In contrast with the neuroprotective efficacy of competitive and non-competitive N-methyl-D-aspartate (NMDA) antagonists versus NMDA neurotoxicity, reported neuroprotective effects of non-NMDA antagonists in limiting alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) toxicity have been less robust. We tested the effect of the non-competitive AMPA receptor antagonist LY 300168 (GYKI 53655; E. Lilly) (0.25 or 2.5 mg/kg per dose i.p. x 3 doses vs. vehicle) on AMPA-induced excitotoxic injury in postnatal day 7 (P7) rats. To assess specificity, we tested the effect of LY 300168 (2.5 mg/kg per dose x 3 doses) on NMDA-induced excitotoxic injury. P7 rats received right intrahippocampal injections of either (S)-AMPA (2.5 nmol, n = 67) or NMDA (12.5 nmol, n = 11). Injection of AMPA resulted in right hippocampal atrophy with pyramidal cell loss. LY 300168 treatment produced dose-dependent attenuation of AMPA-induced right hippocampal injury; based on comparisons with left hippocampal volumes, 2.5 nmol AMPA resulted in 42 +/- 3% (mean +/- SEM) right hippocampal volume loss in controls, but only 10 +/- 5% after LY 300168 2.5 mg/kg per dose (P < 0.001; ANOVA). LY 300168 had no effect on NMDA-induced hippocampal injury. The data support the hypothesis that drugs that allosterically regulate AMPA receptor activity can modulate the response of immature brain to AMPA-mediated injury.