Competitive NMDA receptor antagonists do not block cholinergic kindling with carbachol

Abstract

The role of NMDA receptor activity in kindling was examined in rats pretreated with the competitive NMDA receptor antagonists aminophosphonovaleric acid (APV) or NPC17742 (2R,4R,2S-(2-amino-4,5(cyclohexyl)-7-phosphonoheptanoic acid). After pretreatment, the rats received an infusion of carbachol, a muscarinic agonist, into the amygdala or hippocampus. Kindling sessions with carbachol occurred once every 48 h until a stage 5 convulsion was displayed. Electrical kindling of the amygdala after pretreatment with NPC17742 was also examined. Both APV and NPC17742 retarded the rate of carbachol kindling in its early stages, but all rats displayed kindled stage 5 convulsions under APV or NPC17742 in fewer than 10 sessions. Convulsion development was accompanied by growth in the duration and strength of the accompanying epileptiform activity. All rats exhibited a stage 5 convulsion on the first or second session after cross-over to vehicle pretreatment, confirming the development of kindled convulsions under pretreatment with NMDA antagonists. NPC17742 retarded electrical kindling, but after cross-over to vehicle there was savings in the rate of kindling to stage 5 convulsions. These findings indicate that carbachol kindling of the amygdala or hippocampus readily occurs under NMDA antagonism. They are consistent with the view that NMDA receptor activity may contribute to, but is not required for, the kindling of seizures.