Reduction of Cortical Pyramidal Neuron Excitability by the Action of Phenytoin on Persistent Na⁺ Current1

Abstract

We examined the effect of the anticonvulsant phenytoin (PT) (20–200 μM) on the persistent Na⁺ current (I_NaP), I_NaP-dependent membrane potential responses and repetitive firing in layer 5 pyramidal neurons in a slice preparation of rat sensorimotor cortex. I_NaP 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 I_NaP. 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 I_NaP, the effects of I_NaP 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 I_NaP.