Effects of cholecalciferol on behavior and production of reactive oxygen species in female mice subjected to corticosterone-induced model of depression

  • Suene Vanessa da Silva Souza
  • Priscila Batista da Rosa
  • Vivian Binder Neis
  • Júlia Dubois Moreira
  • Ana Lúcia S. Rodrigues
  • Morgana MorettiEmail author
Original Article


Major depressive disorder (or depression) is one of the most frequent psychiatric illnesses in the population, with chronic stress being one of the main etiological factors. Studies have shown that cholecalciferol supplementation can lead to attenuation of the depressive state; however, the biochemical mechanisms involved in the relationship between cholecalciferol and depression are not very well known. The objective of this study was to investigate the effects of the administration of cholecalciferol on behavioral parameters (tail suspension test (TST), open field test (OFT), splash test (ST)) and redox state (dichlorofluorescein (DCF)) in adult female Swiss mice subjected to a model of depression induced by chronic corticosterone treatment. Corticosterone (20 mg/kg, p.o.) was administered once a day for 21 days. For investigation of the antidepressant-like effect, cholecalciferol (100 IU/kg) or fluoxetine (10 mg/kg, positive control) was administered p.o. within the last 7 days of corticosterone administration. After the treatments, the behavioral tests and biochemical analyses in the hippocampus and prefrontal cortex of the rodent samples were performed. Animals submitted to repeated corticosterone administration showed a depressive-like behavior, evidenced by a significant increase in the immobility time in the TST, which was significantly reduced by the administration of cholecalciferol or fluoxetine. In addition, the groups treated with cholecalciferol and fluoxetine showed a significant decrease in the production of reactive oxygen species (ROS) in the hippocampus. These results show that cholecalciferol, similar to fluoxetine, has a potential antidepressant-like effect, which may be related to the lower ROS production.


Depression Corticosterone Hippocampus Redox state ROS Vitamin D3 





2,7 Dichlorofluorescein




Reactive oxygen species




Nicotinamide adenine dinucleotide phosphate


Open field test


Splash test


Forced swim test


Tail suspension test


Vitamin D receptor


Author contribution statement

MM and ALSR conceived and designed research. SVSS, PBR, VBN, and MM conducted experiments. SVSS, PBR, JDM, and MM analyzed data. SVSS, JDM, and MM wrote the manuscript. All authors read and approved the manuscript.

Funding information

This study was financially supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) [grant numbers 150082/2018-5 and 310113/2017-2], and Coordenação de Aperfeiçoamento de Pessoal de Ensino Superior (CAPES). ALSR is CNPq Research Fellow.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted (Ethics Committee CEUA PP00795).


