Quercetin inhibited chronic unpredictable mild stress-induced mouse depressive behaviors through attenuating lateral Habenula neuronal activities.

As a flavonoid, quercetin has shown anti-tumor, anti-inflammation, and anti-depressant effects. However, the exact anti-depressant mechanism of quercetin remains unclear. In this study, a combination of behavioral tests and neuropharmacological methods were used to investigate whether the endocannabinoid (eCB) system in the lateral habenula (LHb) mediated the anti-depressant pathogenesis of quercetin. Depressive model was prepared by chronic unpredictable mild stress (CUMS) in C57 mice. The CUMS exposure led to depressive-like behaviors and an increase of the miniature excitatory postsynaptic current (mEPSC) frequency in the LHb neurons, which were blocked by quercetin intragastrically administered for 14 days. As quercetin has been shown to upregulate the mRNA expression of cannabinoid receptor 1 (CB1) in cultured tumor cells, and the inhibitory effect of eCB system activation is related to glutamatergic neurons, depolarization-induced suppression of excitation (sDSE) was detected. The results showed that presynaptic inhibitory effect of eCB system was significantly down-regulated in the LHb of CUMS model, and the down-regulation was abolished by quercetin. Blocking eCB system in the LHb with CB1 antagonist AM251 rescued the neuroprotective effects of quercetin in CUMS mice. Taken together, the results suggested that eCB system in the LHb was involved in the anti-depressant effects of quercetin.