Stress-sensitive antidepressant-like effects of ketamine in the mouse forced swim test

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.

重度抑郁症是一种与应激相关的疾病，具有显著的致病负担；麻醉药物氯胺酮（ketamine）在抑郁症治疗领域的关注度与日俱增——对于治疗应答良好的个体，单次给药即可在数小时内产生快速抗抑郁效应，部分案例中疗效可维持一周以上。这种快速起效且药效持续时间远超药物半衰期的特性，提示其存在独特的作用机制。在本项反向转化研究（reverse translational study）中，我们旨在探究氯胺酮对抗应激相关抑郁样行为反应的作用程度，具体通过比较其对未应激动物与应激小鼠的影响是否一致来实现。为验证这一假设，研究人员对雄性C57BL/6J小鼠分别给予单次腹腔注射（intraperitoneal, i.p.）赋形剂（0.9%生理盐水）、10 mg/kg氯胺酮或30 mg/kg氯胺酮，并分别在给药后24小时与7天开展强迫游泳实验（forced swim test, FST），于第8天进行旷场实验（open field test）。未应激小鼠采用正常群居饲养，辅以环境丰容与实验人员每日抓取驯化（为期5天）；而应激动物则接受慢性轻度应激造模：单笼饲养、减少环境丰容且减少抓取操作，其中部分小鼠额外接受为期两周的每日不可预知性慢性应激（unpredictable chronic stress, UCS）。研究结果显示，给药后24小时，氯胺酮可降低不可预知性慢性应激小鼠的不动时长，并提升其游动（游泳）行为占比，呈现抗抑郁样效应；但在未应激小鼠中却呈现相反效果，这与近期的人体研究发现相一致。综上，本研究数据表明，在C57BL/6J小鼠的强迫游泳实验中，慢性心理应激会与氯胺酮治疗相互作用，从而调控其药效，这进一步证实了该实验体系与该品系小鼠在研究人类应激诱导型抑郁症中的相关性。