Abstract
Limbic seizures were evoked in freely moving rats by intrahippocampal administration of the muscarinic agonist pilocarpine viathe microdialysis probe (10 mM for 40 min at 2 μl/min). This study monitored changes in extracellular hippocampal γ-aminobutyric acid (GABA), glutamate and dopamine levels after systemic (30 mg/kg/day) or local (intrahippocampal or intranigral, 5 mM or 600 μM for 180 min at 2 μl/min) vigabatrin administration, and evaluated the effectiveness of this antiepileptic drug against pilocarpine-induced seizure activity. Extracellular GABA and glutamate overflow in the ipsilateral cerebellum was studied simultaneously. Microdialysis was used as anin vivo sampling technique and as a drug-delivery tool. Electrophysiological evidence for the presence or absence of seizures was recorded with electrocorticography. The observed alterations in extracellular hippocampal amino acid levels support the hypothesis that muscarinic receptor stimulation by the intrahippocampal administration of 10 mM pilocarpine is responsible for the seizure onset, and that the amino acids maintain the sustained seizure activity. The focally evoked pilocarpine-induced seizures were completely prevented by intraperitoneal vigabatrin premedication for 7 days or by a single intraperitoneal injection. Effective protection was reflected in a lack of sustained elevations of hippocampal glutamate levels. Rats receiving vigabatrin intrahippocampally or intranigrally still developed seizures, although there appeared to be a partial protective effect. During the intrahippocampal perfusion with 5 mM vigabatrin, extracellular hippocampal GABA levels increased, whereas the extracellular glutamate and dopamine overflow decreased. The lack of a complete neuroprotection after local vigabatrin treatment is discussed.
Footnotes
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Send reprint requests to: Prof. Dr. Yvette Michotte, Department of Pharmaceutical Chemistry and Drug Analysis, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.
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↵1 This work was supported by the National Fund for Scientific Research, the Free University of Brussels, and the Koningin Elisabeth Stichting.
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↵2 Research assistant of the National Fund for Scientific Research (NFWO, Belgium).
- Abbreviations:
- ANOVA
- analysis of variance
- ECoG
- electrocorticography
- Fisher’s PLSD
- Fisher’s protected least significant difference
- GABA
- γ-aminobutyric acid
- LC
- liquid chromatography
- MK-801
- dizocilpine maleate
- NMDA
- N-methyl-d-aspartate
- S.E.M.
- standard error on the mean
- Received January 21, 1997.
- Accepted August 11, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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