Paradoxical role of GABA in a chronic model of petit mal (absence)-like epilepsy in the rat.
Neonatal Long-Evans hooded rats were treated with AY-9944, a cholesterol biosynthesis inhibitor, every 6 days for 7 weeks to induce a permanent absence-like epileptic condition. AY-9944-treated rats averaged 50 +/- 15 generalized non-motor seizures per hour of 2-15 s duration as monitored by electrocorticography. Clinically effective anti-absence drugs were observed to reduce seizure occurrence in a dose-dependent manner. Paradoxically, GABA agonists increased seizure occurrence while GABA antagonists decreased seizure occurrence. Evaluation of the benzodiazepines, diazepam and clonazepam, in this model revealed inhibition of seizure activity by GABA-independent mechanisms. Valproic acid produced a biphasic effect suggesting a GABA-independent, antiabsence action at low doses and GABAergic augmentation of seizure occurrence at higher doses. The results of this study support the hypothesis that increased GABAergic stimulation may induce inhibitory seizures in absence epilepsy.
Department of Pharmacology, University of Nevada School of Medicine, Reno 89557.
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Smith
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Bierkamper
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D002908:Chronic Disease; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography; D004576:Electromyography; D004832:Epilepsy, Absence / Q000503:physiopathology*; D018756:GABA Antagonists; D008297:Male; D010852:Picrotoxin / Q000494:pharmacology; D051381:Rats; D012640:Seizures / Q000503:physiopathology; D005680:gamma-Aminobutyric Acid / Q000502:physiology*; D001371:trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride / Q000494:pharmacology
D000927:Anticonvulsants; D018756:GABA Antagonists; D010852:Picrotoxin; D005680:gamma-Aminobutyric Acid; D001371:trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride