Relative Anticonvulsant Effects of GABAmimetic and GABA Modulatory Agents

Summary: Anticonvulsant properties of compounds that enhance GABA‐mediated inhibition through modulatory sites on the GABA_A 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, GABA_A receptor agonist), (±) baclofen (GABA_B 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.