The non-NMDA glutamate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione and 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline, but not NMDA antagonists, block the intrastriatal neurotoxic effect of MPP+

Altered glutamatergic neurotransmission appears to be central to the pathop hysiology of Parkinson's disease; consequently, considerable effort has bee n made to elucidate neuroprotective mechanisms against such toxicity. In th e present study, the possible neuroprotective effect of glutamate receptor antagonists against MPP+ neurotoxicity on dopaminergic terminals of rat str iatum was investigated. Different doses of glutamate receptor antagonists w ere coinfused with 1.5 mu g of MPP+ into the striatum; kynurenic acid, a no nselective antagonist of glutamate receptors (30 and 60 nmol), partially pr otected dopaminergic terminal degeneration in terms of rescue of dopamine l evels and tyrosine hydroxylase immunohistochemistry. Dizocilpine, a channel blocker of the NMDA receptor (1, 4, and 8 nmol), and 7-chlorokynurenic aci d, a selective antagonist at the glycine site of the NMDA receptor (1 and 1 0 nmol), failed to protect dopaminergic terminals from MPP+ toxicity. Howev er, 6-cyano-7-nitroquinoxaline-2,3-dione (0.5 and 1 nmol) and 2,3-dihydroxy -6-nitro-7-sulfamoylbenzo(f)quinoxaline (1 nmol), two AMPA-kainate receptor antagonists, protected against MPP+ toxicity. Our findings suggest that th e toxic effects of MPP+ on dopaminergic terminals are not mediated through a direct interaction with the NMDA subtype of glutamate receptor, but with the AMPA-kainate subtype.