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Creatine, Similar to Ketamine, Counteracts Depressive-Like Behavior Induced by Corticosterone via PI3K/Akt/mTOR Pathway

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Abstract

Ketamine has emerged as a novel strategy to treat refractory depression, producing rapid remission, but elicits some side effects that limit its use. In an attempt to investigate a safer compound that may afford an antidepressant effect similar to ketamine, this study examined the effects of the ergogenic compound creatine in a model of depression, and the involvement of phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway in its effect. In order to induce a depressive-like behavior, mice were administered with corticosterone (20 mg/kg, per os (p.o.)) for 21 days. This treatment increased immobility time in the tail suspension test (TST), an effect abolished by a single administration of creatine (10 mg/kg, p.o.) or ketamine (1 mg/kg, i.p.), but not by fluoxetine (10 mg/kg, p.o., conventional antidepressant). Treatment of mice with wortmannin (PI3K inhibitor, 0.1 μg/site, intracerebroventricular (i.c.v.)) or rapamycin (mTOR inhibitor, 0.2 nmol/site, i.c.v.) abolished the anti-immobility effect of creatine and ketamine. None of the treatments affected locomotor activity of mice. The immunocontents of p-mTOR, p-p70S6 kinase (p70S6K), and postsynaptic density-95 protein (PSD95) were increased by creatine and ketamine in corticosterone or vehicle-treated mice. Moreover, corticosterone-treated mice presented a decreased hippocampal brain-derived neurotrophic factor (BDNF) level, an effect abolished by creatine or ketamine. Altogether, the results indicate that creatine shares with ketamine the ability to acutely reverse the corticosterone-induced depressive-like behavior by a mechanism dependent on PI3K/AKT/mTOR pathway, and modulation of the synaptic protein PSD95 as well as BDNF in the hippocampus, indicating the relevance of targeting these proteins for the management of depressive disorders. Moreover, we suggest that creatine should be further investigated as a possible fast-acting antidepressant.

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Abbreviations

Akt/PKB:

Protein kinase B

AMPA:

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

ANOVA:

Analysis of variance

BDNF:

Brain-derived neurotrophic factor

CORT:

Corticosterone

DMSO:

Dimethyl sulfoxide

ERK:

Extracellular signal-regulated kinase

FST:

Forced swimming test

GluA1:

AMPA receptor subunit

HPA:

Hypothalamic pituitary adrenal

i.c.v.:

Intracerebroventricular

i.p.:

Intraperitoneal

MEK:

Mitogen-activated protein kinase

mTOR:

Mammalian target of rapamycin

NMDA:

N-methyl d-aspartate

OD:

Optical density

OFT:

Open field test

p.o.:

per os

p70S6K:

p70S6 kinase

PI3K:

Phosphatidylinositol-3-kinase

PSD95:

Postsynaptic density-95 protein

TrkB:

Tropomyosin-related kinase receptor B

TST:

Tail suspension test.

References

  1. Kessler RC, Berglund P, Demler O, Jin R, Koretz D, Merikangas KR, Rush AJ, Walters EE et al (2003) The epidemiology of major depressive disorder: results from the national comorbidity survey replication (NCS-R). JAMA 289(23):3095–3105. doi:10.1001/jama.289.23.3095

    Article  PubMed  Google Scholar 

  2. Holden C (2005) Sex and the suffering brain. Science 308(5728):1574. doi:10.1126/science.308.5728.1574

    Article  CAS  PubMed  Google Scholar 

  3. Nakajima S, Suzuki T, Watanabe K, Kashima H, Uchida H (2010) Accelerating response to antidepressant treatment in depression: a review and clinical suggestions. Prog Neuropsychopharmacol Biol Psychiatry 34(2):259–264. doi:10.1016/j.pnpbp.2009.12.001

    Article  CAS  PubMed  Google Scholar 

  4. Axelson DA, Doraiswamy PM, McDonald WM, Boyko OB, Tupler LA, Patterson LJ, Nemeroff CB, Ellinwood EH Jr et al (1993) Hypercortisolemia and hippocampal changes in depression. Psychiatry Res 47(2):163–173. doi:10.1016/0165-1781(93)90046-J

    Article  CAS  PubMed  Google Scholar 

  5. Sterner EY, Kalynchuk LE (2010) Behavioral and neurobiological consequences of prolonged glucocorticoid exposure in rats: relevance to depression. Prog Neuropsychopharmacol Biol Psychiatry 34(5):777–790. doi:10.1016/j.pnpbp.2010.03.005

