5 alpha-pregnan-3 alpha,20 alpha-diol behaves like a partial agonist in the modulation of GABA-stimulated chloride ion uptake by synaptoneurosomes

Abstract

In rat cortical synaptoneurosomes, the maximum potentiation of GABA-stimulated 36Cl uptake produced by 5 alpha-pregnan-3 alpha,20 alpha-diol (5 alpha-pregnanediol) is significantly less than that elicited by 5 alpha-pregnan-3 alpha-ol-20-one (3 alpha-OH-DHP). This observation suggests that 5 alpha-pregnanediol may be a partial agonist whereas 3 alpha-OH-DHP acts as a full agonist at a common site on or near the GABAA/benzodiazepine receptor-chloride ionophore complex (GBRC). This hypothesis is supported by the finding that 5 alpha-pregnanediol will antagonize in a dose-dependent manner the enhancement of GABA-stimulated 36Cl uptake produced by 3 alpha-OH-DHP under certain conditions. Collectively, these findings support the hypothesis that GBRC-active progesterone metabolites with varying degrees of efficacy exist as reflected by their differential ability to potentiate 36Cl uptake in brain synaptoneurosomes.