# Role of Quercetin in Depressive-Like Behaviors: Findings from Animal Models
## 5 [PERSON] in Animal Models of Depressive-Like Behaviors
### Quercetin Effects in Animal Models Exposed to Acute Stress
Furthermore, as a response to stress, quercetin is able to activate the HPA axis, decreasing the levels of the corticotropin-releasing factor, closely related to the development of factors similar to depression [30]. In this regard, [PERSON] et al. investigated the benefit of quercetin on depressive-like and anxiety-like behaviors caused by a chemotherapeutic agent that activates the HPA axis, Adriamycin. Quercetin (quercetin dihydrate; 60 mg/kg) was intraperitoneally administered 24, 5, and 1 h before the behavioral tests. Quercetin pre-treatment ameliorated the anxiety-depressive-like behavior induced by Adriamycin, reducing immobility and increasing swimming time. Moreover, Adriamycin increased the plasma corticosterone concentration. Conversely, quercetin restored the corticosterone level, highlighting that, at least in part, its antidepressant effects are due to HPA axis modulation. Moreover, the effect of quercetin could be also associated with its ability to stabilize high levels of glutathione (GSH) and to reduce glutathione-S-transferase (GST) and malondialdehydedehyde (MDA) levels. Additionally, quercetin treatment reversed leucopenia and attenuated lymphopenia and monocytosis in rats pre-treated with Adriamycin, restoring stress-induced immune alterations [46]. Contrary to the results obtained in the previous studies [38, 46], [PERSON] et al. showed that the antidepressant effects of quercetin in diabetics are not due to the involvement of the HPA axis. Streptavidin-induced diabetes increased the immobility time of mice in the FST, as observed in depressive-like behavior. After 21 days of treatment quercetin at a dose of 50 mg/kg improved depressive-like behaviors. However, quercetin did not change plasma concentrations of adrenocortic hormone and corticosterone. Instead, the higher dose of quercetin (100 mg/kg) had not exerted antidepressant effects [47]. [PERSON] et al. investigated the antidepressant effects of quercetin in an animal model of depression based on bilateral destruction of the olfactory bulb. Ablation of the olfactory bulb consists of bilateral destruction of the olfactory bulb, that induces behavioral changes similar to depressive symptoms. After 14 days from model induction, the animals were treated with quercetin (25 mg/kg) or fluoxetine (10 mg/kg) by mouth for two weeks. Quercetin, like fluoxetine, showed antidepressant effects by reducing hyperactivity in the open field test, immobility in the forced swim and tail suspension tests, and it improved anhedonic behavior in the splash test. The antioxidant effect of quercetin may be related to its ability to restore lipid hydroperoxide levels in the hippocampus, which increased following olfactory bulbectomy. In order to evaluate the involvement of N-methyl-D-aspartate (NMDA)receptors and the L-arginine-NO-cyclic guanosine monophosphate (cGMP) pathway in the antidepressant effect of quercetin, animals not undergoing olfactory bulbectomy were treated with L-arginine, methylene blue, NMDA, 7-nitroidazole, and sildenafil. Treatment with NMDA and L-arginine inhibited the antidepressant effect of quercetin. Moreover, researchers demonstrated that inhibition of NMDA receptors and NO synthesis may mediate the antidepressive effects of quercetin [48]. Also, in the study performedby [PERSON] et al. treatment with quercetin (40 and 80 mg/kg) for 14 days significantly prevented the behavioral changes induced by olfactory bullectomy. In this study, quercetin reduced oxidative/nitrosative stress markers such as nitrite and MDA; instead, it increased the levels of GSH, SOD, and CAT. It also reduced neuroinflammation significantly attenuating TNF-\(\alpha\) and IL-6 levels in both the cerebral cortex and hippocampus. Chronic treatment with quercetin significantly, also, reduced caspase-3 activity. Furthermore, this flavonoid decreased the levels of microglial cells, compared to the group of animals undergoing olfactory bullectomy. Therefore, the antidepressant effects of quercetin could be mediated by the inhibition of microglia.