The GABA A receptor complex in relation to epilepsy. Reversal of [ 3H]TBOB inhibition: a prediction of proconvulsive properties?

Abstract

[ 3H]-t- Butylbicycloorthobenzoate ([ 3H]TBOB) , a convulsant, is known to label a binding site on the GABA A receptor complex. Bicuculline methochloride (bicuculline MCl), folic acid, pentazocine, naloxone, ethyl-β-carboline-3-carboxylate (βCCE) and Ro 5–4864 have (pro)convulsive properties in vivo. In the present study, we determined the extent to which these compounds modify the binding of [ 3H]TBOB in the presence of IC 50 amounts of GABA (5 μM) or diazepam (50 μM). We found that the GABA antagonist bicuculline MCl reversed the inhibitory effect of GABA on [ 3H]TBOB binding completely, as was expected. Folic acid, pentazocine and naloxone also reversed the inhibitory effect of GABA on [ 3H]TBOB binding. This finding is compatible with the view that the proconvulsive effects of these compounds can be credited to a reduction of GABAergic action at the GABA A receptor complex. We suggest that the reversal of GABA's inhibition of [ 3H]TBOB binding is a sufficient (but not a necessary) condition to predict proconvulsive (side) effects of drugs. βCCE and Ro 5–4864 modified [ 3H]TBOB binding in the presence of GABA in a biphasic fashion. A unique relation between βCCE, Ro –4864 and the GABA A complex might exist. Bicuculline MCl reversed the inhibitory effect of diazepam on [ 3H]TBOB binding only partly. βCCE did not reverse the inhibitory effect of diazepam on [ 3H]TBOB binding, neither did Ro 5–4864. The presence of a GABA-independent interaction between a low affinity benzodiazepine recognition site and the TBOB site is proposed.