Ovarian hormones, but not fluoxetine, impart resilience within a chronic unpredictable stress model in middle-aged female rats

Abstract

Depression is more prevalent in women than in men, and women are at a heightened risk for depression during the postpartum and perimenopause. There is also evidence to suggest that the ovarian hormone milieu may dictate antidepressant efficacy. Thus, it is important to investigate the role of ovarian hormones in the pathogenesis of depression and in the mechanisms that may underlie antidepressant efficacy. In the present study, we used 10-month-old female Sprague-Dawley rats to examine the effects of long-term ovarian hormone deprivation on the development of depressive-like endophenotypes after chronic stress, and on antidepressant efficacy. Four months following ovariectomy (OVX) or sham surgery, all rats were subjected to 6 weeks of chronic unpredictable stress (CUS). During the last 3 weeks of CUS, rats received daily injections of fluoxetine (5 mg/kg) or vehicle. All rats were assessed on measures of anxiety- and depressive-like behavior, hypothalamic-pituitary-adrenal (HPA) negative feedback inhibition, and on markers of neurogenesis and microglia in the dentate gyrus. Our findings demonstrate that long-term ovarian hormone deprivation increased anxiety and depressive-like behavior, as seen by increased immobility in the forced swim test and latency to feed in the novelty suppressed feeding test, and decreased sucrose preference. Further, long-term OVX resulted in impaired HPA negative feedback inhibition, as seen in the dexamethasone suppression test. Fluoxetine treatment showed limited behavioral and neuroendocrine efficacy, however it reduced microglial (Iba-1) expression, and increased cell proliferation, neurogenesis (via cell survival), and the expression of the polysialylated neuronal cell adhesion molecule (PSA-NCAM) in the dentate gyrus, although these effects varied by region (dorsal, ventral) and ovarian status. Taken together, our findings demonstrate that ovarian hormones may impart resilience against the behavioral and neuroendocrine consequences of chronic unpredictable stress, and may modulate the effects of fluoxetine on cell proliferation, neurogenesis, and PSA-NCAM in the middle-aged female.

Sex-dependent mental illnesses and mitochondria

“…Estrogen supplementation has successfully alleviated depression-like symptoms in both human patients and OVX female animals (Berlanga and Flores-Ramos, 2006; Martenyi et al, 2001; Nakagawasai et al, 2009; Rachman et al, 1998; Romano-Torres and Fernandez-Guasti, 2010; Thase et al, 2005). Further, when combined with antidepressants, estrogens can potentiate the antidepressant effects (Mahmoud et al, 2016; Rasgon et al, 2007; Recamier-Carballo et al, 2012). These observations indicate that ovarian hormones critically mediate depressive-like symptoms.…”

Selective activation of estrogen receptors α and β: Implications for depressive-like phenotypes in female mice exposed to chronic unpredictable stress

“…Importantly, these effects of 17β-estradiol may not translate to conditions of chronic stress exposure. Indeed, we have shown that long-term ovarian hormone deprivation in rats increased HPA axis negative feedback impairment under chronic stress exposure (Mahmoud et al, 2016), which parallels findings in MDD indicating greater negative feedback impairment in women post-menopause (Roy et al, 1986;Young et al, 1993). Therefore, we investigated the roles of ERα and ERβ in mediating the effects of estradiol on HPA axis function under chronic stress conditions.…”

“…1). The CUS protocol was adapted from published reports (Kreisel et al, 2014;R. Mahmoud et al, 2016;Wainwright et al, 2016) and stressors used are detailed in Table 1.…”

“…Anxiety-like behaviour was assessed using the novelty suppressed feeding test (NSF), adapted from previously published methods (Samuels and Hen, 2011). Behaviour in this test is sensitive to chronic stress exposure and ovarian status (Mahmoud et al, 2016;Stedenfeld et al, 2011), and chronic antidepressant treatment produces an anxiogenic effect in a neurogenesisdependent manner in males (Santarelli et al, 2003). Briefly, mice were deprived of food for 24 hours, then individually placed in one corner of an open arena (50x50x20cm) containing a froot loop © in the centre, and latency to start feeding was measured.…”

“…Cells were quantified separately in the dorsal and ventral hippocampus as these regions have distinctive functions (Fanselow and Dong, 2010) Raw counts were multiplied by 10 to obtain an estimate of the total number of BrdU-ir cells in the hippocampus (Mahmoud et al, 2016a;Pan et al, 2012). BrdU-ir cells were examined for NeuN co-expression to estimate the proportion of BrdU-ir cells that are neurons (calculated as BrdU/NeuN co-labeled cells divided by the total number of BrdU-ir cells).…”