Pharmacological profiles of generalized absence seizures in lethargic, stargazer and gamma-hydroxybutyrate-treated...

We examined the pharmacological profiles of generalized absence seizures in three mouse models: two mutant strains with spontaneous absence seizures, lethargic and stargazer, and ddY mice (GHB model) in which absence seizures were induced by administering gamma-butyrolactone (GBL), a prodrug of gamma-hydroxybutyric acid (GHB). A typical antiabsence drug, ethosuximide (200 mg/kg), attenuated absence seizure behavior, spike and wave and paroxysmal discharges (SWDs and PDs) in each model. P-[3-Aminopropyl]-P-diethoxymethylphosphinic acid (CGP 35348), a selective gamma-aminobutyric acid (GABA)B antagonist (200 mg/kg), suppressed absence seizure behavior, SWDs and PDs at least as effectively as ethosuximide (200 mg/kg) in lethargic and GHB model mice. P-[3-Aminopropyl]-P-cyclohexylmethylphosphinic acid (CGP 46381) was more effective than CGP 35348 and ethosuximide in these models. Although the antiabsence effect of CGP 46381 was as strong as that of ethosuximide (200 mg/kg) in stargazer mice, CGP 35348 (200-400 mg/kg) was weaker than ethosuximide. (+)-5-Methyl-10,11-dihydro-5H-dibenzo[a,b]cyclohepten-5,10-imine hydrogen maleate (MK-801), a non-competitive N-methyl-D-aspartate (NMDA) antagonist (0.5 mg/kg), had no effects on SWDs and PDs in lethargic or GHB model mice. Although MK-801 (0.5 mg/kg) suppressed SWDs significantly in stargazer mice, irregular electroencephalographic patterns were observed. These results suggest that GABAB receptors play a significant role in the pathogenesis of generalized absence seizures in these models, although the mechanism involved in stargazer mice differ from that in the other two.