Relative Anticonvulsant Effects of GABAmimetic and GABA Modulatory Agents

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Abstract
Summary: Anticonvulsant properties of compounds that enhance GABA-mediated inhibition through modulatory sites on the GABAA receptor [phenobarbital (PB), clonazepam (CZP), α-ethyl-α-methyl-γ-thiobutyrolactone (α-EMTBL)] were compared with anticonvulsant effects of compounds believed to be antagonists at these modulatory sites (Ro 15- 1788 and a-isopropyl-α-methyl-γ-butyrolactone γ-IMGBL)] and to 4,5,6,7-tetrahy-droisoxazolo-[4,5-c]-pyridin-3-ol (THIP, GABAA receptor agonist), (±) baclofen (GABAB receptor agonist), and γ-vinyl GABA, a compound that increases endogenous GABA. The compounds were tested for their ability to block experimental seizures caused by maximal electroshock, pentylenetetrazol, picrotoxin, methyl-6,7-dirnethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM), bicuculline (BIC), aminophylline, strychnine, and τ-butyl-bicyclophosphorothionate (TBPS) in mice. CZP blocked all but strychnine seizures. PB was also highly effective, blocking all but TBPS seizures. α-EMTBL, representing a new class of experimental anticonvulsant drugs, prevented all seizures except strychnine (STR)- and aminophylline-induced seizures. The antagonists are effective only against one convulsant stimulus. Rol S-1788 and α-IMGBL prevented only DMCM- and pentylenetetrazol (PTZ)-induced seizures, respectively. THIP and γ-vinyl GABA both blocked only BIC and picrotoxin seizures. Baclofen had no anticonvulsant activity. These data demonstrate that compounds that increase neuronal inhibition by potentiating the action of GABA have a broader spectrum of anticonvulsant action than either antagonists or GABAmimetic agents or compounds that increase endogenous GABA.