A significant loss of dopamine was found in rat striatal slices incubated with 1-methyl-4-phenylpyridinium ion (MPP+) at a concentration of 2 microM or higher. The addition of 7-nitroindazole, a specific inhibitor of neuronal nitric oxide synthase (nNOS), prevented this effect on dopamine when the concentration of MPP+ was between 2-5 microM, but not at higher concentrations. This protection was reproduced with other less specific NOS-inhibitors, such as nitro-arginine and nitro-arginine methylester. 7-nitroindazole did not protect against the dopamine depletion caused by the non-specific mitochondrial chain blocker rotenone. Neither MPP- nor rotenone significantly increased the nitrite concentration in striatal slices, measured as an index of nitric oxide production. The basal production of nitric oxide may be enough to trigger the dopamine depletion at very low concentrations of MPP+, probably acting synergistically with cytosolic calcium increase. Higher concentrations of MPP+ are toxic by themselves without the mediation of nitric oxide. The inhibition of nNOS may protect against dopamine loss at early stages of a neurodegenerative process, and it could then be considered in the treatment or prevention of neurodegenerative human processes such as Parkinson's disease.