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

Abstract

Picrotoxinin-sensitive binding of a convulsant 4′-ethynyl-4-n[2,3- 3H 2]propyl-bicycloorthobenzoate ([ 3H]EBOB) to γ-aminobutyric 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 [ 3H]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 [ 3H]EBOB binding. Furosemide antagonized the inhibition of cerebellar [ 3H]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 [ 3H]EBOB binding can be used to detect the known pharmacological features of the cerebellar granule cell-specific α6 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.