Thyroid hormones, which are known to act by genomic mechanisms in peripheral tissues, were found to influence the binding and function of the GABA A receptor complex in brain membranes. Submicromolar concentrations of triiodothyronine and thyroxine stereospecifically stimulated the binding of [ 35 S]t-butylbicyclophosphorothionate (a convulsant ligand for the GABA A receptor complex) to highly washed rat brain membranes, while higher concentrations of the hormones inhibited radioligand binding. GABA-stimulated 36 Cl − flux in isolated brain membrane sacs was inhibited byl-triiodothyronine with a half-maximally inhibitory concentration (ic 50 ) of 10 −7 M. Patch-clamp analysis of recombinant GABA A receptor subunits expressed in human embryonic kidney-293 cells showed an inhibition of chloride currents by thyroid hormones. This effect required only theα 1 β 2 subunits, and was not blocked by the benzodiazepine antagonist flumazenil.Since thyroid hormones are known to be concentrated in nerve terminal preparations and subsequently released, the hormones may have non-genomic mechanisms of action as putative neurotransmitters or neuromodulators in brain and act through GABA A receptors.