    Article  CAS  PubMed  Google Scholar 

  6. Gourley SL, Kiraly DD, Howell JL, Olausson P, Taylor JR (2008) Acute hippocampal brain-derived Neurotrophic factor restores motivational and forced swim performance after corticosterone. Biol Psychiatry 64(10):884–890. doi:10.1016/j.biopsych.2008.06.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Hellsten J, Wennstrom M, Mohapel P, Ekdahl CT, Bengzon J, Tingstrom A (2002) Electroconvulsive seizures increase hippocampal neurogenesis after chronic corticosterone treatment. Eur J Neurosci 16(2):283–290. doi:10.1046/j.1460-9568.2002.02093.x

    Article  PubMed  Google Scholar 

  8. Zhao Y, Xie W, Dai J, Wang Z, Huang Y (2009) The varying effects of short-term and long-term corticosterone injections on depression-like behavior in mice. Brain Res 1261:82–90. doi:10.1016/j.brainres.2008.12.083

    Article  CAS  PubMed  Google Scholar 

  9. Morales-Medina JC, Sanchez F, Flores G, Dumont Y, Quirion R (2009) Morphological reorganization after repeated corticosterone administration in the hippocampus, nucleus accumbens and amygdala in the rat. J Chem Neuroanat 38(4):266–272. doi:10.1016/j.jchemneu.2009.05.009

    Article  CAS  PubMed  Google Scholar 

  10. Alfarez DN, De Simoni A, Velzing EH, Bracey E, Joels M, Edwards FA, Krugers HJ (2009) Corticosterone reduces dendritic complexity in developing hippocampal CA1 neurons. Hippocampus 19(9):828–836. doi:10.1002/hipo.20566

    Article  CAS  PubMed  Google Scholar 

  11. Dwivedi Y, Rizavi HS, Pandey GN (2006) Antidepressants reverse corticosterone-mediated decrease in brain-derived neurotrophic factor expression: differential regulation of specific exons by antidepressants and corticosterone. Neuroscience 139(3):1017–1029. doi:10.1016/j.neuroscience.2005.12.058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Huang Z, Zhong XM, Li ZY, Feng CR, Pan AJ, Mao QQ (2011) Curcumin reverses corticosterone-induced depressive-like behavior and decrease in brain BDNF levels in rats. Neurosci Lett 493(3):145–148. doi:10.1016/j.neulet.2011.02.030

    Article  CAS  PubMed  Google Scholar 

  13. Jacobsen JP, Mork A (2006) Chronic corticosterone decreases brain-derived neurotrophic factor (BDNF) mRNA and protein in the hippocampus, but not in the frontal cortex, of the rat. Brain Res 1110(1):221–225. doi:10.1016/j.brainres.2006.06.077

    Article  CAS  PubMed  Google Scholar 

  14. Mao QQ, Huang Z, Zhong XM, Xian YF, Ip SP (2014) Piperine reverses the effects of corticosterone on behavior and hippocampal BDNF expression in mice. Neurochem Int 74:36–41. doi:10.1016/j.neuint.2014.04.017

    Article  CAS  PubMed  Google Scholar 

  15. Kunugi H, Hori H, Adachi N, Numakawa T (2010) Interface between hypothalamic-pituitary-adrenal axis and brain-derived neurotrophic factor in depression. Psychiatry Clinical Neurosci 64(5):447–459. doi:10.1111/j.1440-1819.2010.02135.x

    Article  CAS  Google Scholar 

  16. David DJ, Samuels BA, Rainer Q, Wang JW, Marsteller D, Mendez I, Drew M, Craig DA et al (2009) Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression. Neuron 62(4):479–493. doi:10.1016/j.neuron.2009.04.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Gourley SL, Taylor JR (2009) Recapitulation and reversal of a persistent depression-like syndrome in rodents. Curr Protoc Neurosci 9:32. doi:10.1002/0471142301.ns0932s49

