontal cortex and the striatum. We found that the mitochondrial genome was down-regulated after acute cocaine injection. Hydroperoxide and lipid peroxide generation was correlated with an increase in mitochondrial hydrogen peroxide generation and with a reduced functioning of mitochondrial complex I in response to cocaine. As judged from the measurement of caspase-3 activity and TUNEL labeling, neither acute nor chronic cocaine treatment has been found to induce apoptosis in any of the structures examined. This differs dramatically from what has been described for methamphetamine. Cocaine-induced radical formation was accompanied by the induction of the antioxidant enzymes superoxide dismutase and glutathione peroxidase, after both acute and chronic cocaine treatment. In addition, proteasome chymotrypsin-like activity was enhanced following a single cocaine injection in both cortex and striatum. It is proposed that the compensatory mechanisms to oxidative stress occurring in response to cocaine were effective in scavenging reactive oxygen species and in preventing subsequent cellular damage, thus explaining why no significant cell death was found in these brain structures.