REDUCTION OF CORTICAL PYRAMIDAL NEURON EXCITABILITY BY THE ACTION OF PHENYTOIN ON PERSISTENT NA+ CURRENT

We examined the effect of the anticonvulsant phenytoin (PT) (20-200 mu M) on the persistent Na+ current (I-NaP), I-NaP-dependent membrane po tential responses and repetitive firing in layer 5 pyramidal neurons i n a slice preparation of Pat sensorimotor cortex. I-NaP measured direc tly with voltage-clamp was reduced in a concentration-dependent manner with an apparent EC50 Value of 78 mu M. Clear effects an curuent-evok ed membrane potential responses were apparent at 50 mu M PT: Subthuesh old, depolarizing membrane potential rectification was reduced, rheoba se current was increased and the relation between firing rate and inje cted 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 in jected current pulse also became apparent at moderate PT concentration s. When PT concentration was raised to 150 to 200 mu, this slow adapti on was enhanced markedly, and firing ceased during a sufficiently larg e current pulse. This enhanced slow adaptation and the cessation of fi ring were associated with a marked decline of spike amplitude and a ri se in spike firing level during successive interspike intervals. We as cribe these effects largely to the action of PT on the transient Na+ c urrent. We conclude that the reduction in cortical neuronal excitabili ty by PT depends partly on its reduction of I-NaP, the effects of I-Na P blockade are apparent at PT concentrations lower than those required to abolish tonic firing and the cells need not be excessively depolar ized for PT to decrease excitability by its effect an I-NaP.