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Prophylactic ketamine alters nucleotide and neurotransmitter metabolism in brain and plasma following stress

Neuropsychopharmacologyvolume 43pages18131821 (2018) | Download Citation

Abstract

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.

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Acknowledgements

We thank members of the laboratory for insightful comments on this project and manuscript. JCM was supported by the Neurobiology & Behavior Research Training Grant T32 HD007430-19 and by a DGE 16-44869. CTL and AM were supported by an NIH DP5 OD017908. CAD was supported by an NIH DP5 OD017908, a National Alliance for Research on Schizophrenia and Depression (NARSAD) Young Investigator Grant from the Brain & Behavior Research Foundation (BBRF) (P&S Investigator), New York Stem Cell Science (NYSTEM C-029157), and a gift from For the Love of Travis, Inc.

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Affiliations

  1. Doctoral Program in Neurobiology and Behavior, Columbia University, New York, NY, USA

    • Josephine C. McGowan
  2. BERG, Framingham, MA, USA

    • Collin Hill
    • , Alexander Kitayev
    • , Niven R. Narain
    •  & Michael A. Kiebish
  3. Department of Psychiatry, Columbia University, New York, NY, USA

    • Alessia Mastrodonato
    • , Rebecca A. Brachman
    •  & Christine A. Denny
  4. Division of Integrative Neuroscience, Research Foundation for Mental Hygiene, Inc. (RFMH)/New York State Psychiatric Institute (NYSPI), New York, NY, USA

    • Alessia Mastrodonato
    • , Christina T. LaGamma
    •  & Christine A. Denny

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Conflict of interest

AM and CTL reported no biomedical financial interests or potential conflicts of interests. CH, AK, NRN, and MAK are employees of BERG LLC and own stock. NRN is a founder of BERG. JCM, RAB, and CAD are named on non-provisional patent applications for the prophylactic use of ketamine against stress-related psychiatric disorders.

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Correspondence to Christine A. Denny.

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DOI

https://doi.org/10.1038/s41386-018-0043-7