    PubMed  Google Scholar 

  18. Jernigan CS, Goswami DB, Austin MC, Iyo AH, Chandran A, Stockmeier CA, Karolewicz B (2011) The mTOR signaling pathway in the prefrontal cortex is compromised in major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 35(7):1774–1779. doi:10.1016/j.pnpbp.2011.05.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Szewczyk B, Palucha-Poniewiera A, Poleszak E, Pilc A, Nowak G (2012) Investigational NMDA receptor modulators for depression. Expert Opin Investig Drugs 21(1):91–102. doi:10.1517/13543784.2012.638916

    Article  CAS  PubMed  Google Scholar 

  20. Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH (2000) Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 47(4):351–354. doi:10.1016/S0006-3223(99)00230-9

    Article  CAS  PubMed  Google Scholar 

  21. Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK (2006) A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 63(8):856–864. doi:10.1001/archpsyc.63.8.856

    Article  CAS  PubMed  Google Scholar 

  22. Li N, Liu RJ, Dwyer JM, Banasr M, Lee B, Son H, Li XY, Aghajanian G, Duman RS (2011) Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry 69(8):754–761. doi:10.1016/j.biopsych.2010.12.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, Li XY, Aghajanian G, Duman RS (2010) mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329(5994):959–964. doi:10.1126/science.1190287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zhou W, Wang N, Yang C, Li XM, Zhou ZQ, Yang JJ (2014) Ketamine-induced antidepressant effects are associated with AMPA receptors-mediated upregulation of mTOR and BDNF in rat hippocampus and prefrontal cortex. Eur Psychiatry 29(7):419–423. doi:10.1016/j.eurpsy.2013.10.005

    Article  CAS  PubMed  Google Scholar 

  25. Hoeffer CA, Klann E (2010) mTOR signaling: at the crossroads of plasticity, memory and disease. Trends Neurosci 33(2):67–75. doi:10.1016/j.tins.2009.11.003

    Article  CAS  PubMed  Google Scholar 

  26. Cantley LC (2002) The phosphoinositide 3-kinase pathway. Science 296(5573):1655–1657. doi:10.1126/science.296.5573.1655

    Article  CAS  PubMed  Google Scholar 

  27. Budni J, Lobato KR, Binfare RW, Freitas AE, Costa AP, Martin-de-Saavedra MD, Leal RB, Lopez MG et al (2012) Involvement of PI3K, GSK-3beta and PPARgamma in the antidepressant-like effect of folic acid in the forced swimming test in mice. J Psychopharmacol 26(5):714–723. doi:10.1177/0269881111424456

    Article  CAS  PubMed  Google Scholar 

  28. Horwood JM, Dufour F, Laroche S, Davis S (2006) Signalling mechanisms mediated by the phosphoinositide 3-kinase/Akt cascade in synaptic plasticity and memory in the rat. Eur J Neurosci 23(12):3375–3384. doi:10.1111/j.1460-9568.2006.04859.x

    Article  PubMed  Google Scholar 

  29. Abdallah CG, Averill LA, Krystal JH (2015) Ketamine as a promising prototype for a new generation of rapid-acting antidepressants. Ann NY Acad Sci 1344:66–77. doi:10.1111/nyas.12718

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Cunha MP, Martin-de-Saavedra MD, Romero A, Egea J, Ludka FK, Tasca CI, Farina M, Rodrigues AL et al. (2014) Both creatine and its product phosphocreatine reduce oxidative stress and afford neuroprotection in an in vitro Parkinson's model. ASN Neuro 6 (6). doi:10.1177/1759091414554945.

  31. Cunha MP, Martin-de-Saavedra MD, Romero A, Parada E, Egea J, Del Barrio L, Rodrigues AL, Lopez MG (2013) Protective effect of creatine against 6-hydroxydopamine-induced cell death in human neuroblastoma SH-SY5Y cells: involvement of intracellular signaling pathways. Neuroscience 238:185–194. doi:10.1016/j.neuroscience.2013.02.030

    Article  CAS  PubMed  Google Scholar 

  32. Cunha MP, Pazini FL, Ludka FK, Rosa JM, Oliveira A, Budni J, Ramos-Hryb AB, Lieberknecht V, Bettio LE, Martin-de-Saavedra MD, Lopez MG, Tasca CI, Rodrigues AL (2015) The modulation of NMDA receptors and L-arginine/nitric oxide pathway is implicated in the anti-immobility effect of creatine in the tail suspension test. Amino Acids 47(4):795–811. doi:10.1007/s00726-014-1910-0

