Anticonvulsant and antiepileptogenic effects of GABA A receptor ligands in pentylenetetrazole-kindled mice

Abstract

Although animal models based on pentylenetetrazole (PTZ) are widely used, the mechanism by which PTZ elicits its action is not very well understood. At the molecular level, a generally accepted mechanism of PTZ is noncompetitive antagonism of the γ-aminobutyric acid (GABA) A receptor complex. By a systematic pharmacological investigation of various GABA A receptor ligands, our aim was to gain a better understanding of the GABAergic mechanisms involved in different PTZ-induced seizures. We investigated anticonvulsant effects of various specific GABA A receptor ligands, which are believed to bind to different binding sites on the GABA A receptor complex, on PTZ-induced clonic seizures in drug naive and PTZ-kindled mice as well as their effects on the development of PTZ kindling. Diazepam and alphaxalone produced potent anticonvulsant effects and completely suppressed the development of kindling. In contrast, the antagonists bicuculline and dehydroepiandrosterone sulfate (DHEAS) displayed neither anticonvulsant nor antiepileptogenic effects. Flumazenil, often used as a reference antagonist at the GABA A receptor benzodiazepine (BZ) binding site, lacked anticonvulsant effects but surprisingly inhibited the development of PTZ-kindled seizures. The agonist 4,5,6,7-tetrahydroisoxazolo-(5,4- c)pyridin-3-ol (THIP) was devoid of both anticonvulsant and antiepileptogenic effects. Marked differences in drug sensitivity were observed between models based on single and chronic administration of PTZ showing that the two sets of models are fundamentally different. These results describe the pharmacology of a set of ligands believed to bind to different sites at the GABA A receptor complex in animal models based on PTZ and demonstrate that a drug's action in these models cannot be readily explained by agonistic or antagonistic properties at the receptor level.