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' (AMP A receptor-mediated) CA1 population spike, evoked by electrical stimul ation of the Schaffer collateral/commissural pathway, was abolished by 5 min treatment with 5 x 10(-6) M 6-cyano-7-nitroquinoxaline-2,3-dion e (CNQX), after which superfusion with a nominally Mg2+-free Krebs sol ution (containing 5 x 10(-6) M CNQX) led to the appearance of an epile ptiform population spike which was fully developed by 30-40 min. 3 The epileptiform population spike was abolished by the non-competitive NM DA antagonist, dizocilpine (1 x 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 x 10(-7) M), demonstr ating that the response was mediated by activation of NMDA receptors a nd validating its use as an assay for antagonists acting at the NMDA r eceptor/channel complex. 4 Phenytoin (0.1, 0.3 and 1 x 10(-4) M applie d cumulatively for 30 min at each concentration) failed to inhibit the NMDA receptor-mediated epileptiform population response (n = 7 slices ). 5 Phenytoin (3 x 10(-6) M to 1 x 10(-4) M) attenuated the effects o f the sodium channel activator, veratridine (2 x 10(-6) M), on the CA1 population spike amplitude (recorded in normal Krebs solution), indic ating that the previously observed lack of effect of phenytoin on the NMDA receptor-mediated response was not due to impaired access of phen ytoin to the biophase. 6 These data support the conclusion that antago nism of NMDA receptor-mediated events is not a pharmacological propert y of phenytoin and that such an action is therefore unlikely to contri bute to the anticonvulsant activity of this drug.