Objective:

2

To explore the rapid antidepressant potential and the underlying mechanism of Chaihu Shugan San (CSS) in female mice.

Methods:

2

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:

2

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:

2

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.