Type 1 5α-reductase may be required for estrous cycle changes in affective behaviors of female mice

There are estrous cycle differences in affective behaviors of rodents that are generally attributed to cyclic variations in estradiol, progesterone (P) and its metabolites. A question is the role of the steroid metabolism enzyme, 5α-reductase, for these estrous cycle differences. To address the requirement of 5α-reductase, estrous cycle variations in the behavior of wildtype mice and their littermates that are deficient in the 5α-reductase type 1 enzyme (5αRKO mice) were examined. The hypothesis was that if some of the estrous cycle differences in exploratory (open field) and anxiety (elevated plus maze) are due to P's 5α-reduction to 5α-pregnan-3α-ol-20-one (3α,5α-THP), then wildtype mice will have estrous cycle differences in the expression of these behaviors, but 5αRKO mice will not. Mice were tested in these tasks and then had plasma and brains collected so that steroid levels (estradiol, P, 3α,5α-THP, corticosterone) could be measured in these tissues. Results supported this hypothesis. There were estrous cycle differences among wildtype, but not 5αRKO, mice. Proestrous wildtype mice made more central entries in the open field and spent more time on the open arms of the plus maze, coincident with higher 3α,5α-THP levels in plasma and brain regions important for these behaviors, such as the hippocampus and cortex, compared to their diestrous counterparts. Variability in the open field and elevated plus maze could be explained by circulating and hippocampus levels of 3α,5α-THP, respectively. Thus, 5α-reductase may be required for the estrous cycle variations in affective behavior and 3α,5α-THP levels of female mice.

► There are estrous cycle changes in exploratory and anxiety behavior of adult female mice.
► 5α-reductase may be required for proestrous increases in exploration and anti-anxiety behavior.
► 5α-reduction in the hippocampus and cortex is important for exploration and anti-anxiety effects.