Rapid Antidepressant-Like Potential of Chaihu Shugan San Depends on Suppressing Glutamate Neurotransmission and Activating Synaptic Proteins in Hippocampus of Female Mice

Objective To explore the rapid antidepressant potential and the underlying mechanism of Chaihu Shugan San(CSS)in female mice.Methods Liquid chromatography mass spectrometry(LC-MS)/MS was used to determine the content of main components in CSS to determine its stability.Female C57BL/6J mice were randomly divided into 4 groups,including control(saline),vehicle(saline),CSS(4 g/kg)and ketamine(30 mg/kg)groups.Mice were subjected to irregular stress stimulation for 4 weeks to establish the chronic mild stress(CMS)model,then received a single administration of drugs.Two hours later,the behavioral tests were performed,including open field test,tail suspension test(TST),forced swimming test(FST),novelty suppression feeding test(NSF),and sucrose preference test(SPT).Western blot analysis was used to detect the expression levels of N-methyl-D-aspartate receptor(NMDA)subtypes[N-methyl-D-aspartate receptor 1(NR1),NR2A,NR2B],synaptic proteins[synapsin1 and post synaptic density protein 95(PSD95)],and brain-derived neurotrophic factor(BDNF).Moreover,the rapid antidepressant effect of CSS was tested by pharmacological technologies and optogenetic interventions that activated glutamate receptors,NMDA.Results Compared with the vehicle group,a single administration of CSS(4 g/kg)reversed all behavioral defects in TST,FST,SPT and NSF caused by CMS(P<0.05 or P<0.01).CSS also significantly decreased the expressions of NMDA subtypes(NR1,NR2A,NR2B)at 2 h in hippocampus of mice(all P<0.01).In addition,similar to ketamine,CSS increased levels of synaptic proteins and BDNF(P<0.05 or P<0.01).Furthermore,the rapid antidepressant effects of CSS were blocked by transient activation of NMDA receptors in the hippocampus(all P<0.01).Conclusion Rapid antidepressant effects of CSS by improving behavioral deficits in female CMS mice depended on rapid suppression of NMDA receptors and activation of synaptic proteins.

Regulation of Circadian Genes by the MAPK Pathway:Implications for Rapid Antidepressant Action

Accumulating evidence suggests that the circadian rhythm plays a critical role in mood regulation,and circadian disturbances are often found in patients with major depressive disorder(MDD).The mitogen-activated protein kinase(MAPK)/extracellular signal-regulated kinase(ERK)pathway is involved in mediating entrainment of the circadian system.Furthermore,the MAPK/ERK signaling pathway has been shown to be involved in the pathogenesis of MDD and the rapid onset of action of antidepressant therapies,both pharmaceutical and non-pharmaceutical.This review provides an overview of the involvement of the MAPK/ERK pathway in modulating the circadian system in the rapid action of antidepressant therapies.This pathway holds much promise for the development of novel,rapid-onset-of-action therapeutics for MDD.