Opposite effects of GABAB receptor antagonists on absences and convulsive seizures.
In Wistar rats with spontaneous non-convulsive absence epilepsy, absence seizures were dose dependently suppressed by intraperitoneal administration of the GABAB receptor antagonists CGP 36742, 50-400 mg/kg, and CGP 56999, 0.25-0.75 mg/kg, and by bilateral microinjections of the same compounds into the lateral nuclei of the thalamus. In rats susceptible to audiogenic seizures, intraperitoneal administration of both GABAB receptor antagonists, at doses which suppressed absence seizures, facilitated the elicitation of sound-induced tonic seizures. In non-epileptic control rats, intraperitoneal injections of higher doses of CGP 36742 (800-2400 mg/kg) and CGP 56999 (3-6 mg/kg) induced delayed clonic convulsions, which were suppressed by pretreatment with baclofen. c-Fos protein was expressed after GABAB receptor antagonist-induced seizures in the cortex, hippocampus, amygdala, perirhinal and piriform cortex. Intra-cortical and hippocampal microinfusion of both GABAB receptor antagonists produced focal seizures. In conclusion, GABAB receptor antagonists suppress non-convulsive absence seizures by blocking thalamic GABAB receptors, while they induce convulsions in cortical and limbic structures.
Vergnes
M
M
Unité INSERM 398, Faculté de Médecine, Strasbourg, France. vergnes@neurochem.U-strasbg.fr
Boehrer
A
A
Simler
S
S
Bernasconi
R
R
Marescaux
C
C
D000818:Animals; D001921:Brain / Q000378:metabolism; D004832:Epilepsy, Absence / Q000188:drug therapy* / Q000503:physiopathology; D018756:GABA Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D058788:GABA-B Receptor Antagonists; D008297:Male; D009943:Organophosphorus Compounds / Q000494:pharmacology / Q000627:therapeutic use; D010721:Phosphinic Acids / Q000494:pharmacology / Q000627:therapeutic use; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D051381:Rats; D012640:Seizures / Q000188:drug therapy* / Q000503:physiopathology
C102659:CGP 56999A; D018756:GABA Antagonists; D058788:GABA-B Receptor Antagonists; D009943:Organophosphorus Compounds; D010721:Phosphinic Acids; D016760:Proto-Oncogene Proteins c-fos; C079148:(3-aminopropyl)(n-butyl)phosphinic acid