Effects of (S)-ketamine on depression-like behaviors in a chronic variable stress model: a role of brain lipidome

Abstract

Introduction: Compelling evidence indicates that a single sub-anesthetic dose of (S)-ketamine elicits rapid and robust antidepressant effects. However, the underlying mechanisms behind the antidepressant effects of (S)-ketamine remain unclear.Methods: Here, using a chronic variable stress (CVS) model in mice, we analyzed changes inthe lipid compositions of the hippocampus and prefrontal cortex (PFC) with a mass spectrometry-based lipidomic approach.Results: Similar to previous research outcomes, the current study also showed that (S)-ketamine reversed depressive-like behaviors in mice produced by CVS procedures. Moreover, CVS induced changes inthe lipid compositions of the hippocampus and PFC, notably in the contents of sphingolipids, glycerolipids, and fatty acyls. With the administration of (S)-ketamine, CVS-induced lipid disturbances were partially normalized, particularly in the hippocampus.Conclusion: Altogether, our results indicated that (S)-ketamine could rescue CVS-induced depressive-like behaviors in mice through region-specific modulation of the brain lipidome, contributing to the understanding of (S)-ketamine’s antidepressant effects.

Effects of esketamine and fluoxetine on depression-like behaviors in chronic variable stress: a role of plasma inflammatory factors

“…The behavioral, macrobiotic, neural, and inflammatory changes induced by this model closely mirror the characterization in patients with MDD, which can be reversed by anti-depressant treatments such as fluoxetine ( 24 , 25 ;. In the current study, mice exposed to CVS exhibited depressive-like behaviors such as reduced locomotion in OFT, increased immobility in the tail suspension, and forced swimming tests, which have been reported in our previous study ( 15 ). In recent years, some studies, including ours, also reported that a single dose of esketamine could produce rapid anti-depressant effects.…”

“…The depressive- and anxiety-like behaviors were established through a CVS procedure reported by previous studies, including ours ( 15 , 24 ). Briefly, mice were exposed to three different stressors for 21 consecutive days.…”

“…As shown in the supplemental material 1 , all behavioral tests were confirmed 24 h after the last i.p. injection of esketamine, fluoxetine, or saline with the following timeline as reported previously: open field test (OFT), novelty suppressed feeding test (NSFT), elevated plus maze (EPM), tail suspension test (TST), and forced swim test (FST) with a 24-hour interval in order to avoid unnecessary stress on rodents ( 15 , 24 – 26 ). The mice were acclimated to the test environment for at least 60 minutes before performing behavioral tests.…”

“…Recent years have witnessed a surge in studies ( 9 ) investigating the underlying mechanism of the esketamine’s rapid onset anti-depressive potency. Primarily, esketamine exerts its anti-depressant effect by NMDA receptor inhibition and membrane stabilization via the modulation of intracellular ionic flow of Na+ and Ca2+ ( 10 , 11 ) Additionally, recent studies have reported that the esketamine’s rapid anti-depressant action involves upregulation of brain-derived neurotrophic factor (BDNF) mediated by sirtuin type 1 activation (SIRT1) and rapamycin complex target (mTORC) signaling pathway ( 12 – 15 ). However, the precise mechanisms of the rapid anti-depressant effects of esketamine remain incompletely understood.…”

Linking stress with urocortin in rats

“…When phrases like "long-term" and "chronic" are used to characterize stressors and their effects, stress duration and persistence of stress effects must be taken into account separately [ 6 ]. This susceptibility to chronic stress-related disease in rodents has been successfully duplicated by the widely used chronic variable stress (CVS) paradigm, most notably through the creation of a depressive-like behavioural state [ 7 ]. Upon stress exposure, CRF is rapidly released from the paraventricular nucleus (PVN) of the hypothalamus into the periphery to activate the hypothalamic-pituitary-adrenal (HPA) axis by stimulating the release of adrenocorticotropic hormone from the anterior pituitary, which then triggers the synthesis and secretion of corticosteroids (cortisol in humans, corticosterone in rodents) from the adrenal gland [ 8 ].…”