Prophylactic (R,S)-Ketamine Is Effective Against Stress-Induced Behaviors in Adolescent but Not Aged Mice.
Prophylactic (R,S)-Ketamine Is Effective Against Stress-Induced Behaviors in Adolescent but Not Aged Mice.
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DOI：
10.1093/ijnp/pyac020
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发表时间：
2022-06-21
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（R，S）-氯胺酮是一种n -甲基- d-天冬氨酸受体拮抗剂，常被用作麻醉剂和速效抗抑郁药。我们和其他人已经报道了（R，S）-氯胺酮对成年小鼠的应激有预防作用，但尚未在青少年或老年人群中测试其功效。在本研究中，我们给青春期（5周龄）和老年（24月龄）129S6/SvEv小鼠不同剂量的生理盐水或（R，S）-氯胺酮作为预防剂，在3次情境恐惧调节（CFC）应激源前1周给药。在CFC之后，我们评估了行为绝望、回避、持续性行为、运动和情境恐惧歧视。为了评估这种预防作用是否能持续到成年，研究人员给青春期小鼠注射生理盐水或不同剂量的（R，S）-氯胺酮，并在1个月后给予3次电击CFC作为应激源。5天后，小鼠再次暴露于厌恶环境中，并进行上述行为测试。大脑也经过处理，量化环氧化酶2的表达，作为炎症的代理，以确定（R，S）-氯胺酮的预防作用是否部分归因于脑炎症的变化。我们的数据表明（R，S）-氯胺酮在性别特异性剂量下对青春期小鼠有预防作用，而对老年小鼠没有。（R，S）-氯胺酮减轻了女性习得性恐惧和持久性行为，减少了男性的行为绝望，并促进了两性的情境恐惧歧视。（R，S）-氯胺酮显著降低雄性小鼠腹侧角氨区3环氧化酶2的表达。这些发现表明（R，S）-氯胺酮的预防性疗效与性别、剂量和年龄有关，并将为未来研究（R，S）-氯胺酮在整个生命周期中的疗效提供信息。
(R,S)-ketamine, an N-methyl-D-aspartate receptor antagonist, is frequently used as an anesthetic and as a rapid-acting antidepressant. We and others have reported that (R,S)-ketamine is prophylactic against stress in adult mice but have yet to test its efficacy in adolescent or aged populations. Here, we administered saline or (R,S)-ketamine as a prophylactic at varying doses to adolescent (5-week-old) and aged (24-month-old) 129S6/SvEv mice of both sexes 1 week before a 3-shock contextual fear-conditioning (CFC) stressor. Following CFC, we assessed behavioral despair, avoidance, perseverative behavior, locomotion, and contextual fear discrimination. To assess whether the prophylactic effect could persist into adulthood, adolescent mice were injected with saline or varying doses of (R,S)-ketamine and administered a 3-shock CFC as a stressor 1 month later. Mice were then re-exposed to the aversive context 5 days later and administered behavioral tests as aforementioned. Brains were also processed to quantify Cyclooxygenase 2 expression as a proxy for inflammation to determine whether the prophylactic effects of (R,S)-ketamine were partially due to changes in brain inflammation. Our data indicate that (R,S)-ketamine is prophylactic at sex-specific doses in adolescent but not aged mice. (R,S)-ketamine attenuated learned fear and perseverative behavior in females, reduced behavioral despair in males, and facilitated contextual fear discrimination in both sexes. (R,S)-ketamine reduced Cyclooxygenase 2 expression specifically in ventral Cornu Ammonis region 3 of male mice. These findings demonstrate that prophylactic (R,S)-ketamine efficacy is sex, dose, and age dependent and will inform future studies investigating (R,S)-ketamine efficacy across the lifespan.
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