Anxiolytic activity of progesterone in progesterone receptor knockout mice

Progesterone is an anxiolytic steroid that could play a role in the regulation of anxiety in women. However, the mechanism by which progesterone decreases anxiety is incompletely understood. Progesterone affects the function of the brain by two distinct mechanisms. Progesterone regulates reproductive behavior by activating intracellular progesterone receptors (PRs). In addition, progesterone is believed to influence neuronal activity through its conversion to allopregnanolone, a neurosteroid that acts as a positive allosteric modulator of GABAA receptors. The extent to which the anxiolytic action of progesterone requires PRs is uncertain. In this study, we utilized PR knockout (PRKO) mice bearing a targeted null mutation of the PR gene that abrogates the function of both PR-A and PR-B subtypes to determine the requirement for PRs in the anxiolytic actions of progesterone. The absence of PR receptor protein expression in PRKO brain was confirmed by immunocytochemistry. In PRKO mice and their isogenic wild-type (WT) littermates, progesterone administration was associated with a dose-dependent rise in plasma allopregnanolone concentrations and corresponding anxiolytic effects in the elevated plus maze test. PRKO mice exhibited a greater anxiolytic response than WT animals although the allopregnanolone levels were similar in the two genotypes. Allopregnanolone also exhibited anxiolytic effects, but the magnitude of the response was similar in both genotypes. Pretreatment of PRKO mice with finasteride, a 5alpha-reductase inhibitor that blocks the conversion of progesterone to allopregnanolone, completely prevented the anxiolytic activity of progesterone, but had no effect on the response to allopregnanolone, demonstrating that allopregnanolone (or other 5alpha-reduced metabolites of progesterone) accounts for the response to the parent steroid hormone. These results provide direct evidence that the anxiolytic action of progesterone does not require PRs. However, PR activation by progesterone may influence the anxiolytic response since PRKO mice were more sensitive to progesterone.