Abstract

gamma-Aminobutyric acid (GABA) stimulated 36Cl- influx into membrane vesicles from rat cerebral cortex at 3 to 300 microM in a concentration-dependent manner with near maximum response at 100 microM. Inhibitory potencies for this GABA (100 microM)-dependent 36Cl- uptake were determined for 16 cage convulsants including 10 bicycloorthocarboxylates and 3 bicyclophosphorus esters and for 8 polychlorocycloalkane insecticides. Inhibition by derivatives of t-butylbicycloorthobenzoate (TBOB) and t-butylbicyclophosphorothionate (TBPS) depended on the substituents at both positions 1 and positions 4. Among them, the 4-cyano-phenyl analog of TBOB was the most potent inhibitor with an IC50 value of 40 nM. Other cage convulsants such as picrotoxinin, tetramethylenedisulfotetramine and p-chlorophenylsilatrane were less potent than TBOB and TBPS. The potencies of bicycloorthocarboxylates, bicyclophosphorus esters and other cage convulsants in inhibiting GABA-stimulated 36Cl- uptake by rat cerebral cortex were significantly correlated with those in inhibiting [35S]TBPS binding to the human and mouse brain receptors (r = 0.96, P less than .01). There also was a significant correlation between the potencies of the polychlorocycloalkanes examined in inhibiting GABA-stimulated 36Cl- uptake and [35S]TBPS binding to the mouse brain receptor (r = 0.94, P less than .01). In these correlations, the polychlorocycloalkanes appear to fall on a different line than that for the bicycloorthocarboxylates, bicyclophosphorus esters and other cage convulsants. Both the cage convulsants and the polychlorocycloalkanes are considered to act at convulsant sites coupled functionally to the GABA receptor chloride ionophore complex and thereby to modulate allosterically or directly the GABA-gated chloride channel leading to their toxic action.