Perturbations of energy metabolism and activation of N-methyl-D-aspartate (NMDA) receptors have been suggested to play a role in the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In the present study, the concentrations of the excitatory amino acids, L-glutamate and L-aspartate, were evaluated in the mouse brain after administration of MPTP and correlated with MPTP-induced energy impairment. Levels of glutamate and aspartate were determined in the brain of C57BL/6 mice exposed to a single dose of MPTP (40 mg/kg, s.c.). MPTP significantly decreased glutamate and aspartate concentrations in the striatum and ventral mesencephalon but not in the cerebellar cortex 4 h after MPTP administration. This effect was only temporary, however, since glutamate and aspartate concentrations returned to control levels 24 h after MPTP exposure. Pretreatment with the monoamine oxidase B inhibitor deprenyl (10 mg/kg, i.p.) or the catecholamine uptake blocker mazindol (20 mg/kg, s.c.) 30 min before MPTP administration prevented MPTP-induced decrease in glutamate and aspartate. Moreover, injection of 2-deoxyglucose, a competitive inhibitor of cellular glucose transport and utilization, significantly potentiated MPTP-induced decrease in striatal levels of glutamate and aspartate. The present results indicate that systemic administration of MPTP causes a decrease in tissue concentrations of glutamate and aspartate in the striatum and ventral mesencephalon. These effects may result from the perturbation of energy metabolism induced by MPTP in the nigrostriatal dopamine system.