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 developme nt (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 electrica l kindling, an animal model of human complex partial and secondary gen eralised focal seizures. Pretreatment with NMDA significantly increase d the electrical afterdischarge threshold in this model. With subseque nt daily suprathreshold electrical stimulation, however, NMDA pretreat ment enhanced the kindling process as shown by both electroencephalogr aphic and motor seizure responses. Marked reductions in the number of stimulations required to reach each distinct stage of kindling develop ment 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 a nimals (11.6 +/- 1.4 stimulations; mean +/- S.E.M.; P < 0.05). Consist ent with this, the mean durations of the electrically-evoked afterdisc harges on most NMDA pretreatment days were significantly increased com pared to those recorded in control animals. Importantly, fully kindled animals showed a markedly enhanced sensitivity to focally applied NMD A. The results of the present experiments provide strong in vivo evide nce to support the concept that ion fluxes through NMDA receptor-linke d cation channels play a major role in the mechanisms of kindling epil eptogenesis. Extracellular glutamate at abnormally raised levels, acti ng at least in part via NMDA receptors, may be the principal agent tri ggering many forms of epilepsy.