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Abstract:
Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, has
fast-acting antidepressant activities and is used for major depressive
disorder (MDD) patients who show treatment resistance towards drugs of
the selective serotonin reuptake inhibitor (SSRI) type. In order to
better understand Ketamine's mode of action, a prerequisite for improved
drug development efforts, a detailed understanding of the molecular
events elicited by the drug is mandatory. In the present study we have
carried out a timedependent hippocampal metabolite profiling analysis of
mice treated with Ketamine. After a single injection of Ketamine, our
metabolomics data indicate time-dependent metabolite level alterations
starting already after 2 h reflecting the fast antidepressant effect of
the drug. In silico pathway analyses revealed that several hippocampal
pathways including glycolysis/gluconeogenesis, pentose phosphate pathway
and citrate cycle are affected, apparent by changes not only in
metabolite levels but also connected metabolite level ratios. The
results show that a single injection of Ketamine has an impact on the
major energy metabolism pathways. Furthermore, seven of the identified
metabolites qualify as biomarkers for the Ketamine drug response.