    Article  CAS  PubMed  Google Scholar 

  33. Allen PJ, D'Anci KE, Kanarek RB, Renshaw PF (2010) Chronic creatine supplementation alters depression-like behavior in rodents in a sex-dependent manner. Neuropsychopharmacology 35(2):534–546. doi:10.1038/npp.2009.160

    Article  CAS  PubMed  Google Scholar 

  34. Cunha MP, Machado DG, Capra JC, Jacinto J, Bettio LEB, Rodrigues ALS (2012) Antidepressant-like effect of creatine in mice involves dopaminergic activation. J Psychopharmacol 26(11):1489–1501. doi:10.1177/0269881112447989

    Article  CAS  PubMed  Google Scholar 

  35. Cunha MP, Pazini FL, Oliveira A, Bettio LEB, Rosa JM, Machado DG, Rodrigues ALS (2013) The activation of α1-adrenoceptors is implicated in the antidepressant-like effect of creatine in the tail suspension test. Prog Neuropsychopharmacol Biol Psychiatry 44:39–50. doi:10.1016/j.pnpbp.2013.01.014

    Article  CAS  PubMed  Google Scholar 

  36. Cunha MP, Pazini FL, Oliveira A, Machado DG, Rodrigues AL (2013) Evidence for the involvement of 5-HT1A receptor in the acute antidepressant-like effect of creatine in mice. Brain Res Bull 95:61–69. doi:10.1016/j.brainresbull.2013.01.005

    Article  CAS  PubMed  Google Scholar 

  37. Kondo DG, Sung YH, Hellem TL, Fiedler KK, Shi X, Jeong EK, Renshaw PF (2011) Open-label adjunctive creatine for female adolescents with SSRI-resistant major depressive disorder: a 31-phosphorus magnetic resonance spectroscopy study. J Affect Dis 135(1–3):354–361. doi:10.1016/j.jad.2011.07.010

    Article  PubMed  PubMed Central  Google Scholar 

  38. Lyoo IK, Yoon S, Kim TS, Hwang J, Kim JE, Won W, Bae S, Renshaw PF (2012) A randomized, double-blind placebo-controlled trial of oral creatine monohydrate augmentation for enhanced response to a selective serotonin reuptake inhibitor in women with major depressive disorder. Am J Psychiatry 169(9):937–945. doi:10.1176/appi.ajp.2012.12010009

    Article  PubMed  PubMed Central  Google Scholar 

  39. Cunha MP, Budni J, Ludka FK, Pazini FL, Rosa JM, Oliveira A, Lopes MW, Tasca CI et al (2015) Involvement of PI3K/Akt signaling pathway and its downstream intracellular targets in the antidepressant-like effect of creatine. Mol Neurobiol. doi:10.1007/s12035-015-9192-4

    Google Scholar 

  40. Sheline YI, Wang PW, Gado MH, Csernansky JG, Vannier MW (1996) Hippocampal atrophy in recurrent major depression. Proc Nat Ac Sci USA 93(9):3908–3913

    Article  CAS  Google Scholar 

  41. Kaster MP, Gadotti VM, Calixto JB, Santos AR, Rodrigues AL (2012) Depressive-like behavior induced by tumor necrosis factor-alpha in mice. Neuropharmacology 62(1):419–426. doi:10.1016/j.neuropharm.2011.08.018

    Article  CAS  PubMed  Google Scholar 

  42. Ago Y, Arikawa S, Yata M, Yano K, Abe M, Takuma K, Matsuda T (2008) Antidepressant-like effects of the glucocorticoid receptor antagonist RU-43044 are associated with changes in prefrontal dopamine in mouse models of depression. Neuropharmacology 55(8):1355–1363. doi:10.1016/j.neuropharm.2008.08.026

    Article  CAS  PubMed  Google Scholar 

  43. 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):137–148. doi:10.1016/j.bbr.2012.06.021

    Article  CAS  PubMed  Google Scholar 

  44. Ludka FK, Zomkowski AD, Cunha MP, Dal-Cim T, Zeni AL, Rodrigues AL, Tasca CI (2013) Acute atorvastatin treatment exerts antidepressant-like effect in mice via the L-arginine-nitric oxide-cyclic guanosine monophosphate pathway and increases BDNF levels. Eur Neuropsychopharmacol 23(5):400–412. doi:10.1016/j.euroneuro.2012.05.005

