Selective susceptibility to inhibitors of GABA synthesis and antagonists of GABA(A) receptor in rats with genetic absence epilepsy

Thalamocortical spike-and-wave discharges characterize the nonconvulsive ab sence seizures that occur spontaneously in genetic absence epilepsy rats fr om Strasbourg (GAERS), a selected strain of Wistar rats, GABA is crucial in the generation of absence seizures. The susceptibility to convulsions indu ced by threshold doses of various GABA receptor antagonists and inhibitors of GABA synthesis, kainic acid and strychnine, was compared in GAERS and in nonepileptic rats from a selected control strain (NE). The brain structure s involved in the drug-elicited convulsive seizures were mapped by c-Fos im munohistochemistry. Injection of various antagonists of the GABAA receptor, bicuculline and picrotoxin, and inverse agonists of the benzodiazepine sit e (FG 7142 and DMCM) induced myoclonic spike-and-wave discharges followed b y clonic or tonic-clonic seizures with high paroxysmal activity on the cort ical EEG. The incidence of the convulsions was dose-dependent and was highe r in GAERS than in NE rats. Mapping of c-Fos expression showed that the fro ntoparietal cortex was constantly involved in the convulsive seizures elici ted by a threshold convulsant dose, whereas limbic participation was variab le. In contrast, GAERS were less susceptible than NE rats to the tonic-clon ic convulsions induced by the inhibitors of glutamate decarboxylase, isonia zide and 3-mercaptopropionic acid. The GABA(B) receptor antagonist CGP 5699 9 and kainic acid induced a similar incidence of seizures in GAERS and NE r ats and predominantly activated the hippocampus. No difference in the tonic seizures elicited by strychnine could be evidenced between the strains. Th ese results suggest that an abnormal cortical GABAergic activity may underl ie absence seizures in GAERS. (C) 2000 Academic Press.