Abstract
A metabolomic investigation of depression and chronic fluoxetine treatment was conducted using a chronic unpredictable mild stress model with C57BL/6N mice. Establishment of the depressive model was confirmed by body weight measurement and behavior tests including the forced swim test and the tail suspension test. Behavioral despair by depression was reversed by four week-treatment with fluoxetine. Hippocampus, serum, and feces samples collected from four groups (control + saline, control + fluoxetine, model + saline, and model + fluoxetine) were subjected to metabolomic profiling based on ultra-high performance liquid chromatography-quadrupole-time-of-flight mass spectrometry. Alterations in the metabolic patterns were evident in all sample types. The antidepressant effects of fluoxetine appeared to involve various metabolic pathways including energy metabolism, neurotransmitter synthesis, tryptophan metabolism, fatty acid metabolism, lipid metabolism, and bile acid metabolism. Predictive marker candidates of depression were identified, including β-citryl-L-glutamic acid (BCG) and docosahexaenoic acid (DHA) in serum and chenodeoxycholic acid and oleamide in feces. This study suggests that treatment effects of fluoxetine might be differentiated by altered levels of tyramine and BCG in serum, and that DHA is a potential serum marker for depression with positive association with hippocampal DHA. Collectively, our comprehensive study provides insights into the biochemical perturbations involved in depression and the antidepressant effects of fluoxetine.
Highlights
Depression is a debilitating condition that can have profound effects on both the mind and body of individuals who suffer from the disorder[1]
Our previous metabolomic investigation of the hippocampus based on gas chromatography-mass spectrometry (GC-MS) provided insights into the molecular mechanisms of depression and revealed different biochemical changes induced by fluoxetine and imipramine under sub-chronic drug treatment in the chronic unpredictable mild stress (CUMS) mouse model[6]
Because immobility time can be measured under different time periods and settings of video tracking system, its values of control groups have been reported in a wide range even within the same mouse strain
Summary
Depression is a debilitating condition that can have profound effects on both the mind and body of individuals who suffer from the disorder[1]. Our previous metabolomic investigation of the hippocampus based on gas chromatography-mass spectrometry (GC-MS) provided insights into the molecular mechanisms of depression and revealed different biochemical changes induced by fluoxetine and imipramine under sub-chronic (two weeks) drug treatment in the CUMS mouse model[6]. The slow onset of action of fluoxetine in rodents and in the clinic[4] led us to hypothesize that longer (chronic) treatment is needed to mitigate the symptoms of stress-related behaviors in the CUMS model with this mouse strain. We conducted a comprehensive metabolomics study to investigate the effects of chronic treatment of fluoxetine in the CUMS model with C57BL/6N mice. To the best of our knowledge, this is the first comprehensive metabolomics study of biochemical changes in hippocampus, serum, and feces by chronic treatment with fluoxetine using the CUMS mouse model
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