Diferenças sexuais no comportamento de ratos submetidos ao modelo do estresse crônico moderado

Abstract

Stress is characterized by physical and psychological changes triggered by external and internal pressures. Repeated exposure to stressful events promotes changes in an individual's cognitive, emotional, and behavioral processes, and such changes may be related to mental illness such as depression. Studies point to different stress coping strategies and data from the World Health Organization show that the incidence of depression and the response to antidepressant treatment are different between men and women and that this difference is related to the hormonal cycling that occurs in females. In addition, stress-induced cognitive changes and response to treatment in males and females are distinct, especially memories with emotional context, which are known to be directly influenced by sex hormones, and are still related to the mechanism of action of antidepressants used in the clinical practice. In this sense, we submitted male (M) and female (F) Wistar rats to the model of chronic mild stress (CMS), widely used to induce depressive-like behavior in animals, to investigate possible behavioral changes related to depression and fear memory, and its response to FLX treatment. At first, two pilot experiment were held to establish the time required to animals present depressivelike behavior and the moment of treatment beginning. The animals were submitted to 35 days of CMS and treated in the last 15 days with fluoxetine (FLX) or its vehicle (VEH), and were submitted to forced swimming (FST), open field (OF) and splash test (ST) before and after the FLX treatment (TTT), and contextual fear conditioning (CFC) at the end of the protocol. F were separated by estrous cycle phases with high (proestrus and estrus - P/E) and low (metaestrus and diestrus - M/D) hormonal levels. Our data demonstrate that before treatment only M-CMS showed depressive-like behavior represented by increased immobility time in FST compared to M-control (CTR), but not after TTT possibly because immobility memory retention impairment. After TTT, F-CMS showed increased climbing time, independent of FLX, and P/E-CTR showed reduced immobility time and increased active time compared to M/D-CTR, suggesting that estrogen may have an antidepressant effect. Also, CMS-FLX showed reduced immobility and increased active time compared to M/D-CTR-FLX but not P/E-CTR-FLX and CMS-VEH. In ST, M-CMS showed increased grooming time compared to M-CTR before TTT and male-CMS-VEH showed increased grooming time compared to M-CTR-VEH after TTT. After TTT F-CTR-FLX showed reduced grooming time compared to F-CMS-FLX, showing conflicting results to literature. The animals of both sexes showed no differences in locomotor activity in OF, demonstrating that the effects observed in the other tests were not due to locomotion impairment. P/E-CTR explored more the center of the field than its P/E-CMS, suggesting an anxiolytic effect, possibly mediated by estrogen. In CFC, M-CMS showed reduction in freezing time compared to M-CTR, regardless of treatment with FLX, suggesting impairment in fear memory caused by CMS only in M. In conclusion, our data show sex differences of CMS in response to FST and CFC. Male rats demonstrated to be more vulnerable to CMS exhibiting depressive-like behaviors earlier than females and also fear memory impairment. On the other hand, female express depressive-like behaviors in phases of estrous cycle with low hormone levels (M/D) and high levels of hormones (increased estrogen) may have protective effect in females in anxious- and depressive-like behavior after chronic stress but no impact on fear memory.