Bimodal action of furosemide on convulsant [3H]EBOB binding to cerebellar and cortical GABAA receptors

Picrotoxinin-sensitive binding of a convulsant 4'-ethynyl-4-n[2,3-H-3(2)]Propyl-bicycloorthobenzoate ([H-3]EBOB) to gamma-amino butyric acid type A (GABA(A)) receptors was characterized in rat cerebrocortical and cerebellar membranes. The non-penetrating organic anions, furosemide and niflumate, in spite of their structural similarities, exerted differential effects on [H-3]EBOB binding. Furosemide, a loop diuretic and a specific antagonist of a cerebellar GABA(A) receptor population, and GABA decreased the inhibitory potencies of each other in the cerebellum while enhanced them in the cortex. The inhibitory potencies of niflumate, an anti-inflammatory and a chloride channel blocker, and GABA were enhanced by each other both in the cerebellum and cortex. Removal of chloride ions did not modify the effects of furosemide on [H-3]EBOB binding. Furosemide antagonized the inhibition of cerebellar [H-3]EBOB binding by a low pentobarbital concentration (0.1 mM), but enhanced the inhibition by a high concentration (0.5 mM). The results indicate that [H-3]EBOB binding can be used to detect the known pharmacological features of the cerebellar granule cell-specific alpha 6 subunit-containing GABA(A) receptors. The data extends the properties of furosemide antagonism of this receptor subtype to chloride insensitivity and interactions with barbiturate sites. (C) 1998 Elsevier Science Ltd. All rights reserved.