AMPA and GABA(B) receptor antagonists and their interaction in rats with a genetic form of absence epilepsy.
The effects of combined and single administration of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, 7,8-methylenedioxy-1-(4-aminophenyl)-4-methyl-3-acetyl-4,5-dihydro-2,3-benzodiazepine (LY 300164), and of the GABA(B) receptor antagonist gamma-aminopropyl-n-butyl-phosphinic acid (CGP 36742), on spontaneously occurring spike-wave discharges were investigated in WAG/Rij rats. LY 300164 had minor effects; only the highest dose (16 mg/kg) reduced the number of spike-wave discharges in a short time window. CGP 36742 was more effective as it significantly reduced the number of spike-wave discharges and shortened their duration at the doses of 25 and 100 mg/kg. The ED(50) values for the inhibition of spike-wave discharges by LY 300164 and CGP 36742 in a time window 30-60 min after injection were 15.5 and 16.6 mg/kg, respectively. The ED(50) of CGP 36742 was reduced to 8.0 mg/kg when this antagonist was administered in combination with LY 300164 (6 mg/kg). The interaction between the two antagonists appeared to be additive according to isobolographic analysis. Importantly, CGP 36742 and LY 300164 administered either alone or in combination had no apparent effects on behavior. These results may provide information for a rational approach to polytherapy for the treatment of generalized absence epilepsy.
Kamiński
R M
RM
Department of Comparative and Physiological Psychology, Nijmegen Institute for Cognition and Information, University of Nijmegen, P.O. Box 9104, 6500 HE, Nijmegen, The Netherlands. rkaminsk@intra.nida.nih.gov
Van Rijn
C M
CM
Turski
W A
WA
Czuczwar
S J
SJ
Van Luijtelaar
G
G
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001569:Benzodiazepines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004569:Electroencephalography / Q000187:drug effects; D004832:Epilepsy, Absence / Q000235:genetics / Q000503:physiopathology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D018756:GABA Antagonists / Q000494:pharmacology*; D058788:GABA-B Receptor Antagonists; D008297:Male; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors; D013997:Time Factors
D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D058788:GABA-B Receptor Antagonists; D009943:Organophosphorus Compounds; D018091:Receptors, AMPA; D001569:Benzodiazepines; C079148:(3-aminopropyl)(n-butyl)phosphinic acid; C085266:talampanel