  1. Alekhya P, Sriharsha M, Ramudu VR et al (2015) Adherence to antidepressant therapy: sociodemographic factor wise distribution. Int J Pharm Clin Res 7:180–184Google Scholar
  2. Alrefaie Z, Alhayani A (2015) Vitamin D improves decline in cognitive function and cholinergic transmission in prefrontal cortex of streptozotocin-induced diabetic rats. Behav Brain Res 287:156–162CrossRefPubMedGoogle Scholar
  3. Anglin RE, Samaan Z, Walter SD, McDonald SD (2013) Vitamin D deficiency and depression in adults: systematic review and meta-analysis. Br J Psychiatry 202:100–107CrossRefPubMedPubMedCentralGoogle Scholar
  4. Balcombe JP, Barnard ND, Sandusky C (2004) Laboratory routines cause animal stress. Contemp Top Lab Anim Sci 43:42–51Google Scholar
  5. Bet PM, Hugtenburg JG, Penninx BW, Hoogendijk WJ (2013) Side effects of antidepressants during long-term use in a naturalistic setting. Eur Neuropsychopharmacol 23:1443–1451CrossRefPubMedGoogle Scholar
  6. Beyer JL, Payne ME (2016) Nutrition and bipolar depression. Psychiatr Clin North Am 39:75–86CrossRefPubMedGoogle Scholar
  7. Brouwer-Brolsma EM, Dhonukshe-Rutten RA, Van Wijngaarden JP et al (2016) Low vitamin D status is associated with more depressive symptoms in Dutch older adults. Eur J Nutr 55:1525–1534CrossRefPubMedGoogle Scholar
  8. Camargo A, Dalmagro AP, Rikel L, da Silva EB, Simão da Silva KAB, Zeni ALB (2018) Cholecalciferol counteracts depressive-like behavior and oxidative stress induced by repeated corticosterone treatment in mice. Eur J Pharmacol 833:451–461CrossRefPubMedGoogle Scholar
  9. Casseb GAS, Kaster MP, Rodrigues ALS (2019) Potential role of vitamin D for the management of depression and anxiety. CNS Drugs 33:619–637CrossRefPubMedGoogle Scholar
  10. Chen KB, Lin AM, Chiu TH (2003) Systemic vitamin D3 attenuated oxidative injuries in the locus coeruleus of rat brain. Ann N Y Acad Sci 993:313–249CrossRefPubMedGoogle Scholar
  11. Circu ML, Aw TY (2010) Reactive oxygen species, cellular redox systems and apoptosis. Sciences (New York) 48:749–762Google Scholar
  12. Cui C, Song S, Cui J, Feng Y, Gao J, Jiang P (2017) Vitamin D receptor activation influences NADPH oxidase (NOX2) activity and protects against neurological deficits and apoptosis in a rat model of traumatic brain injury. Oxidative Med Cell Longev 2017:9245702Google Scholar
  13. Curtis KS, Davis LM, Johnson AL, Therrien KL, Contreras RJ (2004) Sex differences in behavioral taste responses to and ingestion of sucrose and NaCl solutions by rats. Physiol Behav 80:657–664CrossRefPubMedGoogle Scholar
  14. Erbaş O, Solmaz V, Aksoy D, Yavaşoğlu A, Sağcan M, Taşkıran D (2014) Cholecalciferol (vitamin D 3) improves cognitive dysfunction and reduces inflammation in a rat fatty liver model of metabolic syndrome. Life Sci 103:68–72CrossRefPubMedGoogle Scholar
  15. Eyles DW, Burne TH, McGrath JJ (2013) Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease. Front Neuroendocrinol 34:47–64CrossRefPubMedGoogle Scholar
  16. Fedotova J, Dudnichenko T, Kruzliak P, Puchavskaya Z (2016) Different effects of vitamin D hormone treatment on depression-like behavior in the adult ovariectomized female rats. Biomed Pharmacother 84:1865–1872CrossRefPubMedGoogle Scholar
  17. Gupta D, Radhakrishnan M, Kurhe Y (2015) Effect of a novel 5-HT 3 receptor antagonist 4i , in corticosterone-induced depression-like behavior and oxidative stress in mice. Steroids 96:95–102CrossRefPubMedGoogle Scholar
  18. Hallgren M, Stubbs B, Vancampfort D, Lundin A, Jääkallio P, Forsell Y (2017) Treatment guidelines for depression: greater emphasis on physical activity is needed. Eur Psychiatry 40:1–3CrossRefPubMedGoogle Scholar
