The N-methyl-D-aspartate antagonists aminophosphonovalerate and carboxypiperazinephosphonate retard the development and expression of kindled seizures

To investigate the possible role of N-methyl-D-aspartate (NMDA) receptors in the development and expression of amygdaloid-kindled seizures, rats were either chronically infused with 2-amino-5-phosphonovalerate (APV, 20-40 mM) or pre-injected with carboxypiperazine-phosphonate (CPP, 1-10 mg/kg), both selective NMDA-receptor antagonists, and then kindled from the amygdala. At the higher dose (40 mM), APV blocked the induction of long-term potentiation in the dentate gyrus. APV also retarded clinical seizure development dose-dependently and increased seizure thresholds without affecting afterdischarge (AD) duration. These same doses of APV had only small anticonvulsant effects on established kindled seizures. Although CPP (1-10 mg/kg) had no effect when rats were kindled 45 min after injection it dose-dependently retarded focal and generalization stages at the 150 min injection-kindling interval. Once relieved of drug, animals proceeded to develop stage 5 seizures with shorter duration ADs than saline-control animals. When the previously-kindled, saline groups were crossed to CPP a small depressant effect on seizure expression was observed. These results suggest that NMDA receptors are primarily involved in kindling development rather than in maintaining the kindled state.