Stress-sensitive antidepressant-like effects of ketamine in the mouse forced swim test
Stress-sensitive antidepressant-like effects of ketamine in the mouse forced swim test
复制标题
DOI：
10.1371/journal.pone.0215554
复制
发表时间：
2019-04-15
期刊：
影响因子：
3.7
通讯作者：
Watson, Brendon O.
中科院分区：
文献类型：
--
作者：
Fitzgerald, Paul J.;Yen, Jessica Y.;Watson, Brendon O.
重度抑郁症是一种与压力有关的疾病，发病率很高，麻醉药物氯胺酮在抑郁症治疗中越来越受到关注，因为在反应性个体中，单次剂量具有快速（数小时内）抗抑郁作用，在某些情况下可持续一周以上。这种快速作用和持续时间远远超过药物半衰期的治疗效果的结合表明了一种独特的作用机制。在这项反向转化研究中，我们通过确定氯胺酮对非应激动物的影响是否与应激小鼠相似，来研究氯胺酮对应激相关抑郁样行为反应的抵消程度。为了验证这一点，雄性C57BL/6J小鼠分别给药1次（0.9%生理盐水，每日1次）、10 mg/kg氯胺酮、30 mg/kg氯胺酮，24小时和7天后进行强迫游泳试验（FST），第8天进行野外试验。未受应激的小鼠接受正常的群体饲养、环境富集和实验者预处理（5天），而受应激的小鼠则接受慢性轻度应激（单次饲养、减少富集和最少处理），其中一些小鼠还每天接受为期两周的不可预测的慢性应激（UCS）。我们发现氯胺酮（注射后24小时）减少了UCS动物的不动性，增加了活动（游泳）行为（抗抑郁样作用），但在无压力小鼠中则相反，与最近的人类研究结果相似。综上所述，这些数据表明慢性心理应激与氯胺酮治疗相互作用，调节其在C57BL/6J小鼠FST中的作用，这加强了该试验以及该小鼠品系与人类应激性抑郁症的相关性。
Major depression is a stress-linked disease with significant morbidity and the anesthetic drug ketamine is of growing interest in the treatment of depression, since in responsive individuals a single dose has rapid (within hours) antidepressant effects that can be sustained for over a week in some instances. This combination of fast action and a therapeutic effect that lasts far beyond the drug's half-life points to a unique mechanism of action. In this reverse translational study, we investigate the degree to which ketamine counteracts stress-related depression-like behavioral responses by determining whether it affects unstressed animals similarly to stressed mice. To test this, male C57BL/6J mice were given a single injection of vehicle (0.9% saline; i.p.), 10 mg/kg ketamine, or 30 mg/kg ketamine, and were tested in the forced swim test (FST) 24 hours and 7 days later, as well as in the open field test on the eighth day. Unstressed mice had normal group housing, environmental enrichment, and experimenter pre-handling (5 days), whereas stressed animals were subjected to chronic mild stress (single housing, reduced enrichment and minimal handling), where some mice also had daily two-week unpredictable chronic stress (UCS). We find that ketamine (24 hours post-injection) decreases immobility and increases mobile (swimming) behavior (antidepressant-like effects) in UCS animals but does the opposite in unstressed mice, similar to recent human findings. In summary, these data suggest that chronic psychological stress interacts with ketamine treatment to modulate its effects in the C57BL/6J mouse FST, which reinforces the relevance of this test, and this strain of mice, to human, stress-induced depression.