Phenytoin blocks N-methyl-D-aspartate responses of mouse central neurons

AW Wamil and MJ McLean

Department of Neurology, Department of Veterans Affairs Medical Center, Nashville, Tennessee.

Intracellularly recorded depolarizing responses of mouse spinal cord neurons in cell culture to N-methyl-D-aspartate (NMDA) applied by pressure ejection at 37 degrees C had a reversal potential of about -13 mV. Amplitude increased when [Mg++]o was less than 1.0 mM or glycine was added to the buffer. Desensitization was complete within 30 pressure applications of NMDA (P30) at 2-s inter-response intervals (IRI; timed from return of one response to resting potential until next application) in bicarbonate buffer and was glycine-sensitive. Desensitization was insignificant in phosphate buffer. In both buffers, 8 x 10(-6) M phenytoin (PT) blocked responses reversibly by P10 of 10(- 5) M NMDA at 0.2 Hz (overlapping responses) and at short 2-s IRI (responses not overlapping). At frequencies < or = 0.1 Hz or IRI > or = 5 s, desensitization and block were less prominent or inapparent. Block by PT was observed 1) in single isolated neurons; 2) in 7 mM [Mg++]o-, 150 mM [K+]o-, or tetrodotoxin (TTX)-containing buffer to suppress spontaneous synaptic activity and action potentials and 3) when voltage- dependent Mg++ block was removed by depolarization or in 0.1 mM Mg++, with or without glycine supplementation. The block was not competitive. The PT metabolite, 5-(4-hydroxyphenyl)-5-phenylhydantoin (80 microM), did not block responses to NMDA. Use- and frequency-dependent block of NMDA responses may contribute to clinical effects of PT, e.g., during sustained rapid activity along pathways excited by NMDA-preferring glutamate receptors.

Volume 267, Issue 1, pp. 218-227, 10/01/1993
Copyright © 1993 by American Society for Pharmacology and Experimental Therapeutics

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