Mahmoud Rand, Wainwright Steven R, Chaiton Jessica A, Lieblich Stephanie E, Galea Liisa A M
Graduate Program in Neuroscience, University of British Columbia, Vancouver, Canada; Centre for Brain Health, University of British Columbia, Vancouver, Canada.
Department of Psychology, University of British Columbia, Vancouver, Canada.
Neuropharmacology. 2016 Aug;107:278-293. doi: 10.1016/j.neuropharm.2016.01.033. Epub 2016 Mar 24.
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.
抑郁症在女性中比在男性中更为普遍，并且女性在产后和围绝经期患抑郁症的风险更高。也有证据表明卵巢激素环境可能决定抗抑郁药的疗效。因此，研究卵巢激素在抑郁症发病机制以及抗抑郁药疗效潜在机制中的作用非常重要。在本研究中，我们使用10月龄雌性Sprague-Dawley大鼠来研究长期卵巢激素剥夺对慢性应激后抑郁样内表型发展以及抗抑郁药疗效的影响。卵巢切除（OVX）或假手术后4个月，所有大鼠均接受6周的慢性不可预测应激（CUS）。在CUS的最后3周，大鼠每天注射氟西汀（5mg/kg）或溶剂。对所有大鼠进行焦虑样和抑郁样行为、下丘脑-垂体-肾上腺（HPA）负反馈抑制以及齿状回神经发生和小胶质细胞标志物的评估。我们的研究结果表明，长期卵巢激素剥夺会增加焦虑和抑郁样行为，如强迫游泳试验中不动时间增加以及新奇抑制摄食试验中摄食潜伏期延长，同时蔗糖偏好降低。此外，长期OVX导致HPA负反馈抑制受损，如地塞米松抑制试验所示。氟西汀治疗显示出有限的行为和神经内分泌疗效，然而它降低了小胶质细胞（Iba-1）表达，并增加了细胞增殖、神经发生（通过细胞存活）以及齿状回中多唾液酸神经细胞黏附分子（PSA-NCAM）的表达，尽管这些影响因区域（背侧、腹侧）和卵巢状态而异。综上所述，我们的研究结果表明卵巢激素可能赋予对慢性不可预测应激行为和神经内分泌后果的恢复力，并可能调节氟西汀对中年雌性大鼠细胞增殖、神经发生和PSA-NCAM 的影响。
