Studies on the acute and long-term changes in dopamine and noradrenaline metabolism in mouse brain following administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).

Abstract

Previous studies from these laboratories have revealed that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced acute profound release of dopamine together with a marked reduction in dopamine synthesis. The present study was undertaken in an attempt to further elucidate these acute alterations. MPTP produced dose-dependent marked reductions in the concentrations of dopamine and noradrenaline in mouse brain 2 hours as well as 7 days after the administration. Both the acute and long-term reductions in dopamine were most pronounced in the striatum, whereas the reductions in noradrenaline (acute and long-term) were most pronounced in the cortical region. Contemporaneous with the acute reduction in the catecholamines, MPTP increased the levels of the dopamine metabolites 3-methoxytyramine and homovanillic acid (HVA), and the noradrenaline metabolite normetanephrine. In contrast, the levels of the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were reduced. These data are indicative of a profound release of both dopamine and noradrenaline from the storage sites into the extraneuronal space. Pretreatment with the monoamine oxidase inhibitor pargyline totally prevented the acute reduction in dopamine and partially also the reduction in noradrenaline produced by MPTP. However, MPTP increased the levels of 3-methoxytyramine and normetanephrine also in pargyline treated mice. The selective dopamine uptake inhibitor GBR 13098 antagonized the MPTP-induced reduction in dopamine and increase in 3-methoxytyramine, but had no effect on the MPTP-induced reduction in noradrenaline. MPTP produced a marked acute reduction in tyrosine hydroxylation in the dopamine predominated areas striatum and limbic region, whereas a slight increase in tyrosine hydroxylation was noted in the noradrenaline predominated cortical region. Similar effects of MPTP were observed in reserpine pretreated animals. Pargyline prevented the MPTP-induced reduction in dopamine synthesis. Recent in vitro observations indicate that MPP+, the toxic metabolite of MPTP, is capable of inhibiting the electron-transport carrier, an action which may account for the neurotoxicity of the compound. It appears possible that this effect of MPP+ could explain the currently observed acute changes in catecholamine metabolism.