Abstract
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.
Footnotes
-
Send reprint requests to: Dr. P. C. Schwindt, Department of Physiology and Biophysics, University of Washington School of Medicine, Box 357290, Seattle, WA 98195-7290. E-mail:schwindt{at}u.washington.edu
-
↵1 This work was supported by International Human Frontiers Science Program Grant LT-544/94 (I.L.) and National Institutes of Health Grant NS16792 and the Keck Foundation (P.C.S. and W.E.C.).
- Abbreviations:
- PT
- phenytoin sodium
- TTX
- tetrodotoxin
- INaP
- persistent sodium current
- GNaP
- persistent sodium current conductance
- INa
- transient sodium current
- EC50
- concentration causing half-inhibition
- ANOVA
- analysis of variance
- DMSO
- dimethylsulfoxide
- I-V
- current-voltage
- Received May 22, 1997.
- Accepted September 25, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|