1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) given in 4 daily s.c. injections to mice resulted in marked depletion of striatal dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) 1 week after the last dose. Pretreatment of mice with alpha-methyltyrosine or Ro 4-1284 to deplete dopamine prior to MPTP injection did not prevent these effects of MPTP, nor did pretreatment with haloperidol, a dopamine receptor antagonist. The depletion of striatal dopamine by MPTP in mice therefore differs from the persistent depletion of striatal dopamine by amphetamine in iprindole-treated rats, which is prevented by pretreatment with either alpha-methyltyrosine or haloperidol. The depletion of dopamine, DOPAC and HVA in mouse striatum by MPTP was totally prevented by pretreatment with amfonelic acid, an inhibitor of dopamine uptake. This finding suggests that these effects of MPTP, like those of amphetamine in iprindole-treated rats, are dependent upon a functional transport system into the dopamine neuron.