Depletion of striatal dopamine by the N-oxide of 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP)

The N-oxide of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is the major metabolite found in vivo and excreted in urine after the parenteral administration of the neurotoxicant, MPTP. In mice (C57BL/6), stereotaxic injection of MPTP N-oxide (15 μg) into the neostriatum produced dopamine (DA) depletion similar to that caused by MPTP. The DA depleting effect of MPTP N-oxide was a direct action, whereas the action of MPTP was mediated by the generation of oxidative metabolites. In the mouse striatal synaptosomal preparation, MPTP, MPP⁺ and MPTP N-oxide all competed with [³H]DA at its uptake site. In addition, MPP⁺ and MPTP N-oxide promoted [³H]DA release. In contrast to MPTP and MPDP⁺, MPTP N-oxide did not alter the electrophysiologically recorded field potential in nigro-striatal slices. These observations suggest that MPTP N-oxide can directly cause the chemical depletion of striatal DA without modifying the characteristics of cortico- striate synaptic transmission.