Early life trauma dramatically increases the risk of developing major depressive disorder (MDD), and is associated with a markedly decreased adult treatment response to antidepressants. Novel treatment approaches are required to treat childhood trauma-associated MDD. Recent studies suggest that the (R,S)-ketamine (ketamine) metabolite, (2R,6R)-hydroxynorketamine (HNK), exerts fast- and long-lasting antidepressant-like effects without ketamine's NMDAR-inhibition-associated adverse side-effect profile. We investigated the therapeutic potential of (2R,6R)-HNK against behavioral despair produced by a novel live-predator stress exposure during adolescence. Male and female C57BL/6J mice were exposed to a live snake or control conditions at post-natal (PND) days 31, 45 and 61. In order to assess the enduring consequences of trauma-exposure, at a minimum of 14 days following the last exposure, mice received inescapable shocks followed by a session with available escape options twenty-four hours later. Mice that manifested enduring escape deficits (helplessness) were treated with vehicle or (2R,6R)-HNK (20 mg/kg, i.p.), 24 h prior to retesting for reversal of escape deficits. We found that a significantly greater number of mice developed the helpless phenotype when they were exposed to the live predator and that the helpless phenotype was reversed in mice treated with (2R,6R)-HNK. There were no sex differences in the response to predator-stress exposure or (2R,6R)-HNK treatment. The live-predator model developed in this study provides an opportunity to further refine our understanding of the neurobiological substrates impacted by adolescent trauma and improve treatment strategies. The demonstrated efficacy of (2R,6R)-HNK in this model suggests a novel therapeutic intervention for a treatment-resistant population.

早期生活创伤会显着增加患重度抑郁症 (MDD) 的风险，并且与成人对抗抑郁药的治疗反应显着降低有关。需要新的治疗方法来治疗与儿童创伤相关的 MDD。最近的研究表明，( R,S )-氯胺酮 (ketamine) 代谢物 ( 2R,6R )-羟基去甲氯胺酮(HNK) 发挥快速和持久的抗抑郁样作用，而没有氯胺酮的 NMDAR 抑制相关的不良副作用轮廓。我们研究了（2R，6R)-HNK 对抗由青春期新的活体捕食者压力暴露产生的行为绝望。雄性和雌性 C57BL/6J 小鼠在出生后 (PND) 的第 31、45 和 61 天暴露于活蛇或对照条件。为了评估创伤暴露的持久后果，在出生后至少 14 天最后一次暴露，老鼠受到了不可避免的电击，然后在二十四小时后进行了一次可用的逃生选项。表现出持久逃逸缺陷（无助）的小鼠用载体或（2 R ,6 R)-HNK (20 mg/kg, ip)，在重新测试逆转逃逸缺陷之前 24 小时。我们发现，当它们暴露于活的捕食者时，显着更多的小鼠出现了无助表型，并且在用 ( 2R,6R )-HNK处理的小鼠中，无助表型发生了逆转。对捕食者应激暴露或 ( 2R,6R )-HNK 治疗的反应没有性别差异。本研究中开发的活体捕食者模型提供了一个机会，可以进一步完善我们对受青少年创伤影响的神经生物学基质的理解并改进治疗策略。( 2R, 6R )-HNK 在该模型中显示出的功效表明了一种针对抗治疗人群的新型治疗干预。