Recently, we have shown that ketamine given prior to stress exposure protects against the development of depressive-like behavior in mice. These data suggest that it may be possible to prevent the induction of affective disorders before they develop by administering prophylactic pharmaceuticals, a relatively nascent and unexplored strategy for psychiatry. Here, we performed metabolomics analysis of brain and plasma following prophylactic ketamine treatment in order to identify markers of stress resilience enhancement. We administered prophylactic ketamine in mice to buffer against fear expression. Following behavioral analyses, untargeted metabolomic profiling was performed on both hemispheres of the prefrontal cortex (PFC) and the hippocampus (HPC), and plasma. We found that prophylactic ketamine attenuated learned fear. Eight metabolites were changed in the PFC and HPC upon ketamine treatment. Purine and pyrimidine metabolism were most significantly changed in the HPC, PFC, and, interestingly, plasma of mice two weeks after prophylactic administration. Moreover, most precursors to inhibitory neurotransmitters were increased whereas precursors to excitatory neurotransmitters were decreased. Strikingly, these long-term metabolomic changes were not observed when no stressor was administered. Our results suggest that prophylactic treatment differentially affects purine and pyrimidine metabolism and neurotransmission in brain and plasma following stress, which may underlie the long-lasting resilience to stress induced by a single injection of ketamine. These data may provide novel targets for prophylactic development, and indicate an interaction effect of prophylactic ketamine and stress. To our knowledge, this is the first study that identifies metabolomic alterations and biomarker candidates for prophylactic ketamine efficacy in mice.

中文翻译：

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应激后，预防性氯胺酮会改变大脑和血浆中核苷酸和神经递质的代谢。

最近，我们已经显示，在压力暴露之前给予的氯胺酮可以防止小鼠出现类似抑郁的行为。这些数据表明，通过施用预防性药物（一种相对较新的，尚未开发的精神病学策略），有可能在情感性疾病发展之前防止其诱发。在这里，我们进行了氯胺酮预防性治疗后对大脑和血浆的代谢组学分析，以识别增强应激适应性的标志物。我们在小鼠中施用了预防性的氯胺酮，以缓冲恐惧表达。进行行为分析后，在前额叶皮层（PFC）和海马（HPC）的半球以及血浆上进行了非靶向的代谢组学分析。我们发现预防性的氯胺酮减轻了学习中的恐惧感。氯胺酮治疗后，PFC和HPC中的八种代谢物发生了变化。预防性给药后两周，HPC，PFC和小鼠血浆中的嘌呤和嘧啶代谢最明显。此外，大多数抑制性神经递质的前体增加，而兴奋性神经递质的前体减少。令人惊讶的是，当不使用应激源时，未观察到这些长期的代谢组学变化。我们的研究结果表明，预防性治疗会在应激后差异影响嘌呤和嘧啶的代谢以及脑和血浆中的神经传递，这可能是氯胺酮单次注射对应激产生持久抵抗力的基础。这些数据可能为预防性发展提供新的靶点，并表明预防性氯胺酮与压力的相互作用。据我们所知，这是第一项鉴定代谢组学改变和候选生物标志物以预防小鼠氯胺酮功效的研究。