The present study was designed to evaluate the effects of 5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10imine [(+)MK-801] on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced nigrostriatal damage in the mouse, with the goal of clearly defining what protective effects, if any, this noncompetitiveN-methyl-phenyl-1,2,3,6-tetrahydropyridine receptor antagonist may have against MPTP neurotoxicity. Animals were treated with MPTP (40 mg/kg s.c.) and/or (+)MK-801 (3 × 1 mg/kg i.p. at 4-hr intervals starting 30 min before MPTP) and were killed at 8 hr and 1, 7 and 21 days after MPTP exposure. Dopamine concentrations were measured in the striatum and ventral mesencephalon, and the total number of neurons in the substantia nigra was estimated using an unbiased stereological technique. Administration of (+)MK-801 before MPTP temporarily prevented MPTP-induced dopamine depletion. This was observed at 8 hr in the striatum and 1 week in the ventral mesencephalon, but not at other time-points studied. In both areas of the brain, (+)MK-801 appeared to delay the elimination of the metabolite 1-methyl-4-phenylpyridinium ion without affecting its formation. A 30% loss of nigral neurons with tyrosine hydroxylase immunoreactive and cresyl violet staining was seen at 1 and 3 weeks in both groups of MPTP-exposed animals, regardless of whether they received (+)MK-801. These data suggest that (+)MK-801 may affect the acute pharmacological/biochemical events induced by MPTP, but it does not have any enduring protective effects on either dopamine concentrations and/or the cell loss induced by this neurotoxin in mice.