# 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 Chronic Stress  
Several evidence showed that quercetin improves stress and depressive-like symptoms enhancing antioxidant enzymes [127; 128]. Quercetin, due to its ability to cross the blood-brain barrier, appears in the brain after several hours of administration, playing an important role in the central nervous system and induces neuronal survival [25]. It is known to improve stress-induced behavioral dysfunction decreasing oxidative stress in the hippocampus [29; 35]. Additionally, quercetin ameliorated serotonergic and cholinergic functions following repeated treatment [129]. In this regard, [PERSON] et al. evaluated the effects of repeated administration of quercetin on cognitive function, stress responses, cholinergic function, and serotonin metabolism in animals following 2 h of immobilization stress. Immobilization stress was performed by pressing the forelegs of the rats through the gaps in the metal grids and taping them together with zinc oxide plaster tape, in order to mimics potent physical and psychological stress. Results showed that quercetin treatment (20 mg/mL/kg), for 14 days, ameliorated stress-induced anxiety and depression. Quercetin reduced the stress-induced lipid peroxidation and increased antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Moreover, quercetin significantly increased acetylcholine (Ach) levels in the brain of stressed than unstressed mice. After 2 h the immobilization stress increased 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels in untreated and treated stressed mice. However, quercetin pre-treatment reduced 5-HIAA levels, showing how quercetin may ameliorate 5-HT function abnormalities under stress. In conclusion, pre-treatment with quercetin mitigated stress-induced behavioral deficits at least in a part due to its antioxidant functional properties. Also, this compound, induced antidepressant and anxiolytic properties, reducing the activity of the serotonergic and cholinergic systems [32]. [PERSON] et al., evaluated the effects of quercetin (10 or 20 mg/kg) and quercetin 4\({}^{\prime}\)-O-glucose (10 or 20 mg/kg) isolated from _Allium cepa_ in a mouse model of unpredictable mild chronic stress-induced depressive behavior. In order to induce the depression model, mice were subjected to several stress regimes of different duration and severity in an unpredictable manner for 3 weeks. After 24 h of the last stressor, both compounds demonstrated a decrease in immobility time in the FST and an enhancement of the locomotor activity in the open field test compared to the control group. These findings highlighted the antidepressant effect of these compounds. However, quercetin 4\({}^{\prime}\)-O-glucose showed comparable antidepressant action to the fluoxetine (20 mg/kg) treated group. For this reason, the action of quercetin 4\({}^{\prime}\)-O-glucose (10 and 20 mg/kg) was further investigated in a depressive-type mouse model induced by unpredictable mild chronic stress. For 2 weeks, the animals were subjected to various stresses once a day 30 min after administering the treatments. Quercetin 4\({}^{\prime}\)-O-glucose at both doses restored ROS levels such as thiobarbituric acid reactive species (TBARS) and GSH, reduced monoamine oxidase-A (MAO-A) activity, and increased 5-HT levels in the brain. Therefore, the antidepressant action of quercetin and its glucoside may be linked to their antioxidant action, ability to inhibit MAO-A and restore 5-HT levels [33]. In the same animal model of depression, [PERSON] et al. showed that quercetin administered for 28 days, 2 weeks after the onset of stress, induced antidepressant effects such as fluoxetine. Indeed, quercetin (25 mg/kg), albeit to a lesser extent than fluoxetine (10 mg/kg), improved the locomotor activity of animals subjected to unpredictable mild chronic stress.