Metabolic mapping of discrete brain regions using cytochrome oxidase histochemistry was used as a marker for alterations in mitochondrial function and cytochrome oxidase enzymatic activity in response to high doses of amphetamine derivatives. The activity of cytochrome oxidase, complex IV of the electron transport chain, was determined at three different time-points following administration of high doses of methamphetamine or 3,4-methylenedioxymethamphetamine (MDMA) (four injections of 10-15 mg/kg administered over 8 h). There was a rapid decrease in cytochrome oxidase staining in the striatum (23-29%), nucleus accumbens (29-30%) and substantia nigra (31-43%), 2 h following administration of either methamphetamine and MDMA. This decrease in cytochrome oxidase activity was transient and returned to control levels within 24 h. Since the methamphetamine and MDMA-induced decrease in cytochrome oxidase activity was localized to dopamine-rich regions, increased extracellular concentrations of dopamine may contribute to the inhibition of metabolic function via its metabolism to form quinones or other reactive oxygen species. These results support previous studies demonstrating that psychostimulants induce a rapid and transient decrease in striatal ATP stores and provide further evidence that these drugs of abuse can disrupt mitochondrial function.