  19. Han C, Lim YH, Honget YC (2016) The association between oxidative stress and depressive symptom scores in elderly population : a repeated panel study. J Prev Med Public Health 49:260–274CrossRefPubMedPubMedCentralGoogle Scholar
  20. Hempel SL, Buettner GR, O'Malley YQ, Wessels DA, Flaherty DM (1999) Dihydrofluorescein diacetate is superior for detecting. Free Radic Biol Med 27:146–159CrossRefPubMedGoogle Scholar
  21. Ibi M, Sawada H, Nakanishi M, Kume T, Katsuki H, Kaneko S, Shimohama S, Akaike A (2001) Protective effects of 1α,25–(OH)2D3 against the neurotoxicity of glutamate and reactive oxygen species in mesencephalic culture. Neuropharmacology 40:761–771CrossRefPubMedGoogle Scholar
  22. Jin J, Maren S (2015) Prefrontal-hippocampal interactions in memory and emotion. Front Syst Neurosci 9:170CrossRefPubMedPubMedCentralGoogle Scholar
  23. Joseph JJ, Golden SH (2016) Cortisol dysregulation: the bidirectional link between stress, depression, and type 2 diabetes mellitus. Ann N Y Acad Sci 1391:20-34Google Scholar
  24. Kalueff AV, Lou YR, Laaksi I, Tuohimaa P (2004) Increased grooming behavior in mice lacking vitamin D receptors. Physiol Behav 82:405–409CrossRefPubMedGoogle Scholar
  25. Khawam EA, Laurencic G, Malone DA Jr (2006) Side effects of antidepressants: an overview. Cleve Clin J Med 73:1–9CrossRefGoogle Scholar
  26. Kim GH, Kim JE, Rhie SJ, Yoon S (2015) The role of oxidative stress in neurodegenerative diseases. Exp Neurobiol 24:325–340CrossRefPubMedPubMedCentralGoogle Scholar
  27. Lardner AL (2015) Vitamin D and hippocampal development-the story so far. Front Mol Neurosci 8:58CrossRefPubMedPubMedCentralGoogle Scholar
  28. Liu T, Zhong S, Liao X, Chen J, He T, Lai S, Jia Y (2015) A meta-analysis of oxidative stress markers in depression. PLoS One 10:1–17Google Scholar
  29. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the folinphenol reagent. J Biol Chem 193:265–267Google Scholar
  30. Lucca G, Comim CM, Valvassori SS, Réus GZ, Vuolo F, Petronilho F, Dal-Pizzol F, Gavioli EC, Quevedo J (2009) Effects of chronic mild stress on the oxidative parameters in the rat brain. Neurochem Int 54:358–362CrossRefPubMedGoogle Scholar
  31. Manna P, Achari AE, Jain SK (2017) Vitamin D supplementation inhibits oxidative stress and upregulate SIRT1/AMPK/GLUT4 cascade in high glucose-treated 3T3L1 adipocytes and in adipose tissue of high fat diet-fed diabetic mice. Arch Biochem Biophys 615:22–34Google Scholar
  32. Manoharan S, Guillemin GJ, Abiramasundari RS, Essa MM, Akbar M, Akbar MD (2016) The role of reactive oxygen species in the pathogenesis of Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease: a mini review. Oxidative Med Cell Longev 2016:1–15CrossRefGoogle Scholar
  33. Manosso LM, Moretti M, Rodrigues ALS (2013) Nutritional strategies for dealing with depression. Food Funct 4:1776–1793CrossRefPubMedGoogle Scholar
  34. Maurya PK, Noto C, Rizzo LB, Rios AC, Nunes SO, Barbosa DS et al (2016) The role of oxidative and nitrosative stress in accelerated aging and major depressive disorder. Prog Neuro-Psychopharmacol Biol Psychiatry 65:134–144CrossRefGoogle Scholar
  35. Moniczewski A, Gawlik M, Smaga I, Niedzielska E, Krzek J, Przegaliński E, Pera J, Filip M (2015) Oxidative stress as an etiological factor and a potential treatment target of psychiatric disorders. Part 1. Chemical aspects and biological sources of oxidative stress in the brain. Pharmacol Rep 67:560–568CrossRefPubMedGoogle Scholar
