Differential effect of the 17β-aminoestrogens prolame, butolame and pentolame in anxiety and depression models in rats

Abstract

Estrogens of clinical use produce consistent antidepressant- and anxiolytic-like effects in animal models of menopause. Regulation of the hypothalamic-pituitary-adrenal (HPA) or stress axis, has been proposed as a pathway through which estrogens improve affective-like behaviors. Anticoagulant 17β-aminoestrogens (17β-AEs) butolame and pentolame mimic some effects of estradiol (E2), i.e., on female rodent sexual behavior, with opposite actions on coagulation. However, their psychoactive actions have not been explored. On the basis of similitude with E2's effects, we hypothesized that these 17β-AEs would induce anxiolytic- and antidepressant-like effects, which would be reflected in a reduction of activity in the HPA axis. In ovariectomized female rats, chronic treatment with prolame (60 μg/kg), butolame (65 μg/kg) and pentolame (70 μg/kg) reduced anxiety-like behavior in the elevated plus maze (evidenced by an increase in time in open arms, E2 (40 μg/kg) +176%; prolame +201%; butolame, +237%; and pentolame +295%, in comparison to the control vehicle group 100%). Pentolame also decreased significantly anxiety-like behavior in the burying behavior test. Prolame and E2 produced a significantly antidepressant-like action, which was not induced by butolame and pentolame. Behavioral effects of 17β-AEs (and E2) on anxiety and depression did not follow the same pattern than corticosterone or E2 levels; they also were associated to changes in locomotor activity, evaluated by the open field test. These results constitute the first evidence of specific and selective actions of butolame and pentolame as anxiolytics for females with a hypoestrogenic condition. Results also confirm the potential of prolame as an antidepressant steroid with equivalent actions to E2. Psychoactive properties of 17β-AEs in combinations with reduced adverse effects on coagulation, suggest that 17β-AEs may be a good alternative replacement therapy for women with symptoms associated with menopause.

Keywords: 17β-Aminoestrogens; Animal models; Anxiety; Depression; Hormone replacement therapy.