Anxiolytic properties of endogenously occurring pregnanediols in two rodent models of anxiety

Certain endogenously occurring 3 alpha-hydroxylated, 5-reduced pregnane steroids act at a specific site on the GABA(A) receptor complex (GRC) to modulate the effects of GABA at its receptor. Modulators that potentiate GABA at the GABA(A) receptor often possess anxiolytic properties. The anxiolytic potential of four 5-reduced, 3 alpha, 20-pregnanediols, differing only in the stereochemical orientation of the steroid A-ring and the 20-hydroxyl group, were tested in the Vogel test following intracerebroventricular (ICV) administration. The effects of these pregnanediols were compared to those of their 20-ketone analogues, 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha,5 beta-P) and 3 alpha-hydroxy-5 beta-pregnan-20-one (3 alpha,5 beta-P). All four pregnanediols tested significantly enhanced punished drinking at doses ranging from 10 to 60 mu g. The rank order of potency based on the minimum effective dose (MED) observed was 5 alpha-pregnan-3 alpha,20 alpha-diol = 5 beta-pregnan-3 alpha,20 alpha-diol > 5 beta-pregnan-3 alpha,20 beta-diol > 5 alpha-pregnan-3 alpha,20 beta-diol. 3 alpha,5 beta-P and 3 alpha,5 alpha-P enhanced punished responding when administered at 2.5 and 5 mu g, respectively. 3 beta,5 alpha-P which is inactive at the GRC was also inactive (up to 100 mu g) in the Vogel test. The benzodiazepine control diazepam was efficacious when administered at 2.5 mu g. 5 alpha-Pregnan-3 alpha,20 alpha-diol was further tested in the mouse elevated plus-maze model following systemic administration where it was found to be active in a dose range of 10-40 mg/kg IP. These results raise the possibility that in addition to 3 alpha,5 alpha-P and 3 alpha,5 beta-P, some of their endogenously occurring pregnanediol metabolites may also influence physiological processes related to anxiety via the GRC.