Electrophysiological actions of phenytoin on N‐methyl‐D‐aspartate receptor‐mediated responses in rat hippocampus in vitro

1 The effects of the anticonvulsant, phenytoin, have been examined on N-methyl-D-aspartate (NMDA) receptor-mediated population spikes in the CA1 region of the rat hippocampus in vitro. 2 The ‘conventional’ (AMPA receptor-mediated) CA1 population spike, evoked by electrical stimulation of the Schaffer collateral/commissural pathway, was abolished by 5 min treatment with 5 × 10−6M 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), after which superfusion with a nominally Mg2+-free Krebs solution (containing 5 × 10−6 M CNQX) led to the appearance of an epileptiform population spike which was fully developed by 30–40 min. 3 The epileptiform population spike was abolished by the non-competitive NMDA antagonist, dizocil-pine (1 × 10−6 M, 20–30 min) and inhibited by the competitive NMDA receptor antagonist, D-CPP (IC50 for reducing the amplitude of the first spike in the train = 8.3 × 10−7 M), demonstrating that the response was mediated by activation of NMDA receptors and validating its use as an assay for antagonists acting at the NMDA receptor/channel complex. 4 Phenytoin (0.1, 0.3 and 1 × 10−4M applied cumulatively for 30 min at each concentration) failed to inhibit the NMDA receptor-mediated epileptiform population response (n = 7 slices). 5 Phenytoin (3 × 10−6 M to 1 × 10−4 M) attenuated the effects of the sodium channel activator, veratridine (2 × 10−6M), on the CA1 population spike amplitude (recorded in normal Krebs solution), indicating that the previously observed lack of effect of phenytoin on the NMDA receptor-mediated response was not due to impaired access of phenytoin to the biophase. 6 These data support the conclusion that antagonism of NMDA receptor-mediated events is not a pharmacological property of phenytoin and that such an action is therefore unlikely to contribute to the anticonvulsant activity of this drug.