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Chronic administration of harmine elicits antidepressant-like effects and increases BDNF levels in rat hippocampus

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Abstract

A growing body of evidence has pointed to the β-carboline harmine as a potential therapeutic target for the treatment of major depression. The present study was aimed to evaluate behavioural and molecular effects of the chronic treatment with harmine and imipramine in rats. To this aim, rats were treated for 14 days once a day with harmine (5, 10 and 15 mg/kg) and imipramine (10, 20 and 30 mg/kg) and then subjected to the forced swimming and open-field tests. Harmine and imipramine, at all doses tested, reduced immobility time of rats compared with the saline group. Imipramine increased the swimming time at 20 and 30 mg/kg and harmine increased swimming time at all doses. The climbing time increased in rats treated with imipramine (10 and 30 mg/kg) and harmine (5 and 10 mg/kg), without affecting spontaneous locomotor activity. Brain-derived neurotrophic factor (BDNF) hippocampal levels were assessed in imipramine and harmine-treated rats by ELISA sandwich assay. Interestingly, chronic administration of harmine at the higher doses (10 and 15 mg/kg), but not imipramine, increased BDNF protein levels in rat hippocampus. Finally, these findings further support the hypothesis that harmine could bring about behavior and molecular effects, similar to antidepressants drugs.

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References

  • Assis LC, Rezin GT, Comim CM, Valvassori SS, Jereminas JC, Zugno AI, Quevedo J, Streck EL (2009) Effect of acute administration of ketamine and imipramine on creatine kinase activity in the brain of rats. Rev Bras Psiquiatr 31:247–252

    Article  PubMed  Google Scholar 

  • Berton O, Nestler EJ (2006) New approaches to antidepressant drug discovery: beyond monoamines. Nat Rev Neurosci 7:137–151

    Article  CAS  PubMed  Google Scholar 

  • Castrén E (2005) Is mood chemistry? Nat Rev Neurosci 6:241–246

    Article  PubMed  Google Scholar 

  • Castrén E, Võikar V, Rantamäki T (2007) Role of neurotrophic factors in depression. Curr Opin Pharmacol 7:18–21

    Article  PubMed  Google Scholar 

  • Chen B, Dowlatshahi D, MacQueen GM, Wang J-F, Young LT (2001) Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication. Biol Psych 50:260–265

    Article  CAS  Google Scholar 

  • De Foubert G, Carney SL, Robinson CS, Destexhe EJ, Tomlinson R, Hicks CA, Murray TK, Gaillard JP, Deville C, Xhenseval V, Thomas CE, O’Neill MJ, Zetterström TS (2004) Fluoxetine-induced change in rat brain expression of brain-derived neurotrophic factor varies depending on length of treatment. Neuroscience 128:597–604

    Article  PubMed  Google Scholar 

  • Detke MJ, Rickels M, Lucki I (1995) Active behaviors in the rat forced swimming test differentially produced by serotonergic and noradrenergic antidepressants. Psychopharmacol 121:66–72

    Article  CAS  Google Scholar 

  • Dias VG, Aguni JS, Bezzon AK (2004) Sindrome de Lyell por imipramina: relato de caso. Arg Bras Oftalmol 67:943–955

    Google Scholar 

  • Duman R (2004) Depression: a case of neuronal life and death? Biol Psychiatry 56:140–145

    Article  PubMed  Google Scholar 

  • Duman RS, Monteggia LM (2006) A neurotrophic model for stress-related mood disorders. Biol Psychiatry 59:1116–1127

    Article  CAS  PubMed  Google Scholar 

  • Duman RS, Heninger GR, Nestler EJ (1997) A molecular and cellular theory of depression. Arch Gen Psychiatry 54:597–606

    CAS  PubMed  Google Scholar 

  • Dwivedi Y, Rao JS, Hooriyah SR, Kotowski J, Conley RR, Roberts RC et al (2003) Abnormal expression and functional characteristics of cyclic adenosine monophosphate response element binding protein in postmortem brain of suicide subjects. Arch Gen Psychiatry 60:273–282

    Article  CAS  PubMed  Google Scholar 

  • Farzin D, Mansouri N (2006) Antidepressant-like effect of harmane and other β-carbolines in the mouse forced swim test. Eur Neuropsychopharmacol 324:328–316

    Google Scholar 

  • Fortunato JJ, Réus GZ, Kirsch TR, Stringari RB, Stertz L, Kapczinski F, Pinto JP, Hallak JE, Zuardi AW, Crippa JA, Quevedo J (2009) Acute harmine administration induces antidepressive-like effects and increases BDNF levels in the rat hippocampus. Prog Neuropsychopharmacol Biol Psychiatry 13:1425–1430

    Article  Google Scholar 

  • Fortunato JJ, Réus GZ, Kirsch TR, Stringari RB, Fries G, Kapczinski F, Hallak JE, Zuardi AW, Crippa JA, Quevedo J (2010) Effects of beta-carboline harmine on behavioural and physiological parameters observed in the chronic mild stress model: further evidence of antidepressant properties. Brain Res Bull 81:491–496

