Zinc Inhibition of t -[ 3 H]Butylbicycloorthobenzoate Binding to the GABA A Receptor Complex

Abstract

The effect of Zn 2+ on t -[ 3 H]butylbicycloorthobenzoate ([ 3 H]TBOB) binding to the GABA A receptor complex was studied autoradiographically in rat brain. Zn 2+ inhibited [ 3 H]TBOB binding in a dose-dependent manner at physiological concentrations. Saturation analysis revealed noncompetitive inhibition in various brain regions. The inhibitory effect of Zn 2+ had regional heterogeneity; regions showing the greatest inhibition of [ 3 H]TBOB binding were cortical laminae I–III, most areas of hippocampus, striatum, septum, and cerebellar cortex. Regions with relatively less inhibition of [ 3 H]TBOB binding included cortical laminae V–VI, thalamus, superior colliculus, inferior colliculus, and central gray matter. The effect of Zn 2+ and those of other GABA A ligands, such as benzodiazepines, bicuculline, isoguvacine, and picrotoxin, on [ 3 H]TBOB binding seemed to be additive. Ni 2+ , Cd 2+ , and Cu 2+ also inhibited [ 3 H]TBOB binding with a regional heterogeneity similar to that produced by Zn 2+ . These results are consistent with Zn 2+ acting at the previously detected recognition site on the GABA A receptor complex, distinct from the picrotoxin, GABA, and benzodiazepine sites. The regional heterogeneity of the Zn 2+ effect may reflect differential regional distribution of GABA A receptor subtypes among brain regions. Other divalent cations probably act at the Zn 2+ binding site.