(-801 DOES NOT PREVENT MPTP-INDUCED LOSS OF NIGRAL NEURONS IN MICE()MK)

The present study was designed to evaluate the effects of 0,11-dihydro -5H-dibenzo[a,d]cyclohepten-5,10-imine [(+)MK-801] on 1-methyl-4-pheny l-1,2,3,6-tetrahydropyridine (MPTP)-induced nigrostriatal damage in th e mouse, with the goal of clearly defining what protective effects, if any, this noncompetitive N-methyl-phenyl-1,2,3,6-tetrahydropyridine r eceptor antagonist may have against MPTP neurotoxicity. Animals were t reated with MPTP (40 mg/kg s.c.) and/or (+)MK-801 (3 x 1 mg/kg i.p. at 4-hr intervals starting 30 min before MPTP) and were killed at 8 hr a nd 1, 7 and 21 days after MPTP exposure, Dopamine concentrations were measured in the striatum and ventral mesencephalon, and the total numb er of neurons in the substantia nigra was estimated using an unbiased stereological technique. Administration of(+)MK-801 before MPTP tempor arily 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 ap peared to delay the elimination of the metabolite 1-methyl-4-phenylpyr idinium ion without affecting its formation. A 30% loss of nigral neur ons with tyrosine hydroxylase immunoreactive and cresyl violet stainin g was seen at 1 and 3 weeks in both groups of MPTP-exposed animals, re gardless of whether they received (+)MK-801. These data suggest that ( +)MK-801 may affect the acute pharmacological/biochemical events induc ed by MPTP, but it does not have any enduring protective effects on ei ther dopamine concentrations and/or the cell loss induced by this neur otoxin in mice.