Abstract
In women, perimenopause is a period of high vulnerability to mood disorders which are associated with vasomotor symptoms, sleep disorders and several changes in the reproductive cycle. The general clinical practice to ameliorate these symptoms strongly relies on the use of estradiol therapy (E2T), although perimenopausal women are not estradiol deficient and it is not known whether E2T provides beneficial effects to all perimenopausal symptoms experienced. Our aim was to investigate the effect of E2T on depressive like behavior in rats treated with 4-vinylcycloxene diepoxide (VCD), which accelerates the natural process of ovarian follicular atresia modelling perimenopause in women. For this, prepubertal female rats (PND 28) were injected daily with VCD or oil for 15 days; 55-65 days after the first injection, pellets of 17β-estradiol (VCD+E) or oil (VCD+O and O+O) were inserted subcutaneously. Around 20 days later, the rats underwent 5 min open field (OFT) test followed by 5 min forced swimming test (FST; O+O and VCD+O rats on diestrus). Next, the animals were anesthetized, a blood sample was withdrawn from cardiac puncture for hormonal radioimmunoassay. The liver, adrenal glands, ovaries, kidney and uterus were removed and weighted. Another set of animals were submitted to the same experimental protocol described above; on the day of the experiment the rats were decapitated for noradrenaline (NA) measurement in brain punches of Hippocampus (HP). In the OFT there were no significant differences in the total distance travelled and the time spent in the periphery and central zone among the groups, showing that neither VCD nor E2 treatment were able to alter the locomotor activity. In the FST, on the other hand, VCD rats displayed increased immobility time and decreased climbing (CT) and swimming times compared to the Oil treated animals. VCD+E displayed similar results to VCD+O with an additional stronger effect in decreasing CT, demonstrating a negative effect of E2T in depressive like behavior in VCD-periestropausal rats. Associated to these behavioral responses we found that the content of NA in the HP of VCD+E was reduced compared to O+O and VCD+O. Plasma levels of LH and FSH were similar among the groups. Progesterone plasma levels were decreased in VCD+O compared to O+O rats and E2T increased progesterone and decreased testosterone in VCD+E compared to O+O and VCD+O groups. The weight of the liver, kidney and adrenal glands did not vary among the groups. As expected, in the VCD+E rats, the weight of the ovaries was decreased and that of the uterus increased in response to E2T. In conclusion, we showed that progressive ovarian failure triggers depressive like behavior in VCD-periestropausal rats associated with low progesterone plasma levels. Although progesterone levels are improved by E2T, depressive like behavior is intensified possibly due to a reduction in NA transmission in the hippocampus.
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