Stereotaxic administration of L-cysteine (CySH) into the rat substantia nigra pars compacta (SNC) evokes a dose-dependent fall of striatal levels of dopamine. This, together with decreased tyrosine hydroxylase immunoreactivity in the striatum and SN(c)and decreased nigral staining for Niss1 substance indicate that CySH is a dopaminergic neurotoxin. The neurotoxic effects of CySH infusion into the rat SNC were blocked by prior administration of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801. Previous studies have demonstrated that administration of the neurotoxin l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) not only evokes the degeneration of nigrostriatal dopamine neurons but also causes a significant fall of glutathione (GSH) without corresponding increases of glutathione disulfide (GSSG). Furthermore, microdialysis studies have demonstrated that when perfusions of l-methyl-4-phenylpyridinium (MPP+), the active metabolite of MPTP, into the rat SNC are discontinued extracellular levels of GSH massively but transiently increase followed by a prolonged elevation of extracellular CySH, the latter effect being blocked by inhibition of gamma -glutamyl transpeptidase (gamma -GT). These observations, together with the present results, suggest that the delayed but prolonged elevation of extracellular CySH that occurs as a MPP+-induced dopaminergic SN(c)cell energy impairment begins to subside might evoke NMDA receptor mediated excitotoxicity. The potential roles of elevated extracellular CySH in MPTP/MPP+-induced dopaminergic neurotoxicity and in the pathogenesis of Parkinson's disease are discussed.
