Excitant amino acids are implicated in audiogenic seizure (AGS) susceptibility in the genetically epilepsy-prone rat (GEPR). In the present study systemic administration of NMDA receptor antagonists significantly decreased AGS severity in the GEPR. Systemic administration of the competitive NMDA antagonists 3-((+-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonate (CPP) and 2-amino-7-phosphonoheptanoic acid and the non-competitive antagonist dizocilpine (MK-801) were effectively anticonvulsant in the GEPR. The inferior colliculus is the most critical nucleus for AGS initiation in the GEPR and an excitant amino acid is implicated as an important excitatory transmitter in inferior colliculus neurons. Systemically administered CPP significantly reduced inferior colliculus neuronal firing in the normal behaving rat and the GEPR concurrently with blockade of AGS and this effect occurred at nearly all sound intensities tested. Systemic administration of MK-801, while effective in blocking AGS, produced no consistent change in inferior colliculus neuronal firing, which is consistent with its very low potency in blocking AGS with bilateral microinjection into the inferior colliculus. These findings suggest that an important action of competitive, but not noncompetitive, NMDA antagonists is on brain stem auditory nuclei, especially the inferior colliculus, that are critical to AGS. MK-801 appears to exert its anticonvulsant effects in AGS network sites beyond the inferior colliculus. These findings and recent inferior colliculus slice studies suggest that NMDA receptors in inferior colliculus may have quantitatively different properties from those in other brain regions. These differences in NMDA receptor function in inferior colliculus may reflect NMDA receptor heterogeneity observed in binding studies.(ABSTRACT TRUNCATED AT 250 WORDS)