Mnemonic effects of progesterone to mice require formation of 3alpha,5alpha-THP

Ovarian hormones organize and activate neural circuits for reproduction and may also mediate cognition. Research has focused on estradiol's mnemonic effects, albeit progesterone covaries with estradiol and its mechanisms for cognition require attention. Studies tested the hypothesis that cognitive effects of progesterone occur subsequent to its metabolism to 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP), which does not bind progestin receptors. Cognitive performance and progestogen levels in plasma, hippocampus, and cortex were determined in ovariectomized mice administered vehicle, or progestins that differentially form 3alpha,5alpha-THP and bind progestin receptors (progesterone, 3alpha,5alpha-THP, and/or medroxyprogesterone acetate). Only treatments that increased 3alpha,5alpha-THP levels during memory consolidation (progesterone, 3alpha,5alpha-THP, 3alpha-5alpha-THP plus medroxyprogesterone acetate, but not progesterone plus medroxyprogesterone acetate) improved cognitive performance. Thus, formation of 3alpha,5alpha-THP may be required for progesterone's cognitive-enhancing effects.