Abstract
Progestogens' anti-anxiety and anti-depressive effects and mechanisms are not well-understood. Progestogens are hypothesized to have anti-anxiety and anti-depressive effects on behavior, independent of actions at nuclear progestin receptors (NPRs) and dependent on allopregnanolone (5α-pregnan-3α-ol-20-one; 3α,5α-THP), a 5α-reduced, neuroactive metabolite of progesterone (P(4)). Adult c57 mice in behavioral estrus (proestrus; pro) showed more anti-anxiety-like and anti-depressant-like behavior and higher levels of estradiol (E(2)), P(4), and allopregnanolone in the hippocampus/amygdala complex. Proestrus c57 > 5α-reductase knockout (5αRKO) mice made more central entries in an open field than diestrus c57 and 5αRKO mice that were not different. Ovariectomized (OVX) c57 mice administered 1, 2, or 4 mg/kg P(4) SC showed dosage-dependent increases in central entries in an open field (more anti-anxiety-like behavior); 5αRKO mice had maximal increases at 1-2 mg/kg P(4). OVX c57 and 5αRKO mice showed maximum increases in central entries with SC 3α,5α-THP (4 mg/kg), and c57s showed a similar maximal response to P(4) (4 mg/kg), but 5αRKOs response was half at that dosage. P(4) (4 mg/kg SC to OVX c57 or progestin receptor knockout (PRKO) mice decreased immobility (depression-like behavior) in the forced swim task. Effects of E(2) and veh were similar in both groups. Levels of 3α,5α-THP in the hippocampus/amygdala were consistent with effects on central entries in the open field. Levels of brain-derived neurotrophic factor (BDNF) in the hippocampus/amygdala were greater among E(2)-primed (0.09 mg/kg, SC) vs vehicle-administered mice. In sum, adult female mice can be responsive to P(4) for anti-anxiety/anti-depressant-like behavior; such effects may be independent of NPRs but require 5α-reduction and E(2)'s priming actions at BDNF in the hippocampus/amygdala complex.