title: Modulation of diazepam-insensitive GABA(A) receptors by micromolar concentrations of thyroxine and related compounds in vitro.
abstract: The effects of thyroxine and its related compounds on the benzodiazepine-insensitive γ-aminobutyric acid type A (GABA(A)) receptors were studied. Thyroxine at micromolar concentrations potentiated the (3)H-Ro15-4513 binding to rat brain membranes in-vitro in the thalamus, striatum, cortex and hippocampus, but not in cerebellum. In the thalamus, the rank order of potency was the following: 3,3',5,5'-tetraiodothyroacetic acid (TETRAC)>L-thyroxine>3,5-diiodo-l-thyronine (3,5-T2). TETRAC induced a slight potentiation of flumazenil binding to diazepam-sensitive GABA(A) receptors in the thalamus and striatum while no effect was found in cortex and hippocampus. Consequently, we examined whether these compounds could exert their modulatory effect on the currents mediated by benzodiazepine-insensitive GABA(A) receptors. The diazepam-insensitive GABA(A) receptor-mediated currents were recorded from acutely isolated rat ventrobasal thalamic neurons by applying low concentrations of 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP). TETRAC and thyroxine at low μM concentrations potentiated the THIP-evoked currents, although 3,5-T2 had no effect on the THIP-induced currents. Ethanol had no effect on the enhancing effects of TETRAC. TETRAC itself evoked GABA(A) receptor-mediated currents at high concentrations beyond 30 μM. Although the effects of TETRAC and thyroxine were observed at non-physiological concentrations of hormones, the present results might lead to new lead structures with specificity to diazepam-insensitive GABA(A) receptor subtypes.
authors.affiliation: Department of Developmental Physiology, National Institute for Physiological Sciences, Okazaki 444-8585, Japan. isibasi@nips.ac.jp
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ishibashi
authors.forename: Michael-Robin
authors.initials: MR
authors.lastname: Witt
authors.forename: Junichi
authors.initials: J
authors.lastname: Nabekura
authors.forename: Mogens
authors.initials: M
authors.lastname: Nielsen
mesh_terms: D000345:Affinity Labels; D000818:Animals; D001386:Azides / Q000378:metabolism; D001569:Benzodiazepines / Q000378:metabolism; D001921:Brain / Q000187:drug effects; D002492:Central Nervous System Depressants / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology*; D055724:Electrophysiological Phenomena; D000431:Ethanol / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology*; D007555:Isoxazoles; D008297:Male; D008566:Membranes / Q000187:drug effects; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects*; D013963:Thyroid Hormones / Q000097:blood / Q000494:pharmacology; D013974:Thyroxine / Q000031:analogs & derivatives / Q000097:blood / Q000494:pharmacology*
chemical_list: D000345:Affinity Labels; D001386:Azides; D002492:Central Nervous System Depressants; D018757:GABA Modulators; D007555:Isoxazoles; D011963:Receptors, GABA-A; D013963:Thyroid Hormones; D001569:Benzodiazepines; D000431:Ethanol; C042957:Ro 15-4513; C015542:gaboxadol; C011126:tetraiodothyroacetic acid; D003975:Diazepam; D013974:Thyroxine