Antidepressant-like effect of quercetin in bulbectomized mice and involvement of the antioxidant defenses, and the glutamatergic and oxidonitrergic pathways Iandra Holzmann ⁎, Luísa Mota da Silva, José Afonso Corrêa da Silva, Viviane Miranda Bispo Steimbach, Márcia Maria de Souza Centro de Ciências da Saúde, CCS- Programa de Pós-Graduação em Ciências Farmacêuticas/UNIVALI-Itajaí, SC, Brazil abstract article info Article history: Received 3 March 2015 Received in revised form 4 July 2015 Accepted 8 July 2015 Available online xxxx Keywords: Depression Quercetin Olfactory bulbectomy NMDA Nitric oxide Oxidative stress Olfactory bulbectomy (OB) is an animal model of depression that can mimic symptoms that are characteristic of depressive patients, such as behavioral, neurochemical and neuromorphological changes. Quercetin decreased the immobility time in the forced swimming test and tail suspension test. With the open field test, quercetin did not alter the locomotor activity of mice and in the splash test, quercetin increased the time spent grooming. The repeated treatment with quercetin (25 mg/kg, for 14 days) reversed the behavioral hyperactivity induced by OB in the open field test and was able to prevent depressant-like effects in the forced swimming test and tail sus- pension test. Regarding oxidative stress, OB reduced the levels of glutathione and increase the activity of super- oxide dismutase and lipid hydroperoxide content (LOOH) in the hippocampus. Only the increase in LOOH levels was reversed by treatment with quercetin. In a further series of experiments with non-bulbectomized mice, the antidepressant effect of quercetin in the tail suspension test was reversed by the pretreatment of mice with NMDA, L-arginine or sildenafil. The administration of methylene blue and 7-nitroindazole, in combination with an underactive dose of quercetin (5 mg/kg, p.o.), decreased the immobility time in the tail suspension test com- pared with the use of drug alone. There was no significant change in locomotor activity in the open field test. Our results suggest that the antidepressant effect of quercetin is dependent on the inhibition of the NMDA receptors and/or synthesis of nitric oxide. In addition, considering the reduction of LOOH levels on the hippocampus, we verify that the antioxidant effects of quercetin also contribute to its antidepressive potential. These data contrib- ute to the understanding of the mechanisms involved in the antidepressant effect of quercetin and reinforce the involvement of the NMDA receptors and the nitric oxide on the pathophysiology of depression. © 2015 Elsevier Inc. All rights reserved. 1. Introduction Depression has been recorded since ancient times and affects most diverse populations worldwide. This disease is a chronic mental disor- der, and in some cases, is a potentially fatal disorder, representing a se- rious public health problem that generates high costs to society (Fleck et al., 2009) and that strongly affects quality of life of the patients (Larsen et al., 2010; Van Der Feltz-Cornelis et al., 2010). It is well- established that depression involves a reduction in the monoamine sys- tem, particularly in the neurotransmission of serotonin, dopamine and norepinephrine, or impaired activity of their receptors (Racagni and Popoli, 2010). In summary, the center of action of current drug therapy is to correct monoamine deficits by increasing synaptic concentrations (Higgins and George, 2010; Bennabi et al., 2015). In recent years, studies have demonstrated important sex differences in relation to mood disorders (Brunet et al., 2014; Habel et al., 2015; Hiles et al., 2015). Indeed, depression is more prevalent among women than men, and the associated comorbidities also show differences be- tween genders (Kessler, 2003). In addition, it is well-established that women are more susceptible to anxiety and depressive symptoms, espe- cially associated with the reproductive period (Altemusa et al., 2014). Several sex differences in brain function and structure, as well as differ- ences in exposure to reproductive hormones, can explain these findings. Despite substantial progress achieved with the development of new antidepressants in recent decades, the therapy is not completely effec- tive, and approximately 40% of patients do not respond to treatment (Altomonte et al., 2008). The characterization of the antidepressant- like effect of natural substances is justified by the need to find new com- pounds that have greater clinical efficacy and fewer adverse effects. Phenolic compounds represent a promising class of natural substances in neuropharmacology, taking into account its antioxidant and neuro- protective properties (Dovichi and Lajolo, 2011). These compounds are found in many foods, such as fruits, vegetables and medicinal plants. Pharmacology, Biochemistry and Behavior 136 (2015) 55–63 ⁎ Corresponding author at: Centro de Ciências da Saúde, Pós-Graduação em Ciências Farmacêuticas/UNIVALI 88302901, Itajaí, Brazil. E-mail address: iandrah@hotmail.com (I. Holzmann). http://dx.doi.org/10.1016/j.pbb.2015.07.003 0091-3057/© 2015 Elsevier Inc. All rights reserved. Contents lists available at ScienceDirect Pharmacology, Biochemistry and Behavior journal homepage: www.elsevier.com/locate/pharmbiochembeh