Previous studies from this laboratory demonstrated that (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801), an N-methyl-D-aspartate (NMDA) receptor antagonist, did not prevent neurotoxicity to dopaminergic neurons in mice produced by systemic treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). However, Turski et al. [Nature 349, 414-418 (1991)] reported that extended treatment of rats with NMDA receptor antagonists (six injections at 4-h intervals) did prevent the loss of nigral dopaminergic neurons resulting from an intranigral infusion of 1-methyl-4-phenylpyridinium (MPP+), the neurotoxic metabolite of MPTP. The present studies examined if a similar extended treatment with MK-801 would protect mice from the neurotoxicity of systemically administered MPTP. Six intraperitoneal injections of MK-801 given at 4-h intervals did not protect mice against the MPTP-induced neostriatal dopamine loss measured 1 week after treatment. In other experiments, designed to replicate and expand on the results of Turski et al. (1991), the extended treatment of rats with MK-801 did not prevent MPP(+)-induced cell loss in the infused substantia nigra pars compacta or the dopamine depletion in the ipsilateral neostriatum at 7-11 days after MPP+ infusion. These results do not support the hypothesis that NMDA receptors are involved with MPTP/MPP(+)-induced neurodegeneration.