AMPA and NMDA receptors, abundantly expressed on striatal medium spiny neurons, have been implicated in the regulation of corticostriatal synaptic efficacy. To evaluate the contribution of both glutamate receptor types to the pathogenesis of motor response alterations associated with dopaminergic treatment, we studied the ability of the selective AMPA receptor antagonist GYKI-47261 and the selective NMDA receptor antagonists, MK-801 and amantadine, to mitigate these syndromes in rodent and primate models of Parkinson's disease. The effects of GYKI-47261 and amantadine (or MK-801), alone and in combination, were compared for their ability to modify dyskinesias induced by levodopa. In rats, simultaneous administration of subthreshold doses of AMPA and NMDA receptor antagonists completely normalized the wearing-off response to acute levodopa challenge produced by chronic levodopa treatment (P < 0.05). In primates, the glutamate antagonists GYKI-47261 and amantadine, co-administered at low doses (failing to alter dyskinesia scores), reduced levodopa-induced dyskinesias by 51% (P < 0.05). The simultaneous AMPA and NMDA receptor blockade acts to provide a substantially greater reduction in the response alterations induced by levodopa than inhibition of either of these receptors alone. The results suggest that mechanisms mediated by both ionotropic glutamate receptors make an independent contribution to the pathogenesis of these motor response changes and further that a combination of both drug types may provide relief from these disabling complications at lower and thus safer and more tolerable doses than required when either drug is used alone.