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

Neuropsychopharmacology (2018) 0:1-9

Authors: Josephine C. McGowan, Collin Hill, Alessia Mastrodonato, Christina T. LaGamma, Alexander Kitayev, Rebecca A. Brachman, Niven R. Narain, Michael A. Kiebish and Christine A. Denny

Recently, we have shown that ketamine given prior to stress exposure protects against the development of depressive-like behaviorin mice. These data suggest that it may be possible to prevent the induction of affective disorders before they develop byadministering prophylactic pharmaceuticals, a relatively nascent and unexplored strategy for psychiatry. Here, we performedmetabolomics analysis of brain and plasma following prophylactic ketamine treatment in order to identify markers of stressresilience enhancement. We administered prophylactic ketamine in mice to buffer against fear expression. Following behavioralanalyses, untargeted metabolomic profiling was performed on both hemispheres of the prefrontal cortex (PFC) and thehippocampus (HPC), and plasma. We found that prophylactic ketamine attenuated learned fear. Eight metabolites were changedin 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 inhibitoryneurotransmitters were increased whereas precursors to excitatory neurotransmitters were decreased. Strikingly, these long-termmetabolomic changes were not observed when no stressor was administered. Our results suggest that prophylactic treatmentdifferentially affects purine and pyrimidine metabolism and neurotransmission in brain and plasma following stress, which mayunderlie the long-lasting resilience to stress induced by a single injection of ketamine. These data may provide novel targets forprophylactic development, and indicate an interaction effect of prophylactic ketamine and stress. To our knowledge, this is the firststudy that identifies metabolomic alterations and biomarker candidates for prophylactic ketamine efficacy in mice.

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