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Inhibition of neuronal nitric oxide synthase in the rat hippocampus induces antidepressant-like effects

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Abstract

Rationale

Systemic inhibition of neuronal nitric oxide synthase (nNOS) induces antidepressant-like effects in rodents. The mechanisms and brain regions mediating this effect are still unknown. The hippocampus is a brain region proposed to mediate adaptation to stress and antidepressant behavioral effects. Therefore, it could be involved in the antidepressant effects of NOS inhibitors.

Objectives

To test the hypothesis that nNOS inhibition in the dorsal hippocampus will induce antidepressant-like effects in the forced swimming test (FST) in rats.

Methods

Rats implanted with cannulas aimed at the dorsal hippocampus were submitted to 15 min of forced swimming (pretest). Immediately before or after pretest they received bilateral microinjections of the nNOS inhibitor 7-nitroindazole (7-NI; 50, 100, or 200 nmol/0.5 μl) or vehicle, alone or combined with l-arginine. Additional groups received SIN-1 (125 or 250 nmol/0.5 μl), a NO donor, either before or after the pretest. Twenty-four hours later, immobility time was registered for 5 min in the FST.

Results

7-NI (100 nmol) significantly decreased immobility time when administered either before or after pretest. Pretreatment with l-arginine (100 nmol/0.5 μl) prevented these effects but produced no significant effects per se. SIN-1 did not induce any significant effect.

Conclusion

These data suggest that the reduction of NO levels within the hippocampus can induce antidepressant-like effects; thus implicating endogenous hippocampal NO in the neurobiology of stress and depression.

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References

  • Abel EL, Bilitzke PJ (1990) A possible alarm substance in the forced swimming test. Physiol Behav 48:233–239

    Article  PubMed  Google Scholar 

  • Blier P (2003) The pharmacology of putative early-onset antidepressant strategies. Eur Neuropsychopharmacol 13:57–66

    Article  PubMed  Google Scholar 

  • Brenman JE, Bredt DS (1997) Synaptic signalling by nitric oxide. Curr Opin Neurobiol 7:374–378

    Article  PubMed  Google Scholar 

  • Burette A, Zabel U, Weinberg RJ, Schmidt HH, Valtschanoff JG (2002) Synaptic localization of nitric oxide synthase and soluble guanylyl cyclase in the hippocampus. J Neurosci 22(20):8961–8970

    PubMed  Google Scholar 

  • Bush MA, Pollack GM (2001) Pharmacokinetics and pharmacodinamics of 7-nitroindazole, a selective nitric oxide synthase inhibitor, in the rat hippocampus. Pharm Res 18(11):1607–1612

    PubMed  Google Scholar 

  • Campbell JO, Fogarty JA, Spear LP (1999) Inhibition of nitric oxide synthesis with L-NAME suppresses isolation induced ultrasounds in rat pups. Pharmacol Biochem Behav 63(1):45–53

    Article  PubMed  Google Scholar 

  • Canossa M, Giordano E, Cappello S, Guarnieri C, Ferri S (2002) Nitric oxide down-regulates brain-derived neurotrophic factor secretion in cultured hippocampal neurons. Proc Natl Acad Sci U S A 99(5):3282–3287

    Google Scholar 

  • Cárdenas A, Moro MM, Hurtado O, Leza JC, Lizasoain I (2005) Dual role of nitric oxide in adult neurogenesis. Brain Res Rev 50:1–6

    PubMed  Google Scholar 

  • Contestabile A (2000) Roles of NMDA receptor activity and nitric oxide production in brain development. Brain Res Rev 32:476–509

    Article  PubMed  Google Scholar 

  • Czech DA, Klosterman AE, Le Sueur KT (1998) N G-nitro-l-arginine methyl ester reduces stress-related feeding in the rat tail-pinch model. Pharmacol Biochem Behav 60(1):91–96

    Article  PubMed  Google Scholar 

  • Danzer SC, Crooks KR, Lo DC, McNamara JO (2002) Increased expression of brain derived neurotrophic factor induces formation o basal dendrites and axonal branching in dentate granule cells in hippocampal explanted cultures. J Neurosci 22(22):9754–9763

    PubMed  Google Scholar 

  • Dawson VL, Dawson TM, London ED, Bredt DS, Snyder SH (1991) Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures. Proc Natl Acad Sci U S A 88:6368–6371

    PubMed  Google Scholar 

  • De Oliveira RMW, Guimarães FS (1999) Anxiolytic effect of methylene blue microinjected into the dorsal periaqueductal gray. Braz J Med Biol Res 32:1529–1532

    PubMed  Google Scholar 

  • De Oliveira RMW, Deakin JF, Guimarães FS (2000) Neuronal nitric oxide synthase (NOS) expression in the hippocampal formation of patients with schizophrenia and affective disorder. J Psychopharmacol 14:8 (suppl)

