External Sourcing and Scientific Excellence, Lundbeck Research USA, United States.
Behav Brain Res. 2013 Nov 1;256:520-8. doi: 10.1016/j.bbr.2013.09.002. Epub 2013 Sep 7.
Hormonally induced mood disorders such as premenstrual dysphoric disorder (PMDD) are characterized by a range of physical and affective symptoms including anxiety, irritability, anhedonia, social withdrawal and depression. Studies demonstrated rodent models of progesterone withdrawal (PWD) have a high level of constructive and descriptive validity to model hormonally-induced mood disorders in women. Here we evaluate the effects of several classes of antidepressants in PWD female Long-Evans rats using the forced swim test (FST) as a measure of antidepressant activity. The study included fluoxetine, duloxetine, amitriptyline and an investigational multimodal antidepressant, vortioxetine (5-HT(3), 5-HT(7) and 5-HT(1D) receptor antagonist; 5-HT(1B) receptor partial agonist; 5-HT(1A) receptor agonist; inhibitor of the serotonin transporter (SERT)). After 14 days of administration, amitriptyline and vortioxetine significantly reduced immobility in the FST whereas fluoxetine and duloxetine were ineffective. After 3 injections over 48 h, neither fluoxetine nor duloxetine reduced immobility, whereas amitriptyline and vortioxetine significantly reduced FST immobility during PWD. When administered acutely during PWD, the 5-HT(1A) receptor agonist, flesinoxan, significantly reduced immobility, whereas the 5-HT(1A) receptor antagonist, WAY-100635, increased immobility. The 5-HT(3) receptor antagonist, ondansetron, significantly reduced immobility, whereas the 5-HT(3) receptor agonist, SR-57227, increased immobility. The 5-HT(7) receptor antagonist, SB-269970, was inactive, although the 5-HT(7) receptor agonist, AS-19, significantly increased PWD-induced immobility. None of the compounds investigated (ondansetron, flesinoxan and SB-269970) improved the effect of fluoxetine during PWD. These data indicate that modulation of specific 5-HT receptor subtypes is critical for manipulating FST immobility in this model of hormone-induced depression.
激素诱导的情绪障碍，如经前烦躁障碍（PMDD），其特征是一系列身体和情感症状，包括焦虑、易怒、快感缺失、社交退缩和抑郁。研究表明，孕激素撤退（PWD）的啮齿动物模型具有高度的构建和描述有效性，可以模拟女性激素诱导的情绪障碍。在这里，我们使用强迫游泳试验（FST）评估几种抗抑郁药在 PWD 雌性长耳大鼠中的作用，以评估抗抑郁活性。该研究包括氟西汀、度洛西汀、阿米替林和一种研究性多模式抗抑郁药文拉法辛（5-HT(3)、5-HT(7)和 5-HT(1D)受体拮抗剂；5-HT(1B)受体部分激动剂；5-HT(1A)受体激动剂；5-HT 转运体（SERT）抑制剂）。经过 14 天的给药后，阿米替林和文拉法辛显著减少了 FST 中的不动性，而氟西汀和度洛西汀则无效。在 48 小时内注射 3 次后，氟西汀和度洛西汀均不能减少不动性，而阿米替林和文拉法辛在 PWD 期间显著减少 FST 不动性。在 PWD 期间急性给药时，5-HT(1A)受体激动剂 flesinoxan 显著减少不动性，而 5-HT(1A)受体拮抗剂 WAY-100635 则增加不动性。5-HT(3)受体拮抗剂昂丹司琼显著减少不动性，而 5-HT(3)受体激动剂 SR-57227 则增加不动性。5-HT(7)受体拮抗剂 SB-269970 无效，而 5-HT(7)受体激动剂 AS-19 则显著增加 PWD 诱导的不动性。研究的化合物（昂丹司琼、flesinoxan 和 SB-269970）均未改善 PWD 期间氟西汀的作用。这些数据表明，调节特定的 5-HT 受体亚型对于操纵该激素诱导的抑郁症模型中的 FST 不动性至关重要。
