PHENYTOIN BLOCKS N-METHYL-D-ASPARTATE RESPONSES OF MOUSE CENTRAL NEURONS

Intracellularly recorded depolarizing responses of mouse spinal cord n eurons in cell culture to N-methyl-D-aspartate (NMDA) applied by press ure 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 a pplications of NMDA (P30) at 2-s inter-response intervals (IRI; timed from return of one response to resting potential until next applicatio n) in bicarbonate buffer and was glycine-sensitive. Desensitization wa s insignificant in phosphate buffer. In both buffers, 8 X 10(-6) M phe nytoin (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 overl apping). At frequencies -0.1 Hz or IRI greater-than-or-equal-to 5 s, d esensitization and block were less prominent or inapparent. Block by P T was observed 1) in single isolated neurons; 2) in 7 MM [Mg++]o-, 150 mM [K+]o-, or tetrodotoxin (TTX)-containing buffer to suppress sponta neous synaptic activity and action potentials and 3) when voltage-depe ndent Mg++ block was removed by depolarization or in 0.1 mM Mg++, with or without glycine supplementation. The block was not competitive. Th e PT metabolite, 5-4-hydroxy-phenyl)-5-phenylhydantoin (80 muM), did n ot block responses to NMDA. Use- and frequency-dependent block of NMDA responses may contribute to clinical effects of PT, e.g., during sust ained rapid activity along pathways excited by NMDA-preferring glutama te receptors.