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Opioid System Contributes to the Trifluoromethyl-Substituted Diselenide Effectiveness in a Lifestyle-Induced Depression Mouse Model

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Abstract

Energy-dense foods and ethanol consumption are associated with mood disorders. m-Trifluoromethyl-diphenyl diselenide [(m-CF3-PhSe)2] has been a prominent pharmacological target due to its antidepressant-like effects. This study investigated if the modulation of opioid and glucocorticoid receptors and its well-known antioxidant property contribute to the (m-CF3-PhSe)2 antidepressant-like effect in young mice subjected to an energy-dense diet and ethanol intake. Swiss male mice [postnatal day (PND) 25] were exposed to an energy-dense diet (containing 20% fat and 20% carbohydrate) or standard chow until the PND 67. Mice received ethanol (2 g/kg) or water administration (3 times a week, intragastrically [i.g.]) from PND 45 to PND 60. After that, mice received (m-CF3-PhSe)2 (5 mg/kg/day; i.g) or vegetal oil administration from PND 60 to 66. Mice performed the behavioral tests to evaluate the depressive-like phenotype. The results showed that individually neither an energy-dense diet nor ethanol group induced a depressive-like phenotype, but the association of both induced this phenotype in young mice. Oxidative stress was characterized by the increase of malondialdehyde, the decrease in the superoxide dismutase activity, and non-protein sulfhydryl levels in the cerebral cortex of depressive-like mice. Depressive-like mice showed an increase in the protein levels of opioid receptors and depletion in those of glucocorticoid. (m-CF3-PhSe)2 abolished depressive-like phenotype and oxidative stress as well as modulated the levels of glucocorticoid and opioid receptors. In conclusion, the modulation of opioid and glucocorticoid receptors and the antioxidant property contributed to the (m-CF3-PhSe)2 antidepressant-like effect in young mice exposed to an energy-dense diet and ethanol intake.

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Funding

We gratefully acknowledge Universidade Federal de Santa Maria (UFSM). This study was funded by Fundação de Amparo a Pesquisa do Estado do Rio Grande do Sul (FAPERGS, grant number 17/2551-0000), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, grant number 407118/2018-7), and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES/PROEX #23038.004173/2019-93). C.W.N is recipient of CNPq fellowship (#304864/2015-3). N.S.J (#88882.182156/2018-01) and S.G.M. (#88887.372342/2019-00) are recipient of CAPES fellowships.

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  1. Laboratory of Synthesis, Reactivity, Pharmacological and Toxicological Evaluation of Organochalcogen Compounds, Department of Biochemistry and Molecular Biology, Center of Natural and Exact Sciences, Federal University of Santa Maria, Santa Maria, RS, 97105-900, Brazil

    Sabrina Grendene Müller, Natália Silva Jardim, Milene Arrial Trindade & Cristina Wayne Nogueira

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  2. Natália Silva Jardim
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Contributions

S.G.M, N.S.J, and C.W.N. conceived and designed the study. S.G.M, N.S.J, and M.A.T. conducted behavioral tests and ex vivo and molecular analyses. S.G.M, N.S.J, and C.W.N. wrote and reviewed the manuscript. C.W.N. supervised the study. All authors approved the final version of the manuscript.

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Correspondence to Cristina Wayne Nogueira.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This study was approved by the Committee on the Ethics of Animal Experiments of the Federal University of Santa Maria, Brazil (Permit Number:7141061018), and carried out in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All efforts were made to reduce the number and suffering of animals to minimum.

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Müller, S.G., Jardim, N.S., Trindade, M.A. et al. Opioid System Contributes to the Trifluoromethyl-Substituted Diselenide Effectiveness in a Lifestyle-Induced Depression Mouse Model. Mol Neurobiol 58, 2231–2241 (2021). https://doi.org/10.1007/s12035-020-02255-z

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