    Article  CAS  PubMed  Google Scholar 

  45. 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(1–2):113–120. doi:10.1016/j.ejphar.2007.12.005

    Article  CAS  PubMed  Google Scholar 

  46. 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 127:1–6. doi:10.1016/j.pbb.2014.10.003

    Article  CAS  PubMed  Google Scholar 

  47. Steru L, Chermat R, Thierry B, Simon P (1985) The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology 85(3):367–370

    Article  CAS  PubMed  Google Scholar 

  48. 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(3):150–156

    Article  CAS  PubMed  Google Scholar 

  49. Peterson GL (1977) A simplification of the protein assay method of Lowry et al. which is more generally applicable. Anal Biochem 83(2):346–356

    Article  CAS  PubMed  Google Scholar 

  50. Cordova FM, Aguiar AS, Peres TV, Lopes MW, Gonçalves FM, Remor AP, Lopes SC, Pilati C et al (2012) In vivo manganese exposure modulates Erk, Akt and Darpp-32 in the striatum of developing rats, and impairs their motor function. PLoS One 7(3):e33057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Dwyer JM, Lepack AE, Duman RS (2012) mTOR activation is required for the antidepressant effects of mGluR(2)/(3) blockade. Neuropsychopharmacology 15(4):429–434. doi:10.1017/S1461145711001702

    Article  CAS  Google Scholar 

  52. Yang PC, Yang CH, Huang CC, Hsu KS (2008) Phosphatidylinositol 3-kinase activation is required for stress protocol-induced modification of hippocampal synaptic plasticity. J Biol Chem 283(5):2631–2643. doi:10.1074/jbc.M706954200

    Article  CAS  PubMed  Google Scholar 

  53. Watanabe K, Hashimoto E, Ukai W, Ishii T, Yoshinaga T, Ono T, Tateno M, Watanabe I et al (2010) Effect of antidepressants on brain-derived neurotrophic factor (BDNF) release from platelets in the rats. Prog Neuropsychopharmacol Biol Psychiatry 34(8):1450–1454. doi:10.1016/j.pnpbp.2010.07.036

    Article  CAS  PubMed  Google Scholar 

  54. Rainer Q, Nguyen HT, Quesseveur G, Gardier AM, David DJ, Guiard BP (2012) Functional status of somatodendritic serotonin 1A autoreceptor after long-term treatment with fluoxetine in a mouse model of anxiety/depression based on repeated corticosterone administration. Mol Pharmacol 81(2):106–112. doi:10.1124/mol.111.075796

    Article  CAS  PubMed  Google Scholar 

  55. Rainer Q, Xia L, Guilloux JP, Gabriel C, Mocaer E, Hen R, Enhamre E, Gardier AM et al (2012) Beneficial behavioural and neurogenic effects of agomelatine in a model of depression/anxiety. Neuropsychopharmacology 15(3):321–335. doi:10.1017/S1461145711000356

    Article  CAS  Google Scholar 

  56. Conrad CD, McLaughlin KJ, Harman JS, Foltz C, Wieczorek L, Lightner E, Wright RL (2007) Chronic glucocorticoids increase hippocampal vulnerability to neurotoxicity under conditions that produce CA3 dendritic retraction but fail to impair spatial recognition memory. J Neurosci 27(31):8278–8285. doi:10.1523/JNEUROSCI.2121-07.2007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Qiu G, Helmeste DM, Samaranayake AN, Lau WM, Lee TM, Tang SW, So KF (2007) Modulation of the suppressive effect of corticosterone on adult rat hippocampal cell proliferation by paroxetine. Neurosci Bull 23(3):131–136. doi:10.1007/s12264-007-0019-9

    Article  PubMed  Google Scholar 

  58. Nemets B, Levine J (2013) A pilot dose-finding clinical trial of creatine monohydrate augmentation to SSRIs/SNRIs/NASA antidepressant treatment in major depression. Int Clin Psychopharmacol 28(3):127–133. doi:10.1097/YIC.0b013e32835ff20f

    Article  PubMed  Google Scholar 

  59. Roitman S, Green T, Osher Y, Karni N, Levine J (2007) Creatine monohydrate in resistant depression: a preliminary study. Bipolar Dis 9(7):754–758. doi:10.1111/j.1399-5618.2007.00532.x