    Article  CAS  PubMed  Google Scholar 

  • Frey BN, Andreazza AC, Ceresér KMM, Martins MR, Valvassori SS, Réus GZ, Quevedo J, Kapczinski F (2006) Effects of mood stabilizers on hippocampus BDNF levels in an animal model of mania. Life Sci 79:281–286

    Article  CAS  PubMed  Google Scholar 

  • Garcia LB, Comim CM, Valvassori SS, Réus GZ, Barbosa LM, Andreazza AC, Stertz L, Fries G, Gavioli E, Kapczinski F, Quevedo J (2008a) Acute administration of ketamine induces antidepressant-like effects in the forced swimming test and increases BDNF levels in the rat hippocampus. Prog Psychopharmacol Biol Psychiatry 32:140–144

    Article  CAS  Google Scholar 

  • Garcia LB, Comim CM, Valvassori SS, Réus GZ, Barbosa LM, Andreazza AC, Stertz L, Fries G, Gavioli E, Kapczinski F, Quevedo J (2008b) Chronic administration of ketamine elicits antidepressant-like effects in rats without affecting hippocampal brain-derived neurotrophic factor protein levels. Bas Clin Pharmacol Toxicol 103:502–506

    Article  CAS  Google Scholar 

  • Garcia LSB, Comim CM, Valvassori SS, Réus GZ, Stertz L, Kapczinski F, Gavioli EC, Quevedo J (2009) Ketamine treatment reverses behavioral and physiological alterations induced by chronic mild stress in rats. Prog Psychopharmacol Biol Psychiatry 33:450–455

    Article  CAS  Google Scholar 

  • Glennon RA, Dukat M, Grella B, Hong S, Costantino L, Teitler M, Smith C, Egan C, Davis K, Mattson MV (2000) Binding of beta-carbolines and related agents at serotonin (5-HT(2) and 5- HT(1A)), dopamine (D(2)) and benzodiazepine receptors. Drug Alcohol Depend 60:121–132

    Article  CAS  PubMed  Google Scholar 

  • 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 64:884–890

    Article  CAS  PubMed  Google Scholar 

  • Huang EJ, Reichardt LF (2001) Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 24:677–736

    Article  CAS  PubMed  Google Scholar 

  • Husbands SM, Glennon RA, Gorgerat S, Gough R, Tyacke R, Crosby J, Nutt DJ, Lewis JW, Hudson AL (2001) Betacarboline binding to imidazoline receptors. Drug Alcohol Depend 64:203–208

    Article  CAS  PubMed  Google Scholar 

  • Karege F, Perret G, Bondolfi G, Schwald M, Bertschy G, Aubry JM (2002) Decreased serum brain-derived neurotrophic factor levels in major depressed patients. Psychiatry Res 15:143–148

    Article  Google Scholar 

  • Karege F, Vaudan G, Schwald M, Perroud N, La Harpe R (2005) Neurotrophin levels in postmortem brains of suicide victims and the effects of antemortem diagnosis and psychotropic drugs. Brain Res Mol Brain Res 136:29–37

    Article  CAS  PubMed  Google Scholar 

  • Kim H, Sablin SO, Ramsay RR (1997) Inhibition of monoamine oxidase A by beta-carboline derivatives. Arch Biochem Biophys 337:137–142

    Article  CAS  PubMed  Google Scholar 

  • Kozisek ME, Middlemas D, Bylund DB (2008) Brain-derived neurotrophic factor and its receptor tropomyosin-related kinase B in the mechanism of action of antidepressant therapies. Pharmacol Ther 117:30–51

    Article  CAS  PubMed  Google Scholar 

  • Krishnan V, Nestler EJ (2008) The molecular neurobiology of depression. Nature 455:894–902

    Article  CAS  PubMed  Google Scholar 

  • Larsen MH, Hay-Schimidt A, Ronn LC, Mikkelsen JD (2008) Temporal expression of brain-derived neurotrophic factor (BDNF) mRNA in the rat hippocampus after treatment with selective and mixed monoaminergic antidepressants. Eur J Pharmacol 578:114–122

    Article  CAS  PubMed  Google Scholar 

  • Li N, He X, Qi X, Zhang Y, He S (2010) The mood stabilizer lamotrigine produces antidepressant behavioral effects in rats: role of brain-derived neurotrophic factor. J Psychopharmacol (in press)

  • Lucca G, Comim CM, Valvassori SS, Réus GZ, Vuolo F, Petronilho F, Gavioli EC, Dal-Pizzol F, Quevedo J (2008) Increased oxidative stress in submitocondrial particles into the brain of rats submitted to the chronic mild stress paradigm. J Psychiatr Res 43:864–869

    Article  PubMed  Google Scholar 

  • Lucca G, Comim CM, Valvassori SS, Réus GZ, Vuolo F, Petronilho F, Dal-Pizzol F, Gavioli EC, Quevedo J (2009) Effects of chronic mild stress on the oxidative parameters in the rat brain. Neurochem Int 54:358–362

