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Electrophysiological actions of phenytoin on N ‐methyl‐D‐aspartate receptor‐mediated responses in rat hippocampus in vitro
Author(s) -
Laffling Alison J.,
Scherr Patrick,
McGivern Joseph G.,
Patmore Leslie,
Sheridan Robert D.
Publication year - 1995
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1995.tb16320.x
Subject(s) - cnqx , population spike , nmda receptor , population , veratridine , dizocilpine , chemistry , ampa receptor , pharmacology , electrophysiology , kainate receptor , schaffer collateral , anticonvulsant , neuroscience , excitatory postsynaptic potential , medicine , receptor , sodium channel , biology , biochemistry , epilepsy , sodium , environmental health , organic chemistry
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 −6 M 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione (CNQX), after which superfusion with a nominally Mg 2+ ‐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 (IC 50 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 −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 × 10 −6 M to 1 × 10 −4 M ) attenuated the effects of the sodium channel activator, veratridine (2 × 10 −6 M ), 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.