Antianxiety and antidepressive behavior produced by physiological estradiol regimen may be modulated by hypothalamic-pituitary-adrenal axis activity.

Variations in estradiol (E(2)) may influence expression of stress-related anxiety and depression symptoms among women. Effects of E(2) and stress on anxiety and depressive behavior were investigated using an animal model. E(2) was administered subcutaneously (0, 2, 5, 10, 20, 50 mug/rat) to ovariectomized rats 2 days before testing. In experiment 1, open field (anxiety), elevated plus maze (anxiety), or forced swim test (depressive) behavior was evaluated following 20 min of restraint or no such stressor. Rats administered 5 or 10 mug E(2), which produced physiological plasma E(2) concentrations, showed significantly less anxiety and depressive behavior and lower corticosterone levels compared to vehicle, lower, or higher E(2) dosages. Restraint stress prior to behavioral testing attenuated the antianxiety and antidepressive effects of 5 or 10 mug E(2). In experiment 2, effects of adrenalectomy or sham surgery and vehicle or corticosterone replacement in their drinking water on behavior and neuroendocrine measures of rats administered 0, 10, or 50 mug E(2) were examined. E(2), 10 mug, compared to vehicle or 50 mug, reduced anxiety and depressive behavior of sham and adrenalectomized rats administered the low dosage of corticosterone, but not vehicle or the high dosage of corticosterone, suggesting that there may be an optimal level of corticosterone necessary for E(2) to exert these effects. Together, these data suggest that E(2) may have dose-dependent effects on anxiety and depressive behavior of female rodents, which may depend on the tone of the hypothalamic-pituitary-adrenal axis.