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 absence seizures that occur spontaneously in genetic absence epilepsy rats from Strasbourg (GAERS), a selected strain of Wistar rats. GABA is crucial in the generation of absence seizures. The susceptibility to convulsions induced 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 structures involved in the drug-elicited convulsive seizures were mapped by c-Fos immunohistochemistry. Injection of various antagonists of the GABA(A) receptor, bicuculline and picrotoxin, and inverse agonists of the benzodiazepine site (FG 7142 and DMCM) induced myoclonic spike-and-wave discharges followed by clonic or tonic-clonic seizures with high paroxysmal activity on the cortical EEG. The incidence of the convulsions was dose-dependent and was higher in GAERS than in NE rats. Mapping of c-Fos expression showed that the frontoparietal cortex was constantly involved in the convulsive seizures elicited by a threshold convulsant dose, whereas limbic participation was variable. In contrast, GAERS were less susceptible than NE rats to the tonic-clonic convulsions induced by the inhibitors of glutamate decarboxylase, isoniazide and 3-mercaptopropionic acid. The GABA(B) receptor antagonist CGP 56999 and kainic acid induced a similar incidence of seizures in GAERS and NE rats and predominantly activated the hippocampus. No difference in the tonic seizures elicited by strychnine could be evidenced between the strains. These results suggest that an abnormal cortical GABAergic activity may underlie absence seizures in GAERS.
Vergnes
M
M
Faculté de Médecine, INSERM U 398, 11 rue Humann, Strasbourg Cedex, 67085, France.
Boehrer
A
A
Reibel
S
S
Simler
S
S
Marescaux
C
C
D015097:3-Mercaptopropionic Acid / Q000494:pharmacology; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D002243:Carbolines / Q000494:pharmacology; D003292:Convulsants / Q000494:pharmacology; D004569:Electroencephalography / Q000187:drug effects; D004832:Epilepsy, Absence / Q000235:genetics / Q000503:physiopathology*; D005625:Frontal Lobe / Q000378:metabolism / Q000503:physiopathology; D018756:GABA Antagonists / Q000494:pharmacology*; D058787:GABA-A Receptor Antagonists; D005968:Glutamate Decarboxylase / Q000037:antagonists & inhibitors; D007538:Isoniazid / Q000494:pharmacology; D007608:Kainic Acid / Q000494:pharmacology; D008032:Limbic System / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D010296:Parietal Lobe / Q000378:metabolism / Q000503:physiopathology; D010852:Picrotoxin / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000032:analysis; D051381:Rats; D011922:Rats, Mutant Strains; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology; D013331:Strychnine / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D015097:3-Mercaptopropionic Acid; D001640:Bicuculline; D002243:Carbolines; D003292:Convulsants; D018756:GABA Antagonists; D058787:GABA-A Receptor Antagonists; D005968:Glutamate Decarboxylase; D007538:Isoniazid; D007608:Kainic Acid; D010852:Picrotoxin; D016760:Proto-Oncogene Proteins c-fos; D013331:Strychnine; D005680:gamma-Aminobutyric Acid; C034818:methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate; C035874:FG 7142