Purinergic Signalling

, Volume 9, Issue 3, pp 481–486 | Cite as

The antidepressant-like effect of inosine in the FST is associated with both adenosine A1 and A2A receptors

  • Manuella P. KasterEmail author
  • Josiane Budni
  • Marta Gazal
  • Mauricio P. Cunha
  • Adair R. S. Santos
  • Ana Lúcia S. Rodrigues
Brief Communication


Inosine is an endogenous purine nucleoside, which is formed during the breakdown of adenosine. The adenosinergic system was already described as capable of modulating mood in preclinical models; we now explored the effects of inosine in two predictive models of depression: the forced swim test (FST) and tail suspension test (TST). Mice treated with inosine displayed higher anti-immobility in the FST (5 and 50 mg/kg, intraperitoneal route (i.p.)) and in the TST (1 and 10 mg/kg, i.p.) when compared to vehicle-treated groups. These antidepressant-like effects started 30 min and lasted for 2 h after intraperitoneal administration of inosine and were not accompanied by any changes in the ambulatory activity in the open-field test. Both adenosine A1 and A2A receptor antagonists prevented the antidepressant-like effect of inosine in the FST. In addition, the administration of an adenosine deaminase inhibitor (1 and 10 mg/kg, i.p.) also caused an antidepressant-like effect in the FST. These results indicate that inosine possesses an antidepressant-like effect in the FST and TST probably through the activation of adenosine A1 and A2A receptors, further reinforcing the potential of targeting the purinergic system to the management of mood disorders.


Inosine Adenosine receptors Antidepressant Forced swimming test 



This study was supported by CNPq, CAPES, IBN-Net, Brazil and NENASC project (PRONEX program CNPq/FAPESC).

