Depressão experimental induzida pela administração única e repetida dexametasona em camundongos: ferramenta para estudo do potencial antidepressivo de antagonistas NOP

Abstract

Major depression can be triggered by stressful events which deregulate the hypothalamicpituitary-adrenal axis (HPA) response, thus promoting in some circumstances sustained elevation of circulating glucocorticoid levels. Hypersecretion of glucocorticoids may alter the functionality of glucocorticoid (rG) receptors at the central nervous system, mainly at the HPA axis and hippocampus, causing behavioral abnormalities in depressive patients. Clinical and preclinical findings suggest antidepressant effects due to the blockade of the NOP receptor signaling. This study aimed to investigate the behavioral actions of acute and chronic administration of dexamethasone in mice and the effects of the NOP receptor antagonist, SB-612111, in this experimental model. Male and female Swiss mice were used to develop this study. The depressive-like behavior of mice was evaluated in the tail suspension test (TST), splash test and social interaction test. In addition, mouse spontaneous locomotor activity was assessed in the open field test. Dexamethasone (64 μg/kg, sc) induced depressive-like behavior in mice of both sexes, by increasing the immobility time in the TST, self-cleaning latency in the splash test, and reducing the frequency of interactions with an unknown animal in the social interaction test. Treatment with the antidepressants nortriptyline and venlafaxine (both 30 mg/kg, ip) reversed most of these behaviors, except for reduced social interaction. Dexamethasone acutely administered did not affect mouse spontaneous locomotion. However, nortriptyline and venlafaxine significantly reduced the total distance moved mainly in male mice. The treatment with the NOP antagonist reversed the depressive-like behavior of acute dexamethasone in the TST and reduced the latency for self-cleaning in the splash test, without affecting spontaneous locomotion in male mice. Additionally, dexamethasone (16 μg/kg, sc) was administered for 14 days and mouse behaviors were measured once a week. In the first seven days, the repeated administration of dexamethasone increased immobility time in the TST, and the latency to self-cleaning in the splash test, without altering the spontaneous locomotion. After 14 days of dexamethasone administration, the repeated administration of imipramine (during the last 7 days, 20 mg/kg, ip) reversed the increase in the immobility time in the TST and the elevation in the latency to self-cleaning in the splash test. In conclusion, acute and repeated administration of dexamethasone induces depressive-like effects which were reversed by classical antidepressants and NOP antagonist (acutely). These findings contribute to adding new evidence for a neuroendocrine model of depression able to be performed in mice of both sexes. Ultimately, our data reinforce the growing body of information about the therapeutic potential of NOP antagonists in the treatment of depression.