Development of tolerance to the anticonvulsant effect of valproate but not to ethosuximide in a rat model of absence epilepsy.
Ethosuximide and valproic acid were tested for 4 and 2 weeks, respectively, in rats showing the spontaneous spike-wave syndrome. Ethosuximide suppressed the syndrome at plasma concentrations of 75-100 micrograms/ml. High doses of valproate (170 mg/kg i.p., t.i.d.), resulting in plasma concentrations of about 500 micrograms/ml, were necessary to suppress the syndrome, but signs of tolerance to the drug developed from day 5. Tolerance was confined to the number of spike-wave complexes, whereas the duration of the discharges was shortened to 60% of the control value, without there being signs of tolerance. It is assumed that increases in cerebral GABA, induced by the high concentration of valproate, counteracted the anti-absence effect of the drug in this model.
Wahle
H
H
Department of Pharmacology and Toxicology, School of Veterinary Medicine, Free University of Berlin, F.R.G.
Frey
H H
HH
D000818:Animals; D000927:Anticonvulsants; D004361:Drug Tolerance; D004569:Electroencephalography; D004832:Epilepsy, Absence / Q000097:blood / Q000188:drug therapy*; D005013:Ethosuximide / Q000097:blood / Q000494:pharmacology*; D005260:Female; D051381:Rats; D011919:Rats, Inbred Strains; D014635:Valproic Acid / Q000097:blood / Q000494:pharmacology*
D000927:Anticonvulsants; D005013:Ethosuximide; D014635:Valproic Acid