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 x 10(-6) M 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), after which superfusion with a nominally Mg(2+)-free Krebs solution (containing 5 x 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, 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), 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 x 10(-4) M applied 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 10-4M) attenuated the effects of the sodium channel activator,veratridine (2 x 10-6 M), on the CAl 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.
Laffling
A J
AJ
Department of Pharmacology, Syntex Research Centre, Edinburgh.
Scherr
P
P
McGivern
J G
JG
Patmore
L
L
Sheridan
R D
RD
D000818:Animals; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004558:Electric Stimulation; D004594:Electrophysiology; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D010672:Phenytoin / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000502:physiology; D013569:Synapses / Q000187:drug effects* / Q000502:physiology; D014701:Veratridine / Q000494:pharmacology
D016194:Receptors, N-Methyl-D-Aspartate; D010672:Phenytoin; D016291:Dizocilpine Maleate; D014701:Veratridine