Prophylactic ketamine alters nucleotide and neurotransmitter metabolism in brain and plasma following stress.
Josephine C McGowan, Collin Hill, Alessia Mastrodonato, Christina T LaGamma, Alexander Kitayev, Rebecca A Brachman, Niven R Narain, Michael A Kiebish, Christine A Denny
Neuropsychopharmacology August 2018 DOI: 10.1038/s41386-018-0043-7 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Mice |
| Intervention | Ketamine |
| Duration | Two weeks after prophylactic administration |
| Topics | Esketamine Ketamine |
| Key points | Prophylactic ketamine given before stress attenuated learned fear in mice and, two weeks later, altered purine and pyrimidine metabolism in the prefrontal cortex, hippocampus, and plasma, with increased inhibitory and decreased excitatory neurotransmitter precursors. These long-term metabolomic changes were seen only when a stressor was administered, suggesting an interaction between prophylactic ketamine and stress that may underlie lasting stress resilience. |
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.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cited by 11
- Evidence from preclinical and clinical metabolomics studies on the antidepressant effects of ketamine and esketamine. Neuroscience Letters May 14, 2024
- Ketamine for Depression: Advances in Clinical Treatment, Rapid Antidepressant Mechanisms of Action, and a Contrast with Serotonergic Psychedelics Current Topics in Behavioral Neurosciences March 22, 2022
- Ketamine's Amelioration of Fear Extinction in Adolescent Male Mice Is Associated with the Activation of the Hippocampal Akt-mTOR-GluA1 Pathway. Pharmaceuticals May 22, 2024
- Ketamine differentially affects implicit and explicit memory processes in rats. Psychopharmacology June 1, 2025
- Prophylactic Ketamine: Current Knowledge and Future Directions. Biological Psychiatry March 28, 2025
and 6 more in the library
Cites 10
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- A Randomized Add-on Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Bipolar Depression Archives of General Psychiatry August 1, 2010
- Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder JAMA Psychiatry April 16, 2014
- Ketamine for rapid reduction of suicidal ideation: a randomized controlled trial Psychological Medicine August 12, 2015
- A single infusion of ketamine improves depression scores in patients with anxious bipolar depression Bipolar Disorders November 14, 2014
and 5 more in the library