  36. Moretti M, Colla A, de Oliveira BG, dos Santos DB, Budni J, de Freitas AE, Farina M, Rodrigues ALS (2012) Ascorbic acid treatment, similarly to fluoxetine, reverses depressive-like behavior and brain oxidative damage induced by chronic unpredictable stress. J Psychiatr Res 46:331–340CrossRefPubMedGoogle Scholar
  37. Moretti M, Budni J, Dos Santos DB, Antunes A, Daufenbach JF, Manosso LM, Farina M, Rodrigues ALS (2013) Protective effects of ascorbic acid on behavior and oxidative status of restraint-stressed mice. J Mol Neurosci 46:68–79Google Scholar
  38. Morimoto M, Morita N, Ozawa H, Yokoyama K, Kawata M (1996) Distribution of glucocorticoid receptor immunoreactivity and mRNA in the rat brain: an immunohistochemical and in situ hybridization study. Neurosci Res 26(3):235–269CrossRefPubMedGoogle Scholar
  39. Mozaffari-Khosravi H, Nabizade L, Yassini-Ardakani SM, Hadinedoushan H, Barzegar K (2013) The effect of 2 different single injections of high dose of vitamin D on improving the depression in depressed patients with vitamin D deficiency: a randomized clinical trial. J Clin Psychopharmacol 33:378–385CrossRefPubMedGoogle Scholar
  40. Mpandzou G, Aït Ben Haddou E, Regragui W, Benomar A, Yahyaoui M (2016) Vitamin D deficiency and its role in neurological conditions: a review. Rev Neurol (Paris) 172:109–22Google Scholar
  41. Olescowicz G, Neis VB, Fraga DB, Rosa PB, Azevedo DP, Melleu FF, Brocardo PS, Gil-Mohapel J, Rodrigues ALS (2017) Antidepressant and pro-neurogenic effects of agmatine in a mouse model of stress induced by chronic exposure to corticosterone. Prog Neuro-Psychopharmacol Biol Psychiatry 81:395–407CrossRefGoogle Scholar
  42. Otte C, Gold SM, Penninx BW, Pariante CM, Etkin A, Fava M, Mohr DC, Schatzberg AF (2016) Major depressive disorder. Nat Rev Dis Primers 2:1065CrossRefGoogle Scholar
  43. Parker GB, Brotchie H, Graham RK (2017) Vitamin D and depression. J Affect Disord 208:56–61CrossRefPubMedGoogle Scholar
  44. Rodrigues AL, Rocha JB, Mello CF, Souza DO (1996) Effect of perinatal lead exposure on rat behaviour in open-field and two-way avoidance tasks. Pharmacol Toxicol 79:150–156CrossRefPubMedGoogle Scholar
  45. Rosa PB, Ribeiro CM, Bettio LE, Colla A, Lieberknecht V, Moretti M, Rodrigues AL (2014) Folic acid prevents depressive-like behavior induced by chronic corticosterone treatment in mice. Pharmacol Biochem Behav 127:1–6CrossRefPubMedGoogle Scholar
  46. Sanacora G, Treccani G, Popoli M (2012) Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders. Neurophamarcology 62:63–77CrossRefGoogle Scholar
  47. Sato H, Takahashi T, Sumitani K, Takatsu H, Urano S (2010) Glucocorticoid generates ROS to induce oxidative injury in the hippocampus, leading to impairment of cognitive function of rats. J Clin Biochem Nutr 47(3):224–232Google Scholar
  48. Sepehrmanesh Z, Kolahdooz F, Abedi F, Mazroii N, Assarian A, Asemi Z, Esmaillzadeh A (2016) Vitamin D supplementation affects the Beck depression inventory, insulin resistance, and biomarkers of oxidative stress in patients with major depressive disorder: a randomized, controlled clinical trial. J Nutr 46:243–248Google Scholar
  49. Shin YC, Jung CH, Kim HJ, Kim EJ, Lim SW (2016) The associations among vitamin D deficiency, C-reactive protein, and depressive symptoms. J Psychosom Res 90:98–104CrossRefPubMedGoogle Scholar
  50. Silva MC, de Sousa CN, Gomes PX, de Oliveira GV, Araújo FY, Ximenes NC, da Silva JC et al (2016) Evidence for protective effect of lipoic acid and desvenlafaxine on oxidative stress in a model depression in mice. Prog Neuro-Psychopharmacol Biol Psychiatry 64:142–148CrossRefGoogle Scholar
