EFFECTIVENESS OF VIGABATRIN AGAINST FOCALLY EVOKED PILOCARPINE-INDUCED SEIZURES AND CONCOMITANT CHANGES IN EXTRACELLULAR HIPPOCAMPAL AND CEREBELLAR GLUTAMATE, GAMMA-AMINOBUTYRIC-ACID AND DOPAMINE LEVELS, A MICRODIALYSIS-ELECTROCORTICOGRAPHY STUDY IN FREELY MOVING RATS

Limbic seizures were evoked in freely moving rats by intrahippocampal administration of the muscarinic agonist pilocarpine via the microdial ysis probe (10 mM for 40 min at 2 mu l/min). This study monitored chan ges in extracellular hippocampal gamma-aminobutyric acid (GABA), gluta mate and dopamine levels after systemic (30 mg/kg/day) or local (intra hippocampal or intranigral, 5 mM or 600 mu M for 180 min at 2 mu l/min ) vigabatrin administration, and evaluated the effectiveness of this a ntiepileptic drug against pilocarpine-induced seizure activity. Extrac ellular GABA and glutamate overflow in the ipsilateral cerebellum was studied simultaneously. Microdialysis was used as an in vivo sampling technique and as a drug-delivery tool. Electrophysiological evidence f or the presence or absence of seizures was recorded with electrocortic ography. The observed alterations in extracellular hippocampal amino a cid levels support the hypothesis that muscarinic receptor stimulation by the intrahippocampal administration of 10 mM pilocarpine is respon sible for the seizure onset, and that the amino acids maintain the sus tained seizure activity. The focally evoked pilocarpine-induced seizur es were completely prevented by intraperitoneal vigabatrin premedicati on for 7 days or by a single intraperitoneal injection. Effective prot ection was reflected in a lack of sustained elevations of hippocampal glutamate levels. Rats receiving vigabatrin intrahippocampally or intr anigrally still developed seizures, although there appeared to be a pa rtial protective effect. During the intrahippocampal perfusion with 5 mM vigabatrin, extracellular hippocampal GABA levels increased, wherea s the extracellular glutamate and dopamine overflow decreased. The lac k of a complete neuroprotection after local vigabatrin treatment is di scussed.