The anticonvulsant, (+/-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine (MK-801), blocked single postsynaptic responses of mouse spinal cord neurons in cell culture to N-methyl-D-aspartate (NMDA). The block was concentration dependent with IC50 = 10(-7) M against 10(-5) M NMDA and 2 x 10(-7) M against 10(-3) M NMDA. Serial responses were blocked in use-dependent manner by 10 times lower doses of MK-801, depending on rate of NMDA application. MK-801 (approximate IC50, 8 x 10(-8) M) also limited sustained high-frequency repetitive firing of sodium-dependent action potentials (AP) elicited by long (400 msec) depolarizing pulses. Without changing resting membrane potential, single AP elicited by short (0.5-1 msec) depolarizing current pulses were blocked in voltage-, use- and frequency-dependent manner. Maximal rate of rise of individual AP elicited by short or long pulses decreased progressively until failure to fire. The time constant of recovery of AP from inactivation in a paired pulse protocol was prolonged from about 1 msec in control solution to 12 msec in solution containing 3 x 10(-7) M MK-801. These characteristics suggest that MK-801 blocks voltage-sensitive sodium current, which generates the upstroke of the AP. Overlap of concentrations blocking NMDA responses and sustained repetitive firing suggests that both actions may contribute to anticonvulsant efficacy of MK-801.