Abstract
Cholecalciferol deficiency has been associated with stress-related psychiatric disorders, particularly depression. Therefore, the present study investigated the antidepressant-like effect of cholecalciferol in female mice and the possible role of the serotonergic system in this response. The ability of cholecalciferol to elicit an antidepressant-like effect and to modulate serotonin levels in the hippocampus and prefrontal cortex of mice subjected to chronic unpredictable stress (CUS) was also investigated. The administration of cholecalciferol (2.5, 7.5, and 25 µg/kg, p.o.) for 7 days, similar to fluoxetine (10 mg/kg, p.o., serotonin reuptake inhibitor), reduced the immobility time in the tail suspension test, without altering the locomotor performance in the open-field test. Moreover, the administration of p-chlorophenylalanine methyl ester (PCPA – 100 mg/kg, i.p., for 4 days, a selective inhibitor of tryptophan hydroxylase, involved in the serotonin synthesis) abolished the antidepressant-like effect of cholecalciferol and fluoxetine in the tail suspension test, demonstrating the involvement of serotonergic system. Additionally, CUS protocol (21 days) induced depressive-like behavior in the tail suspension test and decreased serotonin levels in the prefrontal cortex and hippocampus of mice. Conversely, the administration of cholecalciferol and fluoxetine in the last 7 days of CUS protocol completely abolished the stress-induced depressive-like phenotype. Cholecalciferol was also effective to abrogate CUS-induced reduction on serotonin levels in the prefrontal cortex, but not in the hippocampus. Our results indicate that cholecalciferol has an antidepressant-like effect in mice by modulating the serotonergic system and support the assumption that cholecalciferol may have beneficial effects for the management of depression.
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References
Anglin RES, Samaan Z, Walter SD, Sarah DM (2013) Vitamin D deficiency and depression in adults: systematic review and meta-analysis. Br J Psychiatry 202:100–107. https://doi.org/10.1192/BJP.BP.111.106666
Bakhtiari-Dovvombaygi H, Izadi S, ZareMoghaddam M et al (2021) Beneficial effects of vitamin D on anxiety and depression-like behaviors induced by unpredictable chronic mild stress by suppression of brain oxidative stress and neuroinflammation in rats. Naunyn-Schmiedeberg’s Arch Pharmacol 394:655–667. https://doi.org/10.1007/S00210-020-02002-0
Bianchi M, Moser C, Lazzarini C et al (2002) Forced swimming test and fluoxetine treatment: in vivo evidence that peripheral 5-HT in rat platelet-rich plasma mirrors cerebral extracellular 5-HT levels, whilst 5-HT in isolated platelets mirrors neuronal 5-HT changes. Exp Brain Res 143:191–197. https://doi.org/10.1007/S00221-001-0979-3
Borroto-Escuela DO, Ambrogini P, Chruścicka B et al (2021) The Role of Central Serotonin Neurons and 5-HT Heteroreceptor Complexes in the Pathophysiology of Depression: A Historical Perspective and Future Prospects. Int J Mol Sci 22:1–13. https://doi.org/10.3390/IJMS22041927
Brocardo PS, Budni J, Kaster MP et al (2008) Folic acid administration produces an antidepressant-like effect in mice: evidence for the involvement of the serotonergic and noradrenergic systems. Neuropharmacology 54:464–473. https://doi.org/10.1016/J.NEUROPHARM.2007.10.016
Camargo A, Dalmagro AP, Platt N et al (2020) Cholecalciferol abolishes depressive-like behavior and hippocampal glucocorticoid receptor impairment induced by chronic corticosterone administration in mice. Pharmacol Biochem Behav 196:172971. https://doi.org/10.1016/j.pbb.2020.172971
Camargo A, Dalmagro AP, Rikel L et al (2018) Cholecalciferol counteracts depressive-like behavior and oxidative stress induced by repeated corticosterone treatment in mice. Eur J Pharmacol 833:451–461. https://doi.org/10.1016/j.ejphar.2018.07.002
Casseb GAS, Kaster MP, Rodrigues ALS (2019a) Potential role of vitamin D for the management of depression and anxiety. CNS Drugs 33:619–637. https://doi.org/10.1007/s40263-019-00640-4
