Perfusion of rat striatum with 10 mM 1-methyl-4-phenylpyridinium (MPP+) during 1 min caused a rapid reversible increase in dopamine (DA) efflux (maximal after 4 min) that was similar to the effects of 1 or 15 min 10 mM amphetamine. A massive, prolonged, and irreversible release of DA occurred after 15 min 10 mM MPP+, showing a biphasic trend: the rapid amphetamine-like increase was followed by a slower and larger DA efflux, reaching its maximum after 25 min. One minute perfusions with 1-100 mM MPP+ caused a gradual increase in the overflow of striatal lactate, reaching a maximum effect after 20-30 min. The similarity between the time courses of the MPP+-induced efflux of DA and lactate suggests that both effects are probably consequences of inhibition of aerobic glycolysis by MPP+. A comparison with the courses of DA and lactate efflux after death of control rats showed a delay of several minutes before the toxic effects of MPP+ become apparent. These in vivo data are consistent with the hypothesis that MPP+ accumulates and then kills dopaminergic cells, possibly by the irreversible inhibition of mitochondrial respiration.