title: 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.
abstract: 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-4-phenylpyridinium [MPP(+)]. 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 gamma-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 2.5 mM MPP(+) into the rat striatum may reflect, at least in part, the release of these amino acids from astrocytes.
authors.affiliation: Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, USA.
authors.forename: S B
authors.initials: SB
authors.lastname: Foster
authors.forename: H
authors.initials: H
authors.lastname: Tang
authors.forename: K E
authors.initials: KE
authors.lastname: Miller
authors.forename: G
authors.initials: G
authors.lastname: Dryhurst
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000633:toxicity*; D004563:Electrochemistry; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D007150:Immunohistochemistry; D007555:Isoxazoles / Q000494:pharmacology; D008297:Male; D017551:Microdialysis; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism*; D020258:Neurotoxicity Syndromes / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D005723:gamma-Glutamyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000596:Amino Acids; D015259:Dopamine Agents; D004791:Enzyme Inhibitors; D007555:Isoxazoles; D012701:Serotonin; D018698:Glutamic Acid; D005723:gamma-Glutamyltransferase; D005978:Glutathione; C006303:acivicin; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine