GABAB Receptor‐Mediated Inhibition of Histamine H1‐Receptor‐Induced Inositol Phosphate Formation in Slices of Rat Cerebral Cortex

Abstract

Histamine-stimulated accumulation of [3H]inositol monophosphate ([3H]IP1) in lithium-treated slices of rat cerebral cortex was inhibited by .gamma.-aminobutyric acid (GABA) (IC50 0.30 .+-. 0.03 mM). The maximum level of inhibition was 69 .+-. 2%. GABA alone caused a small stimulation of basal accumulation of [3H]IP1. The inhibitory action of GABA on the response to histamine was mimicked by the GABAB agonist (-)-baclofen, IC50 0.69 .+-. 0.04 .mu.M, which was 430-fold more potent as an inhibitor than the (+)-isomer. (-)-Baclofen also inhibited histamine-induced formation of [3H]inositol bisphosphate ([3H]IP2) and [3H]inositol trisphosphate ([3H]IP3). Inhibition curves for GABA and for (-)- and (+)-baclofen had Hill coefficients greater than unity. (-)-Baclofen, at concentrations that caused inhibition of histamine-induced [3H]IP1 accumulation, did not alter the basal level of [3H]IP1 or the incorporation of [3H]inositol into total inositol phospholipids. Isoguvacine, a GABAA agonist, had no effect on either the histamine-stimulated or basal accumulation of [3H]IP1. GABA had no effect on carbachol-stimulated [3H]IP1 formation.