Increased extracellular glutamate evoked by 1-methyl-4-phenylpyridinium (MPP+) in the rat striatum is not essential for dopaminergic neurotoxicity and is not derived from released glutathione

A number of studies have implicated the interactions of the excitatory amino acid L-glutamate (Glu) with its ionotropic and metabotropic receptors as important components of the mechanism underlying the dopaminergic neurotoxicity of 1-methyl-4phenylpyridinium (MMP+). Furthermore, microdialysis experiments have demonstrated that perfusion of relatively high concentrations of MPP+ into the rat striatum evoke a delayed, massive release of Glu. Interestingly, perfusion of MPP+ also mediates a similar release of glutathione (GSH). Together, these observations raise the possibility that the rise of extracellular Glu mediated by MPP+ may be the result of hydrolysis of released GSH by gamma-glutamyl transpeptidase (gamma-GT). In the present investigation it is demonstrated that perfusions of solutions of 0.7 and 1.3 mM MPP+ dissolved in artificial cerebrospinal fluid into the rat striatum evoke neurotoxic damage to dopaminergic terminals, assessed by both a two-day test/challenge procedure and tyrosine hydroxylase immunoreactivity, but without the release of Glu. Perfusions of >= 2.5 mM MPP+ cause more extensive dopaminergic neurotoxicity and a dose-dependent release of Glu. However, neither this release of Glu nor MPP+-induced dopaminergic neurotoxicity are blocked by the irreversible gamma-GT inhibitor acivicin. Together, these observations indicate that a rise of extracellular levels of Glu is not essential for the dopaminergic neurotoxicity of MPP+. Furthermore, the rise of extracellular Glu caused by perfusion of >= 2.5 mM MPP+ is not the result of the y-GT-mediated hydrolysis of released GSH. It is possible that the rise of extracellular levels of Glu, L-aspartate, L-glycine and L-taurine evoked by perfusions of 2:2.5 mM MPP+ into the rat striatum may reflect, at least in part, the release of these amino acids from astrocytes.