Abstract
As a well-known multimodal-acting antidepressant, vortioxetine is thought to aim at several serotonin (5-HT) receptors and the 5-HT transporter. However, recently more and more proteins besides 5-HT are being reported to participate in the antidepressant mechanism of vortioxetine. As a widely known nuclear hormone receptor, peroxisome proliferator activated receptor α (PPARα) possesses transcriptional activity and is very important in the brain. Several reports have suggested that hippocampal PPARα is implicated in antidepressant responses. Here we speculate that hippocampal PPARα may participate in the antidepressant mechanism of vortioxetine. In this study, chronic unpredictable mild stress (CUMS), chronic social defeat stress (CSDS), behavioral tests, the western blotting and adenovirus associated virus (AAV)-mediated gene knockdown methods were used together. It was found that vortioxetine administration significantly reversed the inhibitory actions of both CUMS and CSDS on the hippocampal PPARα expression. Pharmacological blockade of PPARα notably prevented the antidepressant actions of vortioxetine in the CUMS and CSDS models. Moreover, genetic knockdown of PPARα in the hippocampus also significantly blocked the protecting effects of vortioxetine against both CUMS and CSDS. Therefore, the antidepressant effects of vortioxetine in mice require hippocampal PPARα.
Highlights
Depression is a chronic, recurring, and debilitating mental illness
We previously reported that chronic stress down-regulated both the protein and mRNA expression of peroxisome proliferator activated receptor α (PPARα) in the hippocampus, while did not affect PPARα in other brain regions such as medial prefrontal cortex, amygdale, nucleus accumbens (NAc), ventral tegmental area (VTA) and hypothalamus (Song et al, 2018)
The antidepressant actions of vortioxetine were first examined in the chronic unpredictable mild stress (CUMS) and chronic social defeat stress (CSDS) models
Summary
Depression is a chronic, recurring, and debilitating mental illness. People who have major depressive disorder (MDD) experience various psychological symptoms including feeling of hopelessness, sadness, lack of motivation, and difficulties to concentrate (Gartlehner et al, 2017; Sheehan et al, 2017). It is known that chronic stress and psychosocial trauma are prevalent determinants of MDD. Adverse events in early-life increase the vulnerability to chronic stress and facilitate the development of MDD later in life (Vergne and Nemeroff, 2006; VanTieghem and Tottenham, 2018). Current antidepressants used in clinical are mostly designed to modulate monoaminergic neurotransmitters (Pereira and Hiroaki-Sato, 2018). These drugs are widely used to treat MDD and relatively safe. The discrepancy between the acute neurochemical effects and clinical efficacy of monoaminergic antidepressants has puzzled many researchers and reminded us that depression neurobiology is complex and far from elucidated, needing further research (Vidal et al, 2011; PilarCuéllar et al, 2013)
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