Desvenlafaxine prevents white matter injury and improves the decreased phosphorylation of the rate‐limiting enzyme of cholesterol synthesis in a chronic mouse model of depression

Serotonin/norepinephrine reuptake inhibitors antidepressants exert their effects by increasing serotonin and norepinephrine in the synaptic cleft. Studies show it takes 2–3 weeks for the mood‐enhancing effects, which indicate other mechanisms may underlie their treatment effects. Here, we investigated the role of white matter in treatment and pathogenesis of depression using an unpredictable chronic mild stress (UCMS) mouse model. Desvenlafaxine (DVS) was orally administrated to UCMS mice at the dose of 10 mg/kg/day 1 week before they went through a 7‐week stress procedure and lasted for over 8 weeks before the mice were killed. No significant changes were found for protein markers of neurons and astrocytes in UCMS mice. However, myelin and oligodendrocyte‐related proteins were significantly reduced in UCMS mice. DVS prevented the stress‐induced injury to white matter and the decrease of phosphorylated 5′‐AMP‐activated protein kinase and 3‐hydroxy‐3‐methyl‐glutaryl‐CoA reductase protein expression. DVS increased open arm entries in an elevated plus‐maze test, sucrose consumption in the sucrose preference test and decreased immobility in tail suspension and forced swimming tests. These findings suggest that stress induces depression‐like behaviors and white matter deficits in UCMS mice. DVS may ameliorate the oligodendrocyte dysfunction by affecting cholesterol synthesis, alleviating the depression‐like phenotypes in these mice.