  51. Smaga I, Niedzielska E, Gawlik M, Moniczewski A, Krzek J, Przegaliński E, Pera J, Filip M (2015) Oxidative stress as an etiological factor and a potential treatment target of psychiatric disorders. Part 2. Depression, anxiety, schizophrenia and autism. Pharmacol Rep 67:569–580CrossRefPubMedGoogle Scholar
  52. Spiers JG, Chen HJ, Bradley AJ, Anderson ST, Sernia C, Lavidis NA (2013) Acute restraint stress induces rapid and prolonged changes in erythrocyte and hippocampal redox status. Psychoneuroendocrinology 38:2511–2519CrossRefPubMedGoogle Scholar
  53. Spiers JG, Chen HJ, Sernia C, Lavidis NA (2015) Activation of the hypothalamic-pituitary-adrenal stress axis induces cellular oxidative stress. Front Neurosci 8:456CrossRefPubMedPubMedCentralGoogle Scholar
  54. Steru L, Chermat R, Thierry B, Simon P (1985) The tail suspension test - a new method for screening antidepressants in mice. Psychopharmacology 85:367–370CrossRefPubMedGoogle Scholar
  55. Tarbali S, Khezri S (2016) Vitamin D3 attenuates oxidative stress and cognitive deficits in a model of toxic demyelination. Iran J Basic Med Sci 19:80–88PubMedPubMedCentralGoogle Scholar
  56. Velimirović M, Dožudić GJ, Selaković V, Stojković T, Puškaš N, Zaletel I, Živković M, Dragutinović V, Nikolić T, Jelenković A, Djorović D, Mirčić A, Petronijević ND (2018) Effects of vitamin D3 on the NADPH oxidase and matrix metalloproteinase in an animal model of global cerebral ischemia. Oxidative Med Cell Longev 2018:3273654CrossRefGoogle Scholar
  57. World Health Organization (WHO) (2018a) Depression. Accessed 03 october 2018
  58. World Health Organization (WHO) (2018b) Mental Health Gap Action Programme (mhGAP) Intervention Guide.;jsessionid=F7475276A6CADF44441D68B715E1B4DC?sequence=1. Accessed 03 october 2018
  59. Wrzosek M, Łukaszkiewicz J, Wrzosek M, Jakubczyk A, Matsumoto H, Piątkiewicz P et al (2013) Vitamin D and the central nervous system. Pharmacol Rep 65:271–278CrossRefPubMedGoogle Scholar
  60. Yalcin I, Belzung C, Surget A (2008) Mouse strain differences in the unpredictable chronic mild stress: a four-antidepressant survey. Behav Brain Res 193:140–143CrossRefPubMedGoogle Scholar
  61. Yang L, Wu L, Du S, Hu Y, Fan Y, Ma J (2016) 1,25(OH)2D3 inhibits high glucose-induced apoptosis and ROS production in human peritoneal mesothelial cells via the MAPK/P38 pathway. Mol Med Rep 14:839–844CrossRefPubMedGoogle Scholar
  62. Yau WY, Chan MC, Wing YK, Lam HB, Lin W, Lam SP, Lee CP (2014) Noncontinuous use of antidepressant in adults with major depressive disorders – a retrospective cohort study. Brain Behav 4:390–397CrossRefPubMedPubMedCentralGoogle Scholar
  63. Zhang Y, Su WJ, Chen Y, Wu TY, Gong H, Shen XL, Wang YX, Sun XJ, Jiang CL (2016) Effects of hydrogen-rich water on depressive-like behavior in mice. Sci Rep 6:2374Google Scholar
  64. Zhao Y, Ma R, Shen J, Su H, Xing D, Du L (2008) A mouse model of depression induced by repeated corticosterone injections. Eur J Pharmacol 581:113–120CrossRefPubMedGoogle Scholar
  65. Zhao J, Jung YH, Jin Y, Kang S, Jang CG, Lee J (2019) A comprehensive metabolomics investigation of hippocampus, serum, and feces affected by chronic fluoxetine treatment using the chronic unpredictable mild stress mouse model of depression. Sci Rep 9(1):7566CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Graduate Program in Nutrition, Health Sciences CenterFederal University of Santa CatarinaFlorianópolisBrazil
  2. 2.Biochemistry Department, Biological Science CenterFederal University of Santa CatarinaFlorianópolisBrazil

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