The effect of the NMDA receptor antagonist, MK-801, on the course and outcome of kindling

Abstract

A rapid kindling procedure was used to distinguish between the anticonvulsant activity of drugs and their ability to retard the kindling process. MK-801 is a specific ligand at the phencyclidine (PCP) recognition site, and acts as a noncompetitive antagonist of NMDA-type glutamate/aspartate receptors. Intraperitoneal injections of MK-801 (0.5-4.0 mg/kg IP) significantly reduced the cumulated effect of 12 2-hr kindling stimulations, as determined from behavioral measures of seizure activity in immediately ensuing 24-hr drug-free kindling sessions; however, the corresponding electrographic effects did not reach significance. MK-801 also showed significant anticonvulsant activity when injected in fully kindled rats. Higher doses tested were accompanied by locomotor and postural effects. The anticonvulsant benzodiazepine, clonazepam, formulated with a proprietary diluent (as Rivotril, Roche), injected in anticonvulsant doses during the first 12 kindling sessions (0.64 mg/kg IP, repeated after 9 hr) did not significantly affect the course of subsequent sessions of drug-free kindling. Systemic injections of kynurenic acid (300-600 mg/kg IP 4 hours), a nonspecific antagonist of glutamate receptors in vitro, were without significant anticonvulsant or antikindling activity. Activity of NMDA-sensitive glutamate/aspartate receptors associated with the PCP recognition site may induce lasting facilitation of neural transmission; this facilitation may be responsible for the remote propagation and progressive enhancement of seizure activity kindled in the amygdala. The facilitatory process appears to be antagonised by MK-801.