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A comprehensive metabolomics investigation of hippocampus, serum, and feces affected by chronic fluoxetine treatment using the chronic unpredictable mild stress mouse model of depression.

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 ?-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.

SUBMITTER: Zhao J

PROVIDER: S-EPMC6527582 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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A comprehensive metabolomics investigation of hippocampus, serum, and feces affected by chronic fluoxetine treatment using the chronic unpredictable mild stress mouse model of depression.

Zhao Jing J Jung Yang-Hee YH Jin Yan Y Kang Seulgi S Jang Choon-Gon CG Lee Jeongmi J

Scientific reports 20190520 1

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 + fluo ...[more]

PMID: 31110199

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Project description:In the clinic selective serotonin reuptake inhibitors (SSRIs), like Fluoxetine, remain the primary treatment for major depression. It has been suggested that miR-16 regulates serotonin transporters (SERT) via raphe nuclei and hippocampal responses to antidepressants. However, the underlying mechanism and regulatory pathways are still obtuse. Here, a chronic unpredicted mild stress (CUMS) depression model in rats was established, and then raphe nuclei miR-16 and intragastric Fluoxetine injections were administered for a duration of 3 weeks. An open field test and sucrose preference quantification displayed a significant decrease in the CUMS groups when compare to the control groups, however these changes were attenuated by both miR-16 and Fluoxetine treatments. A dual-luciferase reporter assay system verified that hsa-miR-16 inhibitory effects involve the targeting of 3'UTR on the 5-HTT gene. Expression levels of miR-16 and BDNF in the hippocampus were examined with RT-PCR, and it was found that increased 5-HT2a receptor expression induced by CUMS can be decreased by miR-16 and Fluoxetine administration. Immunofluorescence showed that expression levels of neuron NeuN and MAP-2 in CUMS rats were lower. Apoptosis and autophagy levels were evaluated separately through relative expression of Bcl-2, Caspase-3, Beclin-1, and LC3II. Furthermore, CUMS was found to decrease levels of hippocampal mTOR, PI3K, and AKT. These findings indicate that apoptosis and autophagy related pathways could be involved in the effectiveness of antidepressants, in which miR-16 participates in the regulation of, and is likely to help integrate rapid therapeutic strategies to alleviate depression clinically. These findings indicate that miR-16 participates in the regulation of apoptosis and autophagy and could account for some part of the therapeutic effect of SSRIs. This discovery has the potential to further the understanding of SSRIs and accelerate the development of new treatments for depression.

Dataset Information

A comprehensive metabolomics investigation of hippocampus, serum, and feces affected by chronic fluoxetine treatment using the chronic unpredictable mild stress mouse model of depression.

Publications

A comprehensive metabolomics investigation of hippocampus, serum, and feces affected by chronic fluoxetine treatment using the chronic unpredictable mild stress mouse model of depression.

Similar Datasets

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