Metabolomic identification of biochemical changes induced by fluoxetine and imipramine in a chronic mild stress mouse model of depression.

Jing Zhao,Yang-Hee Jung,Choon-Gon Jang,Kwang-Hoon Chun,Jeongmi Lee,Sung Won Kwon

doi:10.1038/srep08890

Abstract

Metabolomics was applied to a C57BL/6N mouse model of chronic unpredictable mild stress (CMS). Such mice were treated with two antidepressants from different categories: fluoxetine and imipramine. Metabolic profiling of the hippocampus was performed using gas chromatography-mass spectrometry analysis on samples prepared under optimized conditions, followed by principal component analysis, partial least squares-discriminant analysis, and pair-wise orthogonal projections to latent structures discriminant analyses. Body weight measurement and behavior tests including an open field test and the forced swimming test were completed with the mice as a measure of the phenotypes of depression and antidepressive effects. As a result, 23 metabolites that had been differentially expressed among the control, CMS, and antidepressant-treated groups demonstrated that amino acid metabolism, energy metabolism, adenosine receptors, and neurotransmitters are commonly perturbed by drug treatment. Potential predictive markers for treatment effect were identified: myo-inositol for fluoxetine and lysine and oleic acid for imipramine. Collectively, the current study provides insights into the molecular mechanisms of the antidepressant effects of two widely used medications.

Highlights

Metabolomic identification of biochemical changes induced by fluoxetine and imipramine in a chronic mild stress mouse model of depression
23 metabolites that had been differentially expressed among the control, chronic unpredictable mild stress (CMS), and antidepressant-treated groups demonstrated that amino acid metabolism, energy metabolism, adenosine receptors, and neurotransmitters are commonly perturbed by drug treatment
The significantly increased locomotor activity of CMS model group (Cms) mice compared to control mice from day 21 in the open field test (OFT) indicated hyperactivity induced by chronic stress in the CMS model[18]

Summary

Introduction

Metabolomic identification of biochemical changes induced by fluoxetine and imipramine in a chronic mild stress mouse model of depression. Metabolomics was applied to a C57BL/6N mouse model of chronic unpredictable mild stress (CMS) Such mice were treated with two antidepressants from different categories: fluoxetine and imipramine. Metabolomics investigates the metabolic response of living systems to any stimuli by measuring variations in the metabolic profiles of the biofluids and tissues of an organism It has been increasingly used as a versatile tool for discovery of molecular biomarkers in many areas including diagnosis or prognosis of clinical diseases and investigation of potential mechanisms of diseases and drugs[15,16]. Molecular alterations induced by traditional Chinese prescriptions for mental disorders have been examined in the urine or plasma of CMS model rats[18,23] and metabolic profiling has been performed in the hippocampus of DBA/2 mice chronically treated with paroxetine, an SSRI class drug[24]

Methods

Results

Conclusion