THE NMDA ANTAGONIST MK-801 SUPPRESSES BEHAVIORAL SEIZURES, AUGMENTS AFTERDISCHARGES, BUT DOES NOT BLOCK DEVELOPMENT OF PERFORANT PATH KINDLING

The role of N-methyl-D-aspartate (NMDA) in the development and expression of kindled seizures was assessed using a crossover design. Rats were stimulated once daily in the perforant path for 10 consecutive days 30 min following daily administration of saline or the NMDA antagonist MK-801 (1.0 mg/kg) (phase I). Five to 10 days elapsed prior to an additional 10 stimulations with the drug treatments reversed (phase II). A separate group of animals was stimulated following saline administration in both phases of the study. MK-801 produced a significant increase in afterdischarge (AD) threshold and a suppression of behavioral seizure development during the first 10 stimulations. However, upon removal of the drug, an immediate increase in seizure stage and the number of animals displaying generalized seizure signs (clonic component) was observed. Paradoxically, MK-801 also produced an increase in mean AD duration in the perforant path and dentate gyrus over the first 10 stimulations. Upon reversal of the dose treatments in phase II of the study, AD duration increased in animals treated with MK-801 for the first time, and decreased in animals taken off MK-801 and stimulated drug free. The augmentation in AD associated with MK-801 was partially attributed to an increase in secondary or rebound AD. Rebound ADs occurred more frequently, had a decreased latency and longer duration in drugged compared to control animals, irrespective of the phase of the study. These data indicate that MK-801 possesses anticonvulsant properties with respect to behavioral seizure, and is less effective as an antiepileptogenic agent - i.e., significant kindling development occurred with MK-801 in the absence of overt behavioral expression of the kindled response. A dissociation between seizure stage and AD duration suggests that independent mechanisms may control the electrographic and behavioral indices of kindling.