Casseb GAS, Ambrósio G, Rodrigues ALS, Kaster MP (2019b) Levels of 25-hydroxyvitamin D 3, biochemical parameters and symptoms of depression and anxiety in healthy individuals. Metab Brain Dis 34:527–535. https://doi.org/10.1007/S11011-018-0371-7
Colla ARS, Oliveira Á, Pazini FL et al (2014) Serotonergic and noradrenergic systems are implicated in the antidepressant-like effect of ursolic acid in mice. Pharmacol Biochem Behav 124:108–116. https://doi.org/10.1016/j.pbb.2014.05.015
Cryan JF, Mombereau C, Vassout A (2005) The tail suspension test as a model for assessing antidepressant activity: Review of pharmacological and genetic studies in mice. Neurosci Biobehav Rev 29:571–625. https://doi.org/10.1016/J.NEUBIOREV.2005.03.009
Dalmagro AP, Camargo A, Rodrigues ALS, Zeni ALB (2019) Involvement of PI3K/Akt/GSK-3β signaling pathway in the antidepressant-like and neuroprotective effects of Morus nigra and its major phenolic, syringic acid. Chem Biol Interact 314:108843. https://doi.org/10.1016/j.cbi.2019.108843
De Almeida GRL, Szczepanik JC, Selhorst I et al (2021) Methylglyoxal-mediated dopamine depletion, working memory deficit, and depression-like behavior are prevented by a dopamine/noradrenaline reuptake inhibitor. Mol Neurobiol 58:735–749. https://doi.org/10.1007/S12035-020-02146-3
De Benedetto GE, Fico D, Pennetta A et al (2014) A rapid and simple method for the determination of 3,4-dihydroxyphenylacetic acid, norepinephrine, dopamine, and serotonin in mouse brain homogenate by HPLC with fluorimetric detection. J Pharm Biomed Anal 98:266–270. https://doi.org/10.1016/J.JPBA.2014.05.039
Delcourte S, Etievant A, Haddjeri N (2021) Role of central serotonin and noradrenaline interactions in the antidepressants’ action: Electrophysiological and neurochemical evidence. Prog Brain Res 259:7–81. https://doi.org/10.1016/BS.PBR.2021.01.002
Delgado P, Price L, Miller H et al (1991) Rapid serotonin depletion as a provocative challenge test for patients with major depression: relevance to antidepressant action and the neurobiology of depression. Psychopharmacol Bull 27:321–330
Delgado PL, Miller HL, Salomon RM et al (1999) Tryptophan-depletion challenge in depressed patients treated with desipramine or fluoxetine: implications for the role of serotonin in the mechanism of antidepressant action. Biol Psychiat 46:212–220. https://doi.org/10.1016/S0006-3223(99)00014-1
Eyles DW, Smith S, Kinobe R et al (2005) Distribution of the Vitamin D receptor and 1α-hydroxylase in human brain. J Chem Neuroanat 29:21–30. https://doi.org/10.1016/j.jchemneu.2004.08.006
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 84:1865–1872. https://doi.org/10.1016/j.biopha.2016.10.107
Fernandes J, Gupta GL (2019) N-acetylcysteine attenuates neuroinflammation associated depressive behavior induced by chronic unpredictable mild stress in rat. Behav Brain Res 364:356–365. https://doi.org/10.1016/J.BBR.2019.02.025
Galts CPC, Bettio LEB, Jewett DC et al (2019) Depression in neurodegenerative diseases: Common mechanisms and current treatment options. Neurosci Biobehav Rev 102:56–84. https://doi.org/10.1016/J.NEUBIOREV.2019.04.002
Godsil BP, Kiss JP, Spedding M, Jay TM (2013) The hippocampal–prefrontal pathway: The weak link in psychiatric disorders? Eur Neuropsychopharmacol 23:1165–1181. https://doi.org/10.1016/J.EURONEURO.2012.10.018
Gupta D, Radhakrishnan M, Kurhe Y (2014) 5HT3 receptor antagonist (ondansetron) reverses depressive behavior evoked by chronic unpredictable stress in mice: Modulation of hypothalamic–pituitary–adrenocortical and brain serotonergic system. Pharmacol Biochem Behav 124:129–136. https://doi.org/10.1016/J.PBB.2014.05.024
Hamon M, Blier P (2013) Monoamine neurocircuitry in depression and strategies for new treatments. Prog Neuropsychopharmacol Biol Psychiatry 45:54–63. https://doi.org/10.1016/J.PNPBP.2013.04.009
He Y, Wu Z, Lan T et al (2020) The 25(OH)D/VDR signaling may play a role in major depression. Biochem Biophys Res Commun 523:405–410. https://doi.org/10.1016/J.BBRC.2019.12.071
