ZINC INHIBITION OF T-[H-3]BUTYLBICYCLOORTHOBENZOATE BINDING TO THE GABA(A) RECEPTOR COMPLEX

The effect of Zn2+ on t-[H-3]butylbicycloorthobenzoate ([H-3]TBOB) binding to the GABA(A) receptor complex was studied autoradiographically in rat brain. Zn2+ inhibited [H-3]TBOB binding in a dose-dependent manner at physiological concentrations. Saturation analysis revealed noncompetitive inhibition in various brain regions. The inhibitory effect of Zn2+ had regional heterogeneity; regions showing the greatest inhibition of [H-3]TBOB binding were cortical laminae I-III, most areas of hippocampus, striatum, septum, and cerebellar cortex. Regions with relatively less inhibition of [H-3]TBOB binding included cortical laminae V-VI, thalamus, superior colliculus, inferior colliculus, and central gray matter. The effect of Zn2+ and those of other GABA(A) ligands, such as benzodiazepines, bicuculline, isoguvacine, and picrotoxin, on [H-3]TBOB binding seemed to be additive. Ni2+, Cd2+, and Cu2+ also inhibited [H-3]TBOB binding with a regional heterogeneity similar to that produced by Zn2+. These results are consistent with Zn2+ 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 Zn2+ effect may reflect differential regional distribution of GABA(A) receptor subtypes among brain regions. Other divalent cations probably act at the Zn2+ binding site.