Abstract
Considering the involvement of the opioid system in major depressive disorder (MDD), mainly concerning refractory MDD, and the evidence that ascorbic acid may exert a beneficial effect for the treatment of this disorder, this study investigated the involvement of the opioid system in the antidepressant-like effect of ascorbic acid in the tail suspension test (TST). Treatment of Swiss mice with the non-selective opioid receptor antagonist naloxone (1 mg/kg, i.p.) prevented the reduced immobility time caused by ascorbic acid (1 mg/kg, p.o.) in the TST. Additionally, administration of the selective μ1-opioid receptor antagonist, naloxonazine (10 mg/kg, i.p.), also abolished the antidepressant-like action of the same dose of ascorbic acid in the TST. We also investigated the possible relationship between the opioid system and NMDA receptors in the mechanism of action of ascorbic acid or ketamine (0.1 mg/kg, i.p.) in the TST. Treatment of mice with naloxone (1 mg/kg, i.p.) blocked the synergistic antidepressant-like effect of ascorbic acid (0.1 mg/kg. p.o.) and MK-801 (0.001 mg/kg, p.o., a non-competitive NMDA receptor antagonist) in the TST. Combined administration of ketamine and MK-801 induced a synergistic antidepressant-like action, and naloxone partially abolished this effect. Our results indicate that the antidepressant-like effect of ascorbic acid in the TST appears to be dependent on the activation of the opioid system, especially μ1-opioid receptors, which might be an indirect consequence of NMDA receptor inhibition elicited by ascorbic acid administration.
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Acknowledgements
This study was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, #308723/2013-9), Coordenação de Aperfeiçoamento de Pessoal de Ensino Superior (CAPES), and NENASC Project (PRONEX-FAPESC/CNPq, #1262/2012-9). ALSR is a CNPq Research Fellow. LEBB is an International Brain Research Organization (IBRO) postdoctoral fellow.
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Animals were used according to the National Institutes of Health Guide for the Care and Use of Laboratory Animals, and the protocol and experiments were approved by the Ethical Committee of Animal Research of Federal University of Santa Catarina.
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Moretti, M., Ribeiro, C.M., Neis, V.B. et al. Evidence for the involvement of opioid system in the antidepressant-like effect of ascorbic acid. Naunyn-Schmiedeberg's Arch Pharmacol 391, 169–176 (2018). https://doi.org/10.1007/s00210-017-1446-4
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DOI: https://doi.org/10.1007/s00210-017-1446-4