Epigenetic Mechanism of 5-HT/NE/DA Triple Reuptake Inhibitor on Adult Depression Susceptibility in Early Stress Mice

Abstract

Major depressive disorder (MDD) is a chronic, remitting and debilitating disease and the etiology of MDD is highly complicated that involves genetic and environmental interactions. Despite many pharmacotherapeutic options, many patients remain poorly treated and the development of effective treatments remains a high priority in the field. LPM570065 is a potent 5-hydroxytryptamine (5-HT), norepinephrine (NE) and dopamine (DA) triple reuptake inhibitor and both preclinical and clinical results demonstrate significant efficacy against MDD. This study extends previous findings to examine the effects and underlying mechanisms of LPM570065 on stress vulnerability using a “two-hit” stress mouse model. The “two-hit” stress model used adult mice that had experienced early life maternal separation (MS) stress for social defeat stress (SDS) and then they were evaluated in three behavioral assays: sucrose preference test, tail suspension test and forced swimming test. For the mechanistic studies, methylation-specific differentially expressed genes in mouse hippocampal tissue and ventral tegmental area (VTA) were analyzed by whole-genome transcriptome analysis along with next-generation bisulfite sequencing analysis, followed by RT-PCR and pyrophosphate sequencing to confirm gene expression and methylation. LPM570065 significantly reversed depressive-like behaviors in the mice in the sucrose preference test, the tail suspension test, and the forced swimming test. Morphologically, LPM570065 increased the density of dendritic spines in hippocampal CA1 neurons. Hypermethylation and downregulation of oxytocin receptor (Oxtr) in the hippocampal tissues along with increased protein expression of Dnmt1 and Dnmt3a in mice that experienced the “two-hit” stress compared to those that only experienced adulthood social defeat stress, and LPM570065 could reverse these changes. Combined, these results suggest that methylation specificity of the gene Oxtr in the hippocampus may play an important role in early life stress-induced susceptibility to depression and that the5-HT/NE/DA triple reuptake inhibitor LPM570065 may reduce depression susceptibility via the reversal of the methylation of the gene Oxtr.

Gabrb2 knock-out mice exhibit double-directed PMDD-like symptoms: GABAAR subunits, neurotransmitter metabolism disruption, and allopregnanolone binding

“…Besides GABA and Glu indicated above, 5-HT, a monoamine neurotransmitter regulates emotions and cognitive functions in the CNS [35]. NE, DA, etc., are important indicators for assessing depression severity [36]. Also, research has demonstrated a strong correlation between dopamine, 5-HT, norepinephrine, and serotonin in the brain with depression-like emotions [37], which is in agreement with our findings [38].…”

Does urinary metabolite signature act as a biomarker of post-stroke depression?

“…Furthermore, DA is converted into noradrenaline (NA) by DA hydroxylase. Numerous studies ( 72 – 83 ) confirmed that the dysfunction of monoamine neurotransmitters such as NE, DA, and 5-HT plays a crucial part in the pathogenesis of depressive disorder. Elevated DA, L-DOPA, and vanillylmandelic acid (VMA) levels were found in the hippocampus of CSDS-induced model mice ( 84 , 85 ).…”

Development of MAO-A and 5-HT2AR Dual Inhibitors with Improved Antidepressant Activity

“…Products were purified by silica gel column chromatography (200−300 mesh, Qingdao, China). 1 H NMR spectra and 13 C NMR spectra were recorded on Bruker AVANCE instrument at 25 °C using TMS as the internal standard in CDCl 3 or DMSO-d 6 . ESI-MS spectra were recorded on a HP 1100LC/MSD spectrometer.…”

“…Depression is a major public health problem, ranking the third leading cause of the global burden of disease and WHO predicts that the disorder will rank first by 2030. 1 Despite many progresses in the development of antidepressants, the clinical use of currently available treatments for depression are limited, as they are not always effective and cause various adverse effects. 2 Thereby, searching for new therapeutic alternatives to treat this mental disorder more effectively and work faster and safer is an urgent need.…”