Ketamine metabolite (2R,6R)-hydroxynorketamine reverses behavioral despair produced by adolescent trauma.
Ketamine metabolite (2R,6R)-hydroxynorketamine reverses behavioral despair produced by adolescent trauma.
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DOI：
10.1016/j.pbb.2020.172973
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发表时间：
2020-09
期刊：
影响因子：
--
通讯作者：
Gould TD
中科院分区：
文献类型：
--
作者：
Elmer GI;Tapocik JD;Mayo CL;Zanos P;Gould TD
早期生活创伤显著增加了发展为重度抑郁症（MDD）的风险，并与成人对抗抑郁药的治疗反应显着下降有关。需要新的治疗方法来治疗儿童创伤相关的MDD。最近的研究表明，（R，S）-氯胺酮（氯胺酮）代谢物（2 R，6 R）-羟基去甲氯胺酮（HNK）发挥快速和持久的抗抑郁药样作用，而没有氯胺酮的NMDAR抑制相关的不良副作用特征。我们研究了（2 R，6 R）-HNK对青春期一种新的活体捕食者压力暴露所产生的行为绝望的治疗潜力。雄性和雌性C57 BL/6 J小鼠在出生后（PND）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，在最后一次暴露后至少14天，小鼠接受不可避免的电击，然后在24小时后进行一次具有可用逃避选择的会议。用载体或（2 R，6 R）-HNK（20 mg/kg，腹膜内）处理表现出持久逃避缺陷（无助）的小鼠，再次测试逃避缺陷逆转前24小时。我们发现，一个显着更多的小鼠开发的无助表型时，他们被暴露于活的捕食者和无助表型逆转（2 R，6 R）-HNK治疗的小鼠。对捕食者应激暴露或（2 R，6 R）-HNK处理的反应没有性别差异。在这项研究中开发的活体捕食者模型提供了一个机会，以进一步完善我们对青少年创伤影响的神经生物学基质的理解，并改善治疗策略。（2 R，6 R）-HNK在该模型中显示的疗效表明了对治疗耐药人群的新型治疗干预。
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 hr 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.
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