    Article  CAS  Google Scholar 

  60. Trivedi MH, Fava M, Wisniewski SR, Thase ME, Quitkin F, Warden D, Ritz L, Nierenberg AA et al (2006) Medication augmentation after the failure of SSRIs for depression. N Eng J Med 354(12):1243–1252. doi:10.1056/NEJMoa052964

    Article  CAS  Google Scholar 

  61. Duman RS, Voleti B (2012) Signaling pathways underlying the pathophysiology and treatment of depression: novel mechanisms for rapid-acting agents. Trends Neurosci 35(1):47–56. doi:10.1016/j.tins.2011.11.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Duman RS, Li N, Liu RJ, Duric V, Aghajanian G (2012) Signaling pathways underlying the rapid antidepressant actions of ketamine. Neuropharmacology 62(1):35–41. doi:10.1016/j.neuropharm.2011.08.044

    Article  CAS  PubMed  Google Scholar 

  63. Covvey JR, Crawford AN, Lowe DK (2012) Intravenous ketamine for treatment-resistant major depressive disorder. Ann Pharmacother 46(1):117–123. doi:10.1345/aph.1Q371

    Article  CAS  PubMed  Google Scholar 

  64. Hou LF, Klann E (2004) Activation of the phosphoinositide 3-kinase-akt-mammalian target of rapamycin signaling pathway is required for metabotropic glutamate receptor-dependent long-term depression. J Neurosci 24(28):6352–6361. doi:10.1523/Jneurosci.0995-04.2004

    Article  CAS  PubMed  Google Scholar 

  65. Chandran A, Iyo AH, Jernigan CS, Legutko B, Austin MC, Karolewicz B (2013) Reduced phosphorylation of the mTOR signaling pathway components in the amygdala of rats exposed to chronic stress. Prog Neuropsychopharmacol Biol Psychiatry 40:240–245. doi:10.1016/j.pnpbp.2012.08.001

    Article  CAS  PubMed  Google Scholar 

  66. Zhong P, Wang W, Pan B, Liu X, Zhang Z, Long JZ, Zhang HT, Cravatt BF et al (2014) Monoacylglycerol lipase inhibition blocks chronic stress-induced depressive-like behaviors via activation of mTOR signaling. Neuropsychopharmacology 39(7):1763–1776. doi:10.1038/npp.2014.24

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Howell KR, Kutiyanawalla A, Pillai A (2011) Long-term continuous corticosterone treatment decreases VEGF receptor-2 expression in frontal cortex. PLoS One 6(5), e20198. doi:10.1371/journal.pone.0020198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Feyissa AM, Chandran A, Stockmeier CA, Karolewicz B (2009) Reduced levels of NR2A and NR2B subunits of NMDA receptor and PSD-95 in the prefrontal cortex in major depression. Prog Neuropsychopharmacol Biol Psychiatry 33(1):70–75. doi:10.1016/j.pnpbp.2008.10.005

    Article  CAS  PubMed  Google Scholar 

  69. Aydemir C, Yalcin ES, Aksaray S, Kisa C, Yildirim SG, Uzbay T, Goka E (2006) Brain-derived neurotrophic factor (BDNF) changes in the serum of depressed women. Prog Neuropsychopharmacol Biol Psychiatry 30(7):1256–1260. doi:10.1016/j.pnpbp.2006.03.025

    Article  CAS  PubMed  Google Scholar 

  70. Aydemir O, Deveci A, Taskin OE, Taneli F, Esen-Danaci A (2007) Serum brain-derived neurotrophic factor level in dysthymia: a comparative study with major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 31(5):1023–1026. doi:10.1016/j.pnpbp.2007.02.013

    Article  CAS  PubMed  Google Scholar 

  71. Dwivedi Y (2010) Brain-derived neurotrophic factor and suicide pathogenesis. Ann Med 42(2):87–96. doi:10.3109/07853890903485730

    Article  PubMed  PubMed Central  Google Scholar 

  72. Basterzi AD, Yazici K, Aslan E, Delialioglu N, Tasdelen B, Tot Acar S, Yazici A (2009) Effects of fluoxetine and venlafaxine on serum brain derived neurotrophic factor levels in depressed patients. Prog Neuropsychopharmacol Biol Psychiatry 33(2):281–285. doi:10.1016/j.pnpbp.2008.11.016

