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Vol. 284, Issue 1, 228-237, 1998
Department of Physiology and Biophysics, University of Washington
School of Medicine, Seattle, Washington 98195-7290
We examined the effect of the anticonvulsant phenytoin (PT) (20-200
µM) on the persistent Na+ current (INaP),
INaP-dependent membrane potential responses and repetitive
firing in layer 5 pyramidal neurons in a slice preparation of rat
sensorimotor cortex. INaP measured directly with
voltage-clamp was reduced in a concentration-dependent manner with an
apparent EC50 value of 78 µM. Clear effects on
current-evoked membrane potential responses were apparent at 50 µM
PT: Subthreshold, depolarizing membrane potential rectification was
reduced, rheobase current was increased and the relation between firing
rate and injected current was shifted to the right, but action
potential amplitude and duration were unaffected. We ascribed these
effects of PT largely to the reduction of INaP. A slow
decline of firing rate during the injected current pulse also became
apparent at moderate PT concentrations. When PT concentration was
raised to 150 to 200 µM, this slow adaption was enhanced markedly,
and firing ceased during a sufficiently large current pulse. This
enhanced slow adaptation and the cessation of firing were associated
with a marked decline of spike amplitude and a rise in spike firing
level during successive interspike intervals. We ascribe these effects largely to the action of PT on the transient Na+ current.
We conclude that the reduction in cortical neuronal excitability by PT
depends partly on its reduction of INaP, the effects of
INaP blockade are apparent at PT concentrations lower than
those required to abolish tonic firing and the cells need not be
excessively depolarized for PT to decrease excitability by its effect
on INaP.
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