Hornung JP (2003) The human raphe nuclei and the serotonergic system. J Chem Neuroanat 26:331–343. https://doi.org/10.1016/J.JCHEMNEU.2003.10.002
Kaneko I, Sabir MS, Dussik CM et al (2015) 1,25-Dihydroxyvitamin D regulates expression of the tryptophan hydroxylase 2 and leptin genes: implication for behavioral influences of vitamin D. FASEB J 29:4023–4035. https://doi.org/10.1096/FJ.14-269811
Kaster MP, Machado NJ, Silva HB et al (2015) Caffeine acts through neuronal adenosine A2A receptors to prevent mood and memory dysfunction triggered by chronic stress. Proc Natl Acad Sci USA 112:7833–7838. https://doi.org/10.1073/pnas.1423088112
Kaster MP, Moretti M, Cunha MP, Rodrigues ALS (2016) Novel approaches for the management of depressive disorders. Eur J Pharmacol 771:236–240. https://doi.org/10.1016/j.ejphar.2015.12.029
Kawaura A, Kitamura Y, Tanida N et al (2017) Antidepressant-like effect of 1α-hydroxyvitamin D3 on mice in the forced swimming test. J Nutr Sci Vitaminol 63:81–84. https://doi.org/10.3177/jnsv.63.81
Köhler S, Cierpinsky K, Kronenberg G, Adli M (2016) The serotonergic system in the neurobiology of depression: Relevance for novel antidepressants. J Psychopharmacol 30:13–22. https://doi.org/10.1177/0269881115609072
Koshkina A, Dudnichenko T, Baranenko D et al (2019) (2019) Effects of Vitamin D3 in Long-Term Ovariectomized Rats Subjected to Chronic Unpredictable Mild Stress: BDNF, NT-3, and NT-4 Implications. Nutrients 11:1726. https://doi.org/10.3390/NU11081726
Langub MC, Herman JP, Malluche HH, Koszewski NJ (2001) Evidence of functional vitamin D receptors in rat hippocampus. Neuroscience 104:49–56. https://doi.org/10.1016/S0306-4522(01)00049-5
Lehmann B, Meurer M (2010) Vitamin D metabolism. Dermatol Ther 23:2–12. https://doi.org/10.1111/J.1529-8019.2009.01286.X
Li G, Yang J, Wang X et al (2020) Effects of EGCG on depression-related behavior and serotonin concentration in a rat model of chronic unpredictable mild stress. Food Funct 11:8780–8787. https://doi.org/10.1039/D0FO00524J
Lu XY, Kim CS, Fraser A, Zhang W (2006) Leptin: A potential novel antidepressant. Proc Natl Acad Sci USA 103:1593–1598. https://doi.org/10.1073/pnas.0508901103
Luchetti A, Bota A, Weitemier A et al (2020) Two Functionally Distinct Serotonergic Projections into Hippocampus. J Neurosci 40:4936–4944. https://doi.org/10.1523/JNEUROSCI.2724-19.2020
Maric NP, Adzic M (2013) Pharmacological modulation of HPA axis in depression New avenues for potential therapeutic benefits. Psychiatr Danub 25:299–305
Moretti M, Colla A, de Oliveira BG et al (2012) Ascorbic acid treatment, similarly to fluoxetine, reverses depressive-like behavior and brain oxidative damage induced by chronic unpredictable stress. J Psychiatr Res 46:331–340. https://doi.org/10.1016/j.jpsychires.2011.11.009
Moretti M, Werle I, da Rosa PB et al (2019) A single coadministration of subeffective doses of ascorbic acid and ketamine reverses the depressive-like behavior induced by chronic unpredictable stress in mice. Pharmacol Biochem Behav 187:172800. https://doi.org/10.1016/j.pbb.2019.172800
Mukherjee N, Chaturvedi SK (2019) Depressive symptoms and disorders in type 2 diabetes mellitus. Curr Opin Psychiatry 32:416–421. https://doi.org/10.1097/YCO.0000000000000528
Neis VB, Bettio LEB, Moretti M et al (2016) Acute agmatine administration, similar to ketamine, reverses depressive-like behavior induced by chronic unpredictable stress in mice. Pharmacol Biochem Behav 150–151:108–114. https://doi.org/10.1016/j.pbb.2016.10.004
O’Leary OF, Bechtholt AJ, Crowley JJ et al (2007) Depletion of serotonin and catecholamines block the acute behavioral response to different classes of antidepressant drugs in the mouse tail suspension test. Psychopharmacology 192:357–371. https://doi.org/10.1007/S00213-007-0728-9
Otte C, Gold S, Penninx B et al (2016) Major depressive disorder. Nat Rev Dis Primers 2:1–20. https://doi.org/10.1038/nrdp.2016.65
Parker GB, Brotchie H, Graham RK (2017) Vitamin D and depression. J Affect Disord 208:56–61. https://doi.org/10.1016/j.jad.2016.08.082
