Brain region-specific metabolite networks regulate antidepressant effects of venlafaxine

Venlafaxine (VLX) is one of the most commonly prescribed clinical antidepressants. Although the initial targets of venlafaxine are known to be neurotransmitter systems, the mechanisms underlying chronic therapeutic effects in different key brain regions have not been fully clarified. In this study, we used depression-related behavior to evaluate the effects of chronic VLX therapy in rats. Gas chromatographymass spectrometry-based metabolomics was used to characterize metabolomic responses to VLX in the hippocampus and prefrontal cortex. The results demonstrated significant differences in despair behaviors between VLX-treated and control groups of rats, and the metabolic profiles of both the hippocampus and prefrontal cortex were significantly altered after VLX treatment. Furthermore, the altered metabolites had significant brain region specificities, and the altered metabolites in the hippocampus had significant correlations with the despair behaviors. The results obtained from such a metabolic profiling strategy potentially provide a unique perspective on the molecular mechanisms of VLX, and these findings could have important implications for antidepressant drug discovery efforts.