The effects of focal N-methyl-D-aspartate pretreatment on the parameters of amygdaloid electrical kindling

Evidence is accumulating for a role of glutamate in both the development (epileptogenesis) and spread of epileptic neuronal hyperactivity in the brain. In the present investigation we examined the influence of daily focal pretreatment with the selective glutamate receptor agonist N-methyl-D-aspartate (NMDA) on the parameters of amygdaloid electrical kindling, an animal model of human complex partial and secondary generalised focal seizures. Pretreatment with NMDA significantly increased the electrical afterdischarge threshold in this model. With subsequent daily suprathreshold electrical stimulation, however, NMDA pretreatment enhanced the kindling process as shown by both electroencephalographic and motor seizure responses. Marked reductions in the number of stimulations required to reach each distinct stage of kindling development were evident. The number of stimulations required to achieve the fully kindled state was approximately halved by pretreatment with NMDA (6.8 +/- 1.6 stimulations) compared with control, buffer-pretreated animals (11.6 +/- 1.4 stimulations; mean +/- S.E.M.; P < 0.05). Consistent with this, the mean durations of the electrically-evoked afterdischarges on most NMDA pretreatment days were significantly increased compared to those recorded in control animals. Importantly, fully kindled animals showed a markedly enhanced sensitivity to focally applied NMDA. The results of the present experiments provide strong in vivo evidence to support the concept that ion fluxes through NMDA receptor-linked cation channels play a major role in the mechanisms of kindling epileptogenesis. Extracellular glutamate at abnormally raised levels, acting at least in part via NMDA receptors, may be the principal agent triggering many forms of epilepsy.