    Article  CAS  PubMed  Google Scholar 

  73. Li S, Wang C, Wang M, Li W, Matsumoto K, Tang Y (2007) Antidepressant like effects of piperine in chronic mild stress treated mice and its possible mechanisms. Life Sci 80(15):1373–1381. doi:10.1016/j.lfs.2006.12.027

    Article  CAS  PubMed  Google Scholar 

  74. Mao QQ, Xian YF, Ip SP, Tsai SH, Che CT (2010) Long-term treatment with peony glycosides reverses chronic unpredictable mild stress-induced depressive-like behavior via increasing expression of neurotrophins in rat brain. Behav Brain Res 210(2):171–177. doi:10.1016/j.bbr.2010.02.026

    Article  CAS  PubMed  Google Scholar 

  75. Cryan JF, O'Leary OF (2010) Neuroscience. A glutamate pathway to faster-acting antidepressants? Science 329(5994):913–914. doi:10.1126/science.1194313

    Article  CAS  PubMed  Google Scholar 

  76. Hill AS, Sahay A, Hen R (2015) Increasing adult hippocampal neurogenesis is sufficient to reduce anxiety and depression-like behaviors. Neuropsychopharmacology 40(10):2368–2378. doi:10.1038/npp.2015.85

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. O'Keane V, Frodl T, Dinan TG (2012) A review of atypical depression in relation to the course of depression and changes in HPA axis organization. Psychoneuroendocrinology 37(10):1589–1599. doi:10.1016/j.psyneuen.2012.03.009

    Article  CAS  PubMed  Google Scholar 

  78. Broadbear JH, Winger G, Woods JH (2004) Self-administration of fentanyl, cocaine and ketamine: effects on the pituitary-adrenal axis in rhesus monkeys. Psychopharmacology 176(3–4):398–406. doi:10.1007/s00213-004-1891-x

    Article  CAS  PubMed  Google Scholar 

  79. Khalili-Mahani N, Martini CH, Olofsen E, Dahan A, Niesters M (2015) Effect of subanaesthetic ketamine on plasma and saliva cortisol secretion. Brit J Anaesth 115(1):68–75. doi:10.1093/bja/aev135

    Article  CAS  PubMed  Google Scholar 

  80. Akbas M, Akbas H, Yegin A, Sahin N, Titiz TA (2005) Comparison of the effects of clonidine and ketamine added to ropivacaine on stress hormone levels and the duration of caudal analgesia. Paediatric Anaesth 15(7):580–585. doi:10.1111/j.1460-9592.2005.01506.x

    Article  Google Scholar 

  81. Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB Jr et al (1994) Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 51(3):199–214. doi:10.1001/archpsyc.1994.03950030035004

    Article  CAS  PubMed  Google Scholar 

  82. van Berckel BN, Oranje B, van Ree JM, Verbaten MN, Kahn RS (1998) The effects of low dose ketamine on sensory gating, neuroendocrine secretion and behavior in healthy human subjects. Psychopharmacology 137(3):271–281. doi:10.1007/s002130050620

    Article  PubMed  Google Scholar 

  83. dos Santos FS, da Silva LA, Pochapski JA, Raczenski A, da Silva WC, Grassiolli S, Malfatti CR (2014) Effects of L-arginine and creatine administration on spatial memory in rats subjected to a chronic variable stress model. Pharm Biol 52(8):1033–1038. doi:10.3109/13880209.2013.876654

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, #308723/2013-9, #449436/2014-4) and Coordenação de Aperfeiçoamento de Pessoal de Ensino Superior (CAPES). NENASC Project (PRONEX-FAPESC/CNPq) # 1262/2012-9.

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  1. Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, Florianópolis, Santa Catarina, 88040-900, Brazil

    Francis L. Pazini, Mauricio P. Cunha, Julia M. Rosa, André R. S. Colla, Vicente Lieberknecht, Ágatha Oliveira & Ana Lúcia S. Rodrigues

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  1. Francis L. Pazini
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  2. Mauricio P. Cunha
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  7. Ana Lúcia S. Rodrigues
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Correspondence to Ana Lúcia S. Rodrigues.

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Pazini, F.L., Cunha, M.P., Rosa, J.M. et al. Creatine, Similar to Ketamine, Counteracts Depressive-Like Behavior Induced by Corticosterone via PI3K/Akt/mTOR Pathway. Mol Neurobiol 53, 6818–6834 (2016). https://doi.org/10.1007/s12035-015-9580-9

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