    Article  CAS  PubMed  Google Scholar 

  • Malberg J, Eisch AJ, Nestler EJ, Duman RS (2000) Chronic antidepressant treatment increases neurogenesis in adult hippocampus. J Neurosci 20:9104–9110

    CAS  PubMed  Google Scholar 

  • Marais L, Stein DJ, Daniels WM (2009) Exercise increases BDNF levels in the striatum and decreases depressive-like behavior in chronically stressed rats. Metab Brain Dis 24:587–597

    Article  CAS  PubMed  Google Scholar 

  • Mathers C, Loncar D (2006) Projections of global mortality, burden of disease from 2002 to 2030. PLoS Med 3:442

    Article  Google Scholar 

  • McArthur R, Borsini F (2006) Animal models of depression in drug discovery: a historical perspective. Pharmacol Biochem Behav 84:436–452

    Article  CAS  PubMed  Google Scholar 

  • Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM (2002) Neurobiology of depression. Neuron 34:13–25

    Article  CAS  PubMed  Google Scholar 

  • Nibuya M, Nestler EJ, Duman RS (1996) Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus. J Neurosci 16:2365–2372

    CAS  PubMed  Google Scholar 

  • Nowak G, Schlegel-Zawadzka M (1999) Alterations in serum and brain trace element levels after antidepressant treatment part I Zinc. Biol Trace Elem Res 67:85–92

    Article  CAS  PubMed  Google Scholar 

  • Porsolt RD, Le Pichon M, Jalfre M (1977) Animal model of depression. Nature 266:730–732

    Article  CAS  PubMed  Google Scholar 

  • Preskorn SH, Baker B, Kolluri S, Menniti FS, Krams M, Landen JW (2008) An innovative design to establish proof of concept of the antidepressant effects of the NR2B subunit selective N-Methyl-d-Aspartate antagonist, CP-101, 606, in patients with treatment-refractory major depressive disorder. J Clin Psychopharmacol 28:631–637

    Article  CAS  PubMed  Google Scholar 

  • Racagni G, Popoli M (2010) The pharmacological properties of antidepressants. Int Clin Psychopharmacol 25:117–131

    Article  PubMed  Google Scholar 

  • Shelton RC (2007) The molecular neurobiology of depression. Psychiatr Clin North Am 30:1–11

    Article  PubMed  Google Scholar 

  • Shirayama Y, Chen AC, Nakagawa S, Russell DS, Duman RS (2002) Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J Neurosci 22:3251–3261

    CAS  PubMed  Google Scholar 

  • Siuciak JA, Lewis DR, Wiegand SJ, Lindsay RM (1997) Antidepressant-like effect of brain-derived neurotrophic factor (BDNF). Pharmacol Biochem Behav 56:131–137

    Article  CAS  PubMed  Google Scholar 

  • Song Y, Kesuma D, Wang J, Deng Y, Duan J, Wang JH, Qi RZ (2004) Specific inhibition of cyclin-dependent kinases and cell proliferation by harmine. Biochem Biophys Res Commun 317:128–132

    Article  CAS  PubMed  Google Scholar 

  • Szewczyk B, Poleszak E, Sowa-Kuaema M, Siwek M, Dudek D, Ryszewska-Pokraoeniewicz B, Radziwoñ-Zaleska M, Opoka W, Czekaj J, Pilc A, Nowak G (2008) Antidepressant activity of zinc and magnesium in view of the current hypotheses of antidepressant action. Pharmacol Rep 60:588–599

    CAS  PubMed  Google Scholar 

  • Tamburella A, Micale V, Navarria A, Drago F (2009) Antidepressant properties of the 5-HT4 receptor partial agonist, SL65.0155: behavioral and neurochemical studies in rats. Prog Neuropsychoparmacol Biol Psychiatry 33:1205–1210

    Article  CAS  Google Scholar 

  • Wang X, Yang Y, Zhou X, Wu J, Li J, Jiang X, Qu Q, Ou C, Liu L, Zhou S (2010) Propofol pretreatment increases antidepressant-like effects induced by acute administration of ketamine in rats receiving forced swimming test. Psychiatry Res (in press)

  • Zarate CA Jr, Singh JB, Carson PJ, Brutshe 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 63:856–864

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported in part by grants from CNPq-Brazil (JQ, FK, JAC, AWZ, and JEH), FAPESP-Brazil (JAC, AWZ, and JEH), FAPESC-Brazil (JQ), Instituto Cérebro e Mente-Brazil (JQ and FK) and UNESC-Brazil (JQ). JQ, FK, JAC and AWZ are recipients of CNPq (Brazil) Productivity fellowships. GZR is holder of a FAPESC/CAPES studentship. This study was also sponsored by THC-Pharm (Frankfurt, Germany) and STI-Pharm (UK) who kindly provided harmine.

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Correspondence to João Quevedo.

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Fortunato, J.J., Réus, G.Z., Kirsch, T.R. et al. Chronic administration of harmine elicits antidepressant-like effects and increases BDNF levels in rat hippocampus. J Neural Transm 117, 1131–1137 (2010). https://doi.org/10.1007/s00702-010-0451-2

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  • DOI: https://doi.org/10.1007/s00702-010-0451-2

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