Conflict of interest



  1. 1.
    Andlin-Sobocki P, Jonsson B, Wittchen HU, Olesen J (2005) Cost of disorders of the brain in Europe. Eur J Neurol 12(Suppl 1):1–27PubMedCrossRefGoogle Scholar
  2. 2.
    Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE (2005) Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psych 62(6):593–602CrossRefGoogle Scholar
  3. 3.
    Gomes CV, Kaster MP, Tome AR, Agostinho PM, Cunha RA (2012) Adenosine receptors and brain diseases: neuroprotection and neurodegeneration. Biochim Biophys Acta 1808(5):1380–1399Google Scholar
  4. 4.
    Cunha RA, Ferré S, Vaugeois JM, Chen JF (2008) Potential therapeutic interest of adenosine A2A receptors in psychiatric disorders. Curr Pharmacol Des 14(15):1512–1524CrossRefGoogle Scholar
  5. 5.
    Scaccianoce S, Navarra D, Sciullo AD, Angelucci L, Endröczi E (1989) Adenosine and pituitary–adrenocortical axis activity in the rat. Neuroendocrinology 50:464–468PubMedCrossRefGoogle Scholar
  6. 6.
    Okada M, Nutt DJ, Murakami T, Zhu G, Kamata A, Kawata Y, Kaneko S (2001) Adenosine receptor subtypes modulate two major functional pathways for hippocampal serotonin release. J Neurosci 21:628–640PubMedGoogle Scholar
  7. 7.
    Barankiewicz J, Cohen A (1985) Purine nucleotide metabolism in resident and activated rat macrophages in vitro. Eur J Immunol 15(6):627–631PubMedCrossRefGoogle Scholar
  8. 8.
    Fredholm BB, Sollevi A (1981) The release of adenosine and inosine from canine subcutaneous adipose tissue by nerve stimulation and noradrenaline. J Physiol 313:351–367PubMedGoogle Scholar
  9. 9.
    Benowitz LI, Goldberg DE, Irwin N (2002) Inosine stimulates axon growth in vitro and in the adult CNS. Prog Brain Res 137:389–399PubMedCrossRefGoogle Scholar
  10. 10.
    Haskó G, Sitkovsky MV, Szabo C (2004) Immunomodulatory and neuroprotective effects of inosine. Trends Pharmacological Sci 25(3):152–157CrossRefGoogle Scholar
  11. 11.
    Kovacs Z, Dobolyi A, Juhasz G, Kekesi KA (2009) Nucleoside map of the human central nervous system. Neurochem Res 35(3):452–464PubMedCrossRefGoogle Scholar
  12. 12.
    Marchand WR, Lee JN, Suchy Y, Johnson S, Thatcher J, Gale P (2012) Aberrant functional connectivity of cortico-basal ganglia circuits in major depression. Neurosci Lett 514(1):86–90PubMedCrossRefGoogle Scholar
  13. 13.
    Liu F, You SW, Yao LP, Liu HL, Jiao XY, Shi M, Zhao QB, Ju G (2006) Secondary degeneration reduced by inosine after spinal cord injury in rats. Spinal Cord 44(7):421–426PubMedGoogle Scholar
  14. 14.
    Hasko G, Kuhel DG, Nemeth ZH, Mabley JG, Stachlewitz RF, Virag L, Lohinai Z, Southan GJ, Salzman AL, Szabo C (2000) Inosine inhibits inflammatory cytokine production by a posttranscriptional mechanism and protects against endotoxin-induced shock. J Immunol 164(2):1013–1019PubMedGoogle Scholar
  15. 15.
    Liaudet L, Mabley JG, Soriano FG, Pacher P, Marton A, Hasko G, Szabo C (2001) Inosine reduces systemic inflammation and improves survival in septic shock induced by cecal ligation and puncture. Am J Respir Crit Medicine 164(7):1213–1220CrossRefGoogle Scholar
  16. 16.
    Nascimento FP, Figueredo SM, Marcon R, Martins DF, Macedo SJ Jr, Lima DA, Almeida RC, Ostroski RM, Rodrigues AL, Santos AR (2010) Inosine reduces pain-related behavior in mice: involvement of adenosine A1 and A2A receptor subtypes and protein kinase C pathways. J Pharmacol Exp Therapeut 334(2):590–598CrossRefGoogle Scholar
  17. 17.
    Macedo-Júnior SJ, Nascimento FP, Luiz-Cerutti M, Santos AR (2013) Role of pertussis toxin-sensitive G-protein, K+ channels, and voltage-gated Ca2+ channels in the antinociceptive effect of inosine. Purinergic Signal 9(1):51–58PubMedCrossRefGoogle Scholar
  18. 18.
    Irwin N, Li YM, O'Toole JE, Benowitz LI (2006) Mst3b, a purine-sensitive Ste20-like protein kinase, regulates axon outgrowth. Proc Natl Acad Sci U S A 103(48):18320–18325PubMedCrossRefGoogle Scholar
  19. 19.
    Chen P, Goldberg DE, Kolb B, Lanser M, Benowitz LI (2002) Inosine induces axonal rewiring and improves behavioral outcome after stroke. Proc Natl Acad Sci USA 99(13):9031–9036PubMedCrossRefGoogle Scholar
  20. 20.
    Giannecchini M, Matteucci M, Pesi R, Sgarrella F, Tozzi MG, Camici M (2005) Uptake and utilization of nucleosides for energy repletion. Int J Biochem Cell Biol 37(4):797–808PubMedCrossRefGoogle Scholar
  21. 21.
    Kaster MP, Rosa AO, Rosso MM, Goulart EC, Santos AR, Rodrigues AL (2004) Adenosine administration produces an antidepressant-like effect in mice: evidence for the involvement of A1 and A2A receptors. Neurosci Lett 355(1–2):21–24PubMedCrossRefGoogle Scholar
  22. 22.
    Martins DF, Mazzardo-Martins L, Soldi F, Stramosk J, Piovezan AP, Santos AR (2013) High-intensity swimming exercise reduces neuropathic pain in an animal model of complex regional pain syndrome type I: evidence for a role of the adenosinergic system. Neuroscience 3(234):69–76CrossRefGoogle Scholar
