Modulation of diazepam-insensitive GABAA receptors by micromolar concentrations of thyroxine and related compounds in vitro

The effects of thyroxine and its related compounds on the benzodiazepine-insensitive γ-aminobutyric acid type A (GABAA) receptors were studied. Thyroxine at micromolar concentrations potentiated the 3H-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 GABAA 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 GABAA receptors. The diazepam-insensitive GABAA 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 GABAA 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 GABAA receptor subtypes.

► Thyroxine potentiated the Ro15-4513 binding to diazepam-insensitive GABAA receptors.
► Thyroxine and TETRAC potentiated the THIP-induced currents in thalamic neurons.
► Ethanol failed to modulate TETRAC action.
► We suggest that thyroid hormones modulate extrasynaptic GABAA receptors.