Changes in striatal dopamine (DA) neurochemistry, tyrosine hydroxylase immunocytochemistry of DA fibers, and behavior following the combined administration of diethyldithiocarbamate (DDC) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to mice were assessed. The combined treatment of DDC and MPTP produced a dose-dependent decrease in striatal DA levels and a dose-related increase in the striatal DOPAC:DA ratio. Cumulative doses of MPTP equal to or exceeding 53.0 (26.5 mg/kg x 2. i.p.), given in combination with DDC, were effective in reducing striatal DA levels to less than 25% of control levels 2 weeks after treatment. Tyrosine hydroxylase immunocytochemistry revealed large deafferentation of DA terminal regions in striatum, moderate reductions in nucleus accumbens and dendritic regions of substantia nigra, and slight reductions in the number of DA cell bodies in substantia nigra. Mice treated with DDC and MPTP became hyperactive during the light phase of their diurnal cycle: psychopharmacological data suggest that postsynaptic DA receptors were supersensitized following this treatment. These data provide evidence that the combined treatment of DDC and MPTP produces severe and enduring depletion of mesostriatal DA, and also concomitant behavioral changes in mice.