Evidence for inhibitory effect of the agonist gaboxadol at human alpha(1)beta(2)gamma S-2 GABA(A) receptors

Gaboxadol (THIP; 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) is an agonist at GABA(A) receptors. THIP concentrations (0.01-50 mM) were applied rapidly to Sf9 cells expressing the human alpha(1)beta(2)gamma(2S) GABA(A) receptors. The EC50 values for the peak current in THIP alone or THIP plus 1 muM diazepam were 154 and 53 muM, respectively. In supersaturating THIP (10-50 mM) the rate of current decay increased and an off-current developed when THIP was rapidly removed. The mean currents measured over the first 4 s in 10 mM and higher THIP concentrations were 0.6 or less of the 1 mM THIP mean current. Diazepam (1 muM) increased the 4 s mean current when evoked by 10 to 20 mM THIP but not 50 mM THIP. No similar effects on the current time-course were recorded in supersaturating gamma-aminobutyric acid (GABA) concentrations (50 and 80 mM). The results demonstrate an inhibitory as well as agonist effect of THIP at alpha(1)beta(2)gamma(2s) GABA(A) receptors. (C) 2003 Elsevier B.V. All rights reserved.