Doctoral Program in Neurobiology and Behavior, Columbia University, New York, NY, USA.
BERG, Framingham, MA, USA.
Neuropsychopharmacology. 2018 Aug;43(9):1813-1821. doi: 10.1038/s41386-018-0043-7. Epub 2018 Mar 29.
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.
最近，我们已经证明，在应激暴露前给予氯胺酮可以预防小鼠出现抑郁样行为。这些数据表明，通过给予预防性药物来预防情感障碍的发生是可能的，这是一种相对新兴和未被探索的精神病学策略。在这里，我们在预防性氯胺酮治疗后对大脑和血浆进行了代谢组学分析，以确定增强应激适应能力的标志物。我们在小鼠中给予预防性氯胺酮以缓冲恐惧表达。在行为分析之后，对前额叶皮层（PFC）和海马（HPC）的两个半球以及血浆进行了非靶向代谢组学分析。我们发现预防性氯胺酮可减轻习得性恐惧。氯胺酮治疗后，8 种代谢物在 PFC 和 HPC 中发生变化。嘌呤和嘧啶代谢在 HPC、PFC 中变化最显著，有趣的是，在预防性给药两周后，小鼠的血浆中也发生了变化。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。引人注目的是，当没有应激源时，这些长期的代谢变化没有观察到。我们的结果表明，预防性治疗在应激后对大脑和血浆中的嘌呤和嘧啶代谢以及神经传递有不同的影响，这可能是单次注射氯胺酮引起的应激适应能力持久的基础。这些数据可能为预防性开发提供新的靶点，并表明预防性氯胺酮和应激之间存在相互作用效应。据我们所知，这是第一项在小鼠中确定预防性氯胺酮疗效的代谢组学改变和生物标志物候选物的研究。
