Xiaoyaosan Ameliorates Chronic Restraint Stress-Induced Depression-Like Phenotype by Suppressing A2AR Signaling in the Rat Striatum

Abstract

Depression is a common mental disorder characterized by pessimism and world-weariness. In our previous study, we found that Xiaoyaosan (XYS) could have antidepressive effects, however the underlying mechanisms remain unclear. Several studies have shown that adenosine A (2 A) receptor (A2AR) in the brain is a key point in the treatment of depression. Our present study aimed to investigate the effects of XYS on A2AR signaling in the striatum of rats exposed to chronic restraint stress (CRS). Ninety-six male Sprague–Dawley rats were randomly divided into 8 groups (control, model, negative control, XYS, A2AR antagonist, A2AR antagonist + XYS, A2AR agonist, A2AR agonist + XYS). The rats in the model group, XYS group, A2AR antagonist group and A2AR antagonist + XYS group were subjected to CRS for 3 h a day. The XYS decoction [2.224 g/(kg·d)] was intragastrical administered by oral gavage to the rats in the negative control group, XYS group, A2AR antagonist + XYS group, and A2AR agonist + XYS group. The rats in the A2AR antagonist group and A2AR antagonist + XYS group were treated with SCH 58261 [0.05 mg/(kg·d)], and the rats in the A2AR agonist and A2AR agonist + XYS group were treated with CGS 21680 [0.1 mg/(kg·d)]. These procedures were performed for 21 consecutive days. Behavioral studies including the open field test, elevated plus maze test, sucrose preference test and forced swimming test, were performed to examine depression-like phenotypes. Then, the effects of XYS on CRS- or A2AR agonist-induced striatal subcellular damage, microglial activation and A2AR signaling changes in the striatum were examined. Here, we report that XYS ameliorates depression-like phenotypes (such as body weight loss as well as depression- and anxiety-like behaviors) and improves synaptic survival and growth in the stratum of the CRS rats. Moreover, XYS reduces A2AR activity and suppresses hyper-activation of striatal microglia. The tissue and cellular effects of XYS were similar to those of the known A2AR antagonists. In conclusion, XYS alleviates depression in the CRS rats via inhibiting A2AR in the striatum.

Striatopallidal adenosine A2A receptor modulation of goal-directed behavior: Homeostatic control with cognitive flexibility

“…Indeed, polymorphisms of the A 2A R gene seem to be a vulnerability factor for methamphetamine dependence/psychosis, especially in females ( Kobayashi et al, 2010 ). Also, both the association of polymorphisms of the A 2A R gene with major depression ( Oliveira et al, 2019 ) and anxiety ( Alsene et al, 2003 ; Domschke et al, 2012 ; Hohoff et al, 2010 ), as well as epidemiological studies linking the consumption of caffeine with a reduced incidence of depression ( Grosso et al, 2016 ; Kim and Kim, 2018 ; Kimura et al, 2020 ; Lucas et al, 2011 ; Navarro et al, 2018b ) and studies in chronically stressed mice ( Kaster et al, 2015 ; Zhu et al, 2022 ) have converged to the conclusion that A 2A R control mood. Chronic stress shifts behavioral control from goal-directed toward habitual strategy ( Radenbach et al, 2015 ), mainly through a frontostriatal reorganization involving DMS and NAc circuits ( Dias-Ferreira et al, 2009 ; Taylor et al, 2014 ).…”

Efficacy and safety of the Chinese herbal medicine Xiao Yao San for treating anxiety: a systematic review with meta-analysis and trial sequential analysis

“…Zhao et al showed that XYS can maintain mitochondrial function by increasing the level of BDNF and phosphorylated AMPK, thus alleviating anxiety (Zhao et al, 2022). XYS can treat anxiety and depression caused by a high-fat diet by regulating metabolites derived from the intestinal microflora (Yang et al, 2022).…”

“…The primary chemicals were flavonoids ( Yuan et al, 2020 ). For thousands of years, XYS has been used to treat mental illnesses and functional gastrointestinal disorders ( Liu et al, 2021 ; Zhu et al, 2022 ). Several studies have also shown that using XYS to treat anxiety results in anxiolytic activity.…”

Flavonoids contribute most to discriminating aged Guang Chenpi (Citrus reticulata ‘Chachi’) by spectrum‐effect relationship analysis between LC‐Q‐Orbitrap/MS fingerprint and ameliorating spleen deficiency activity

“…After drug administration for 9 days, mice were forced to swim in a 15‐cm‐deep glass beaker for 6 min. The 6 min for which they floated were recorded, and the duration of immobility for the last 4 min was calculated (Zhu et al, 2022 ).…”