Abstract

The acute effects of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist 5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine [(+)-MK-801] on 1) dopamine depletion caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP); 2) the biodisposition of the MPTP metabolite 1-methyl-4-phenylpyridinium (MPP+) and 3) MPTP-induced ATP loss were investigated in the mouse striatum. Systemic administration of a single dose of MPTP (40 mg/kg s.c.) to C57BL/6 mice rapidly decreased striatal dopamine levels to 30% of control values. A single injection of (+)-MK-801 (1 mg/kg i.p.) 30 min before MPTP treatment completely prevented striatal dopamine depletion at 1.5 and 4 hr. The competitive NMDA antagonist CGS-19755 also completely protected against MPTP-induced acute dopamine depletion at 4 hr in the striatum. The action of (+)-MK-801 was only temporary, however, because at 12 hr, the degree of dopamine depletion was not different between the (+)-MK-801/MPTP-treated animals and mice treated with MPTP alone. Repeated injections of (+)-MK-801 at 4-hr intervals did not provide any additional protective effect. (+)-MK-801 administration before MPTP exposure did not appear to affect the production of MPP+, but it did significantly delay its elimination from the striatum. There was a significant correlation between levels of dopamine and MPP+ both in the presence and in the absence of (+)-MK-801. Finally, MPTP-induced striatal ATP loss was not affected by pretreatment with (+)-MK-801.(ABSTRACT TRUNCATED AT 250 WORDS)