Intracellular recordings were obtained from hippocampal CA1 and CA3 pyramidal neurons maintained in vitro. The ability of the NMDA receptor antagonists ketamine and APV to suppress picrotoxin-induced epileptiform burst activity was examined. Activity was recorded either after a single orthodromic stimulation, which gave rise to paroxysmal depolarization shift (PDS), or during a 500 msec train of 50 Hz stimulation, which produced a sustained depolarization. In the CA1 and CA3 area, both the PDS and sustained depolarization were reduced by APV (20 μM) and ketamine (100 μM). APV reduced the area under the PDS by 24 ± 3% and 32 ± 4% in CA1 and CA3 neurons, respectively. The corresponding reductions in the sustained depolarization were 10 ± 2% and 22 ± 4%. Ketamine reduced the PDS by 43 ± 4% and 31 ± 4% in CA1 and CA3 and decreased the sustained depolarization by 21 ± 3% and 12 ± 3%. In all cases, NMDA receptor antagonists had a significantly greater effect on the PDS than the sustained depolarization. These results indicate that, although not essential for generation of paroxysmal activity, NMDA receptors make significant contributions to epileptiform activity in both CA1 and CA3 regions of the hippocampus. © 1990.