  23. 23.
    Porsolt RD, Bertin A, Jalfre M (1977) Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn Ther 229(2):327–336PubMedGoogle Scholar
  24. 24.
    Kaster MP, Budni J, Binfare RW, Santos AR, Rodrigues AL (2007) The inhibition of different types of potassium channels underlies the antidepressant-like effect of adenosine in the mouse forced swimming test. Prog Neuropsychopharmacol Biol Psychiatry 31(3):690–696PubMedCrossRefGoogle Scholar
  25. 25.
    Steru L, Chermat R, Thierry B, Simon P (1985) The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology 85(3):367–370PubMedCrossRefGoogle Scholar
  26. 26.
    Posser T, Kaster MP, Barauna SC, Rocha JB, Rodrigues AL, Leal RB (2009) Antidepressant-like effect of the organoselenium compound ebselen in mice: evidence for the involvement of the monoaminergic system. Eur J Pharmacol 602(1):85–91PubMedCrossRefGoogle Scholar
  27. 27.
    Bai F, Li X, Clay M, Lindstrom T, Skolnick P (2001) Intra- and interstrain differences in models of “behavioral despair”. Pharmacol Biochem Behav 70:187–192PubMedCrossRefGoogle Scholar
  28. 28.
    Bettio LE, Cunha MP, Budni J, Pazini FL, Oliveira A, Colla AR, Rodrigues AL (2012) Guanosine produces an antidepressant-like effect through the modulation of NMDA receptors, nitric oxide-cGMP and PI3K/mTOR pathways. Behav Brain Res 234(2):137–148PubMedCrossRefGoogle Scholar
  29. 29.
    Eckeli AL, Dach F, Rodrigues AL (2000) Acute treatments with GMP produce antidepressant-like effects in mice. Neuroreport 11(9):1839–1843PubMedCrossRefGoogle Scholar
  30. 30.
    Deng YH, Kuang SJ, Hei MY, Tian L (2006) Effects of inosine on neuronal apoptosis and the expression of cytochrome C mRNA following hypoxic–ischemic brain damage in neonatal rats. Chinese J Contemp Ped 8(4):266–271Google Scholar
  31. 31.
    Wu MM, You SW, Hou B, Jiao XY, Li YY, Ju G (2003) Effects of inosine on axonal regeneration of axotomized retinal ganglion cells in adult rats. Neurosci Lett 341(1):84–86PubMedCrossRefGoogle Scholar
  32. 32.
    Starling RD, Trappe TA, Short KR, Sheffield-Moore M, Jozsi AC, Fink WJ, Costill DL (1996) Effect of inosine supplementation on aerobic and anaerobic cycling performance. Med Science SportsExerc 28(9):1193–1198CrossRefGoogle Scholar
  33. 33.
    McNaughton L, Dalton B, Tarr J (1999) Inosine supplementation has no effect on aerobic or anaerobic cycling performance. Int J Sport Nut 9(4):333–344Google Scholar
  34. 34.
    Lobato KR, Binfare RW, Budni J, Rosa AO, Santos AR, Rodrigues AL (2008) Involvement of the adenosine A1 and A2A receptors in the antidepressant-like effect of zinc in the forced swimming test. Prog Neuro-Psychopharmacol Biol Psych 32(4):994–999CrossRefGoogle Scholar
  35. 35.
    Gao Z, Li BS, Day YJ, Linden J (2001) A3 adenosine receptor activation triggers phosphorylation of protein kinase B and protects rat basophilic leukemia 2H3 mast cells from apoptosis. Mol Pharmacol 59(1):76–82PubMedGoogle Scholar
  36. 36.
    Szabo C, Dawson VL (1998) Role of poly(ADP-ribose) synthetase in inflammation and ischaemia-reperfusion. Trends Pharmacol Sci 19(7):287–298PubMedCrossRefGoogle Scholar
  37. 37.
    Ames BN, Cathcart R, Schwiers E, Hochstein P (1981) Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proc Natl Acad Sci U S A 78(11):6858–6862PubMedCrossRefGoogle Scholar
  38. 38.
    Becker BF, Reinholz N, Ozcelik T, Leipert B, Gerlach E (1989) Uric acid as radical scavenger and antioxidant in the heart. Pflugers Arch 415(2):127–135PubMedCrossRefGoogle Scholar
  39. 39.
    Wen S, Cheng M, Wang H, Yue J, Wang H, Li G, Zheng L, Zhong Z, Peng F (2012) Serum uric acid levels and the clinical characteristics of depression. Clinical Biochem 45(1–2):49–53CrossRefGoogle Scholar
  40. 40.
    Pastor-Anglada M, Casado FJ, Valdes R, Mata J, Garcia-Manteiga J, Molina M (2001) Complex regulation of nucleoside transporter expression in epithelial and immune system cells. Mol Mem Biol 18(1):81–85CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Manuella P. Kaster
    • 3
    • 4
    Email author
  • Josiane Budni
    • 1
  • Marta Gazal
    • 3
  • Mauricio P. Cunha
    • 1
  • Adair R. S. Santos
    • 2
  • Ana Lúcia S. Rodrigues
    • 1
  1. 1.Department of Biochemistry Center of Biological SciencesUniversidade Federal de Santa CatarinaFlorianópolisBrazil
  2. 2.Laboratory of Neurobiology of Pain and Inflammation, Department of Physiological Sciences, Center of Biological SciencesUniversidade Federal de Santa CatarinaFlorianópolisBrazil
  3. 3.Department of Life and Health SciencesUniversidade Católica de Pelotas (UCPel)PelotasBrazil
  4. 4.Universidade Católica de PelotasPelotasBrazil

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