title: The GABAA 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 GABAA receptor complex. Bicuculline methochloride (bicuculline MCl), folic acid, pentazocine, naloxone, ethyl-beta-carboline-3-carboxylate (beta CCE) 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 IC50 amounts of GABA (5 microM) or diazepam (50 microM). 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 GABAA 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. beta CCE and Ro 5-4864 modified [3H]TBOB binding in the presence of GABA in a biphasic fashion. A unique relation between beta CCE, Ro 5-4864 and the GABAA complex might exist. Bicuculline MCl reversed the inhibitory effect of diazepam on [3H]TBOB binding only partly. beta CCE 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.
authors.affiliation: Department of Comparative and Physiological Psychology, University of Nijmegen, Netherlands.
authors.forename: C M
authors.initials: CM
authors.lastname: van Rijn
authors.forename: E
authors.initials: E
authors.lastname: Willems-van Bree
authors.forename: R
authors.initials: R
authors.lastname: Dirksen
authors.forename: J F
authors.initials: JF
authors.lastname: Rodrigues de Miranda
mesh_terms: D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003292:Convulsants / Q000494:pharmacology*; D004827:Epilepsy / Q000378:metabolism*; D005260:Female; D058787:GABA-A Receptor Antagonists; D066298:In Vitro Techniques; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003292:Convulsants; D058787:GABA-A Receptor Antagonists; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; C046308:tert-butylbicyclo-2-benzoate