UNCORRECTED PROOF 1 Folic acid prevents depressive-like behavior induced by chronic 2 corticosterone treatment in mice 3 Priscila B. Rosa a , Camille M. Ribeiro a , Luis E.B. Bettio a , André Colla a , Vicente Lieberknecht a , 4 Morgana Moretti a,b, ⁎, Ana Lúcia S. Rodrigues a 5 a Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis 88040-900, SC, Brazil 6 b Department of Natural Sciences, Universidade Regional de Blumenau, Blumenau 89012-900, SC, Brazil abstract 7 article info 8 Article history: 9 Received 17 June 2014 10 Received in revised form 26 September 2014 11 Accepted 5 October 2014 12 Available online xxxx 13 Keywords: 14 Antidepressant 15 Corticosterone 16 Depression 17 Folic acid 18 Stress 19 The objective of this study was to investigate the effects of folic acid on depressive-like behavior induced by 20 chronic administration of corticosterone in mice. Corticosterone (20 mg/kg, p.o.) was administered once a day 21 for 21 days. Folic acid (30 mg/kg, p.o.) or fluoxetine (10 mg/kg, positive control, p.o.) was administered imme- 22 diately after corticosterone injection during the last 7 days of corticosterone treatment. On the 22nd day, animals 23 were submitted to tail suspension test, open-field test and splash test. Corticosterone treatment caused a 24 depressive-like behavior, evidenced by increased immobility time in the tail suspension test and decreased 25 time in which mice spent grooming in the splash test. Repeated folic acid or fluoxetine administration significantly 26 abolished corticosterone-induced depressive-like behavior. Chronic administration of corticosterone decreased 27 levels of serum corticosterone in mice. Neither folic acid, nor fluoxetine treatment reversed this impairment. 28 These findings indicate a robust effect of folic acid in reversing behavioral alterations induced by corticosterone 29 model of depression in mice, suggesting that this vitamin may be an alternative approach for the management 30 of depressive symptoms. 31 © 2013 Published by Elsevier Inc. 32 33 34 35 36 1. Introduction 37 Depression is a chronic, multi-factorial and incapacitating psychiatric 38 disorder often associated with high morbidity and mortality throughout 39 the world (Nemeroff, 2007). Lifetime prevalence for depression varied 40 from 4.4 to 20% in general population and it is commonly associated with 41 increased physical illness and decreased social functioning (Nemeroff 42 et al., 1998; Wong and Licinio, 2001; Nestler et al., 2002). A depressed 43 patient may experience low mood, anhedonia, altered appetite and weight, 44 irritability, sleep disturbances, and psychomotor agitation or retardation 45 (Uher et al., 2014). 46 Numerous studies associate depression with stress by showing that 47 stressful life events have an important causal relationship with the 48 onset of depressive episodes (Heim and Nemeroff, 2001; Hammen, 49 2005). Several findings have shown hypothalamic–pituitary–adrenal 50 (HPA) axis dysfunction in stress-related illnesses, including depression 51 (Juruena et al., 2004; Swaab et al., 2005). The HPA axis receives informa- 52 tion from other neural structures including hippocampus and amygdala, 53 and its activity has direct action on glucocorticoids production. Rapid 54 corticosteroid actions in the brain include, among others, a fast negative 55 feedback at the level of the anterior pituitary gland, which leads to sup- 56 pression of the activated HPA axis (Keller et al., 2006). Excessive activity 57 of the HPA axis was pointed out as significant risk factor for depression 58 (Sterner and Kalynchuk, 2010). Accordingly, clinical evidence has 59 reported that cortisol levels are generally higher in depressed patients 60 compared to healthy controls (Keller et al., 2006), an effect which is 61 reduced by fluoxetine treatment (Piwowarska et al., 2012). Despite 62 these findings, it is important to mention that depression is a heteroge- 63 neous disorder and that HPA axis function can be differently regulated 64 in melancholic and atypical depression. A hypoactivation of the stress 65 system, rather than sustained activation, is a consistent finding in pa- 66 tients with atypical and seasonal depression (Gold and Chrousos, 2002). 67 Preclinical studies corroborate the association between stress and 68 depression. Mice repeatedly exposed to different stressors present 69 depressive-like behavior (Zhao et al., 2008) generally associated with 70 increased levels of serum corticosterone, the rodent homologue of cor- 71 tisol (Gregus et al., 2005). Moreover, repeated corticosterone treatment 72 in rats causes increase in immobility time in the forced swimming test 73 (FST), an indicative of depressive-like behavior (Iijima et al., 2010). Ex- 74 posing animals to chronic corticosterone also results in physiological 75 alterations associated with depressive behavior, including reduced body 76 weight gain and adrenal weights (Fernandez et al., 2001; Johnson et al., 77 2006), decreased hippocampal mRNA levels of BDNF and CREB (Chen 78 et al., 2014) and altered dopaminergic and serotonergic neurotransmis- 79 sion in the medial prefrontal cortex (Inoue and Koyama, 1996). The Pharmacology, Biochemistry and Behavior xxx (2013) xxx–xxx ⁎ Corresponding author at: Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, 88040-900 Florianópolis, SC, Brazil. Tel.: +55 48 3721 5043; fax: +55 48 3721 9672. E-mail address: morganamoretti@hotmail.com (M. Moretti). PBB-72057; No of Pages 6 http://dx.doi.org/10.1016/j.pbb.2014.10.003 0091-3057/© 2013 Published by Elsevier Inc. Contents lists available at ScienceDirect Pharmacology, Biochemistry and Behavior journal homepage: www.elsevier.com/locate/pharmbiochembeh Please cite this article as: Rosa PB, et al, Folic acid prevents depressive-like behavior induced by chronic corticosterone treatment in mice, Pharmacol Biochem Behav (2013), http://dx.doi.org/10.1016/j.pbb.2014.10.003