BIMODAL ACTION OF FUROSEMIDE ON CONVULSANT [H-3]EBOB BINDING TO CEREBELLAR AND CORTICAL GABA(A) RECEPTORS

Picrotoxinin-sensitive binding of a convulsant ethynyl-4-n[2,3-H-3(2)] Propyl-bicycloorthobenzoate ([H-3]EBOB) to gamma-amino butyric acid ty pe A (GABA(A)) receptors was characterized in rat cerebrocortical and cerebellar membranes. The non-penetrating organic anions, furosemide a nd niflumate, in spite of their structural similarities, exerted diffe rential 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 cerebell um while enhanced them in the cortex. The inhibitory potencies of nifl umate, an anti-inflammatory and a chloride channel blocker, and GABA w ere 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]EBO B 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-cont aining GABA(A) receptors. The data extends the properties of furosemid e antagonism of this receptor subtype to chloride insensitivity and in teractions with barbiturate sites. (C) 1998 Elsevier Science Ltd. All rights reserved.