The studies examined the effects of three antagonists (CPP, CGS 19755, and CGP 37849) that act competitively at the glutamate recognition site of the NMDA receptor complex on cortical neuronal morphology and cerebral limbic glucose metabolism. Responses were compared to the effects of dizocilpine, an uncompetitive NMDA receptor ion channel antagonist as a positive control. CGS 19755 and CGP 37849 (100 mg kg-1 i.p.) caused vacuolation in cortical pyramidal neurons in the posterior cingulate cortex four hours after dosing and this dose of CGP 37849 caused a pattern of limbic glucose metabolism activation similar to that seen after dizocilpine. CPP was without effect at 100 mg/kg i.p. probably due to poor brain penetration. The data indicates that the functional consequences (structural and metabolic) of NMDA receptor blockade with NMDA antagonists acting competitively at the glutamate recognition site and uncompetitively in the receptor ion channel are ultimately the same. Comparisons of the potential therapeutic window for CGS 19755 and CGP 37849 with dizocilpine (neuroprotection versus vacuolation) suggests that the window for the competitive antagonists is greater. This indicates that the potential therapeutic window for the different classes of NMDA antagonists may vary with the site in the receptor complex at which they interact.