Morrow A L, Pace J R, Purdy R H, Paul S M
Section of Molecular Pharmacology, National Institute of Mental Health, Bethesda, Maryland 20892.
Mol Pharmacol. 1990 Feb;37(2):263-70.
The potentiation of gamma-aminobutyric acid (GABA) receptor-mediated 36Cl- uptake by various steroids has been characterized in rat cerebral cortical synaptoneurosomes. Several of these steroids, including 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha-OH-DHP) and 3 alpha,21-dihydroxy-5 alpha-pregnan-20-one (THDOC), increase the potency of muscimol to stimulate 36Cl- uptake in a concentration-dependent and stereospecific manner. Concentration-response curves for 3 alpha-OH-DHP, THDOC, 3 alpha-hydroxy-pregn-4-en-20-one, and pentobarbital enhancement of muscimol-stimulated 36Cl- uptake are biphasic, with Hill coefficients significantly less than 1.0. Computer-modeling (ALLFIT analysis) of these curves suggests that these steroids and pentobarbital interact with multiple binding sites on GABAA receptor(s). In contrast, the concentration-response curve for THDOC 21-mesylate is monophasic, with a smaller maximal response, and yields a Hill coefficients of 1.0. In addition to modulating GABA receptor-mediated 36Cl- uptake, THDOC enhanced the ability of the benzodiazepine clonazepam to potentiate muscimol-stimulated 36Cl- uptake. The central benzodiazepine antagonist Ro15-1788 failed to inhibit THDOC-induced potentiation of muscimol-stimulated 36Cl- uptake, although it has been previously reported to inhibit some of the behavioral actions of THDOC. In contrast to the A ring-reduced metabolites and analogues of progesterone and deoxycorticosterone, glucocorticoids had no effect on muscimol-stimulated 36Cl- uptake in cerebral cortical synaptoneurosomes at concentrations between 20 nM and 5 microM.
多种类固醇对γ-氨基丁酸（GABA）受体介导的³⁶Cl⁻摄取的增强作用已在大鼠大脑皮质突触神经小体中得到表征。其中几种类固醇，包括3α-羟基-5α-孕烷-20-酮（3α-OH-DHP）和3α,21-二羟基-5α-孕烷-20-酮（THDOC），以浓度依赖性和立体特异性方式增加蝇蕈醇刺激³⁶Cl⁻摄取的效力。3α-OH-DHP、THDOC、3α-羟基孕-4-烯-20-酮和戊巴比妥增强蝇蕈醇刺激³⁶Cl⁻摄取的浓度-反应曲线是双相的，希尔系数显著小于1.0。对这些曲线的计算机建模（ALLFIT分析）表明，这些类固醇和戊巴比妥与GABAA受体上的多个结合位点相互作用。相比之下，THDOC甲磺酸21酯的浓度-反应曲线是单相的，最大反应较小，希尔系数为1.0。除了调节GABA受体介导的³⁶Cl⁻摄取外，THDOC还增强了苯二氮䓬类氯硝西泮增强蝇蕈醇刺激³⁶Cl⁻摄取的能力。中枢苯二氮䓬拮抗剂Ro15-1788未能抑制THDOC诱导的蝇蕈醇刺激³⁶Cl⁻摄取的增强作用，尽管此前有报道称它能抑制THDOC的一些行为作用。与孕酮和脱氧皮质酮的A环还原代谢物及类似物不同，糖皮质激素在20 nM至5 μM的浓度范围内对大脑皮质突触神经小体中蝇蕈醇刺激的³⁶Cl⁻摄取没有影响。
