ROLE OF GLUTAMATE IN NEURODEGENERATION OF DOPAMINE NEURONS IN SEVERALANIMAL-MODELS OF PARKINSONISM

Although controversial, studies with methamphetamine and MPTP suggest a link between glutamate-mediated excitotoxicity and degeneration of d opamine cells. Both compounds are thonght to create a metabolic stress . To further explore glutamate actions in DA degeneration, we investig ated the effects of other metabolic inhibitors. In mesencephalic cultu res, DA cell loss produced by 3-NPA or malonate was potentiated by NMD A and prevented by MK-801. In vivo, striatal DA loss produced by intra nigral infusions of malonate was also potentiated by intranigral NMDA and prevented by systemic MK-801. In contrast, systemic MK-801 did not prevent DA loss produced by intrastriatal malonate. Intrastriatal MK- 801 or CGS 19755 did attenuate DA loss in METH-treated mice, but was c onfounded by the findings that METH-induced hyperthermia, an important component in toxicity, was also attenuated. Taken together, the data support the hypothesis of NMDA receptor involvement in degeneration of DA neurons. Furthermore, the data also suggest that this interaction is likely to occur in the substantia nigra rather than in the striatum .