Patrick RP, Ames BN (2014) Vitamin D hormone regulates serotonin synthesis. Part 1: relevance for autism. FASEB J 28:2398–2413. https://doi.org/10.1096/FJ.13-246546
Pittenger C, Duman RS (2008) Stress, depression, and neuroplasticity: a convergence of mechanisms. Neuropsychopharmacology 33:88–109. https://doi.org/10.1038/sj.npp.1301574
Planchez B, Surget A, Belzung C (2019) Animal models of major depression: drawbacks and challenges. J Neural Transm 126:1383–1408. https://doi.org/10.1007/s00702-019-02084-y
Pludowski P, Holick MF, Grant WB et al (2018) Vitamin D supplementation guidelines. J Steroid Biochem Mol Biol 175:125–135. https://doi.org/10.1016/j.jsbmb.2017.01.021
Puig MV, Gulledge AT (2011) Serotonin and prefrontal cortex function: neurons, networks, and circuits. Mol Neurobiol 44:449–464. https://doi.org/10.1007/S12035-011-8214-0/FIGURES/4
Ribeiro JD, Huang X, Fox KR, Franklin JC (2018) Depression and hopelessness as risk factors for suicide ideation, attempts and death: meta-analysis of longitudinal studies. Br J Psychiatry 212:279–286. https://doi.org/10.1192/BJP.2018.27
Rosa PB, Ribeiro CM, Bettio LEB et al (2014) Folic acid prevents depressive-like behavior induced by chronic corticosterone treatment in mice. Pharmacol Biochem Behav 127:1–6. https://doi.org/10.1016/j.pbb.2014.10.003
Sabir MS, Haussler MR, Mallick S et al (2018) Optimal vitamin D spurs serotonin: 1,25-dihydroxyvitamin D represses serotonin reuptake transport (SERT) and degradation (MAO-A) gene expression in cultured rat serotonergic neuronal cell lines. Genes Nutr 13:19. https://doi.org/10.1186/s12263-018-0605-7
Souza SVS, da Rosa PB, Neis VB et al (2020) Effects of cholecalciferol on behavior and production of reactive oxygen species in female mice subjected to corticosterone-induced model of depression. Naunyn-Schmiedeberg’s Arch Pharmacol 393:111–120. https://doi.org/10.1007/s00210-019-01714-2
Steru L, Chermat R, Thierry B, Simon P (1985) The tail suspension test: A new method for screening antidepressants in mice. Psychopharmacology 85:367–370. https://doi.org/10.1007/BF00428203
Watson S, Mackin P (2006) HPA axis function in mood disorders. Psychiatry 5:166–170. https://doi.org/10.1383/psyt.2006.5.5.166
World Health Organization (2017) Depression and other common mental disorders: global health estimates. World Health Organization 1–24. https://doi.org/CCBY-NC-SA3.0IGO
Yoshimura S, Sakamoto S, Kudo H, Sassa S, Kumai A, Okamoto R (2003) Sex-differences in adrenocortical responsiveness during development in rats. Steroids 68:43. https://doi.org/10.1016/s0039-128x(03)00045-x
Xu Y, Liang L (2021) Vitamin D3/vitamin D receptor signaling mitigates symptoms of post-stroke depression in mice by upregulating hippocampal BDNF expression. Neurosci Res 170:306–313. https://doi.org/10.1016/J.NEURES.2020.08.002
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The authors thank funding agencies CNPq and CAPES by the financial support.
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This study was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, #310113/2017–2; #421143/2018–5; #158126/2018–1), and Coordenação de Aperfeiçoamento de Pessoal de Ensino Superior (CAPES). ALSR and ALD are CNPq Research Fellows.
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ALSR, VBN, IW, and ALD designed the study and wrote the protocol. VBN, IW, MM, PBR, AC, YOD, NP, AFR, WDE, GRLA, IS, and administered the drugs, carried out CUS protocol, performed the behavioral and neurochemical tests. VBN, IW and AC undertook the statistical analysis. VBN, IW and AC wrote the first draft of the manuscript. All authors approved the final manuscript.
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Neis, V.B., Werle, I., Moretti, M. et al. Involvement of serotonergic neurotransmission in the antidepressant-like effect elicited by cholecalciferol in the chronic unpredictable stress model in mice. Metab Brain Dis 37, 1597–1608 (2022). https://doi.org/10.1007/s11011-022-00979-6
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DOI: https://doi.org/10.1007/s11011-022-00979-6