    Google Scholar 

  • Doyle CA, Slater P (1997) Localization of neuronal and endothelial nitric oxide synthase isoforms in human hippocampus. Neuroscience 76(2):387–395

    Google Scholar 

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

    PubMed  Google Scholar 

  • Eroglu L, Çaglayan B (1997) Anxiolytic and antidepressant properties of methylene blue in animal models. Pharmacol Res 36(5):381–385

    PubMed  Google Scholar 

  • Esplugues JV (2002) NO as a signalling molecule in the nervous system. Br J Pharmacol 135:1079–1095

    Article  PubMed  Google Scholar 

  • Fossier P, Blanchard B, Ducrocq C, Leprince C, Tauc L, Baux G (1999) Nitric oxide transform serotonin into an inactive form and this affects neuromodulation. Neuroscience 93(2):597–603

    Article  PubMed  Google Scholar 

  • Garthwaite J, Charles SL, Chess-Williams R (1998) Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain. Nature 336(6197):385–388

    Article  Google Scholar 

  • Gould E, Tanapat P, McEwen BS, Flugge G, Fuchs E (1998) Proliferation of granule cell precursors in the dentate gyrus of adult monkeys is diminished by stress. Proc Natl Acad Sci U S A 95:3168–3171

    Article  PubMed  Google Scholar 

  • Graeff FG, Guimarães FS, Andrade GCS, Deakin JFW (1996) Role of 5-HT in stress, anxiety and depression. Pharmacol Biochem Behav 54(1):129–141

    Article  PubMed  Google Scholar 

  • Guimarães FS, De Aguiar JC, Del Bel EA, Balejjo G (1994) Anxiolytic effect of nitric oxide synthase inhibitor microinjected into the dorsal central grey. Neuroreport 5:1929–1932

    PubMed  Google Scholar 

  • Guimarães FS, Beijamini V, Moreira FA, Aguiar DC, de Lucca ACB (2005) Role of nitric oxide in brain regions related to defensive reactions. Neurosci Biobehav Rev 29(8):1313–1322

    Article  PubMed  Google Scholar 

  • Harkin AJ, Bruce KH, Craft B, Paul IA (1999) Nitric oxide synthase inhibitors have antidepressant-like properties in mice: 1-acute treatments are effective in the forced swimming test. Eur J Pharmacol 372:207–213

    Article  PubMed  Google Scholar 

  • Harkin AJ, Connor TJ, Walsh M, St Jonh N, Kelly JP (2003) Serotonergic mediation of the antidepressant-like effects of nitric oxide inhibitors. Neuropharmacology 44:616–623

    Article  PubMed  Google Scholar 

  • Harvey BH, Bothma T, Nel A, Wegener G, Stein DJ (2005) Involvement of the NMDA receptor, NO-cyclic GMP and nuclear factor K-beta in an animal model of repeated trauma. Hum Psychopharmacol 20(5):367–373

    Article  PubMed  Google Scholar 

  • Hecker M, Mitchell JA, Harris HJ, Katsura M, Thiemermann C, Vane JR (1990) Endothelial cells metabolize N G-monomethyl-l-arginine to l-citrulline and subsequently to l-arginine. Biochem Biophys Res Commun 167:1037–1043

    Article  PubMed  Google Scholar 

  • Heiberg IL, Weneger G, Rosenberg R (2002) Reduction of cGMP and nitric oxide has antidepressant-like effects in the forced swimming test in rats. Behav Brain Res 134:479–484

    Article  PubMed  Google Scholar 

  • Inan SY, Yalcin I, Aksu F (2004) Dual effects of nitric oxide in the mouse in the mouse forced swimming test: possible contribution of nitric oxide mediated serotonin release and potassium channel modulation. Pharmacol Biochem Behav 77:457–464

    Article  PubMed  Google Scholar 

  • Jefferys D, Funder J (1996) Nitric oxide modulates retention of immobility in the forced swimming test in rats. Eur J Pharmacol 295:131–135

    Article  PubMed  Google Scholar 

  • Joca SRL, Padovan CM, Guimarães FS (2003) Activation of post-synaptic 5-HT1A receptors in the dorsal hippocampus prevents learned helplessness development. Brain Res 978(1–2):177–184

    Article  PubMed  Google Scholar 

  • Karolewicz B, Bruce KH, Lee B, Paul IA (1999) Nitric oxide synthase inhibitors have antidepressant-like properties in mice. 2. Chronic treatment results in downregulation of cortical β-adrenoceptors. Eur J Pharmacol 372:215–220

    Article  PubMed  Google Scholar 

  • Kiss JP (2000) Role of nitric oxide in the regulation of monoaminergