Changes in progesterone metabolites in the hippocampus can modulate open field and forced swim test behavior of proestrous rats

The purpose of these experiments was to test the hypothesis that attenuating the endogenous increase of the 5alpha-reduced progesterone metabolite 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP) in the hippocampus will alter anxiety and depression behavior of proestrous rats. In Experiment 1, anxiety (open field) and depression (forced swim test) behavior was compared of rats that should have high (proestrous) and low (diestrous and male rats) endogenous hippocampal 3alpha,5alpha-THP. Proestrous rats exhibited more anxiolytic-like (increased central entries in the open field) and anti-depressant-like (less immobility in the forced swim test) behavior than diestrous or male rats. In Experiments 2 and 3, respectively, systemic and intrahippocampal finasteride, a 5alpha-reductase inhibitor which attenuates progesterone's metabolism to 3alpha,5alpha-THP, versus vehicle administration to proestrous rats was compared for effects on open field and forced swim test behavior. Systemic or intrahippocampal finasteride decreased central entries in the open field and increased immobility in the forced swim tests compared to vehicle administration. In Experiment 4, the effects of systemic and intrahippocampal finasteride vs vehicle administration on hippocampal 3alpha,5alpha-THP of proestrous rats was examined. Finasteride, SC or intrahippocampally, reduced 3alpha,5alpha-THP in the hippocampus compared to vehicle administration. Together these data suggest that variations in 3alpha,5alpha-THP levels in the hippocampus may mitigate proestrous changes in anxiety and depressive behavior of cycling rats.