Xue B G, Whittemore E R, Park C H, Woodward R M, Lan N C, Gee K W
Department of Pharmacology, College of Medicine, University of California, Irvine 92697, USA.
J Pharmacol Exp Ther. 1997 Jun;281(3):1095-101.
3alpha,21-Dihydroxy-5alpha-pregnan-20-one (5alpha-THDOC) and 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-P) have full efficacy as allosteric modulators of [35S]t-butylbicyclophosphorothionate ([35S]TBPS) binding to sites on the gamma-aminobutyric acid (GABA) type A receptor complex (GRC). Relative to 3alpha,5alpha-P and 5alpha-THDOC, 3alpha,21-dihydroxy-5beta-pregnan-20-one (5beta-THDOC) has limited efficacy as an allosteric modulator of [35S]TBPS binding. Interactions between 3alpha,5alpha-P, 5alpha-THDOC and 5beta-THDOC were examined to determine whether these neuroactive steroids share a common site for modulation of the GRC. The concentration-response curves for both 3alpha,5alpha-P and 5alpha-THDOC modulation of [35S]TBPS binding to brain and recombinantly derived GRCs are shifted rightward in the presence of various concentrations of 5beta-THDOC. Similarly, 5beta-THDOC modulates GABA-evoked Cl- currents with low efficacy and inhibits the potentiation of GABA-evoked Cl- currents by 3alpha,5alpha-P. Furthermore, behavioral studies reveal that 5beta-THDOC antagonizes 3alpha,5alpha-P-induced loss of the righting reflex in mice at a dose that has no effect alone. These results represent the first demonstration of antagonist-like actions of a neuroactive steroid on the GRCs at levels ranging from the receptor to animal behavior and suggest the existence of partial agonist neurosteroids.
3α,21 - 二羟基 - 5α - 孕烷 - 20 - 酮（5α - THDOC）和3α - 羟基 - 5α - 孕烷 - 20 - 酮（3α,5α - P）作为[³⁵S]叔丁基双环磷硫代酸盐（[³⁵S]TBPS）与γ - 氨基丁酸（GABA）A型受体复合物（GRC）上位点结合的变构调节剂具有完全效力。相对于3α,5α - P和5α - THDOC，3α,21 - 二羟基 - 5β - 孕烷 - 20 - 酮（5β - THDOC）作为[³⁵S]TBPS结合的变构调节剂效力有限。研究了3α,5α - P、5α - THDOC和5β - THDOC之间的相互作用，以确定这些神经活性类固醇是否共享调节GRC的共同位点。在存在各种浓度的5β - THDOC时，3α,5α - P和5α - THDOC对[³⁵S]TBPS结合到脑和重组衍生的GRCs的浓度 - 反应曲线均向右移动。同样，5β - THDOC以低效力调节GABA诱发的Cl⁻电流，并抑制3α,5α - P对GABA诱发的Cl⁻电流的增强作用。此外，行为学研究表明，5β - THDOC在单独使用无效的剂量下拮抗3α,5α - P诱导的小鼠翻正反射丧失。这些结果首次证明了神经活性类固醇在从受体到动物行为的水平上对GRC具有类似拮抗剂的作用，并提示存在部分激动剂神经类固醇。
