NMDA RECEPTOR-MEDIATED PILOCARPINE-INDUCED SEIZURES - CHARACTERIZATION IN FREELY MOVING RATS BY MICRODIALYSIS

1 Pilocarpine administration has been used as an animal model for temp oral lobe epilepsy since it produces several morphological and synapti c features in common with human complex partial seizures. Little is kn own about changes in extracellular neurotransmitter concentrations dur ing the seizures provoked by pilocarpine, a non-selective muscarinic a gonist. 2 Focally evoked pilocarpine-induced seizures in freely moving rats were provoked by intrahippocampal pilocarpine (10 mM for 40 min at a flow rate of 2 mu l min(-1)) administration via a microdialysis p robe. Concomitant changes in extracellular hippocampal glutamate, gamm a-aminobutyric acid (GABA) and dopamine levels were monitored and simu ltaneous electrocorticography was performed. The animal model was char acterized by intrahippocampal perfusion with the muscarinic receptor a ntagonist atropine (20 mM), the sodium channel blocker tetrodotoxin (1 mu M) and the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (dizocilpine maleate, 100 mu M). The effectiveness of locally (600 mu M) or systemically (10 mg kg(-1) day(-1)) applied lamotrigine against the pilocarpine-induced convulsions was evaluated. 3 Pilocarpine initi ally decreased extracellular hippocampal glutamate and GABA levels. Du ring the subsequent pilocarpine-induced limbic convulsions extracellul ar glutamate, GABA and dopamine concentrations in hippocampus were sig nificantly increased. Atropine blocked all changes in extracellular tr ansmitter levels during and after co-administration of pilocarpine. Al l pilocarpine-induced increases were completely prevented by simultane ous tetrodotoxin perfusion. Intrahippocampal administration of MK-801 and lamotrigine resulted in an elevation of hippocampal dopamine level s and protected the rats from the pilocarpine-induced seizures. Piloca rpine-induced convulsions developed in the rats which received lamotri gine perorally. 4 Pilocarpine-induced seizures are initiated via musca rinic receptors and further mediated via NMDA receptors. Sustained inc reases in extracellular glutamate levels after pilocarpine perfusion a re related to the limbic seizures. These are arguments in favour of ea rlier described NMDA receptor-mediated excitotoxicity. Hippocampal dop amine release may be functionally important in epileptogenesis and may participate in the anticonvulsant effects of MK-801 and lamotrigine. The pilocarpine-stimulated hippocampal GABA, glutamate and dopamine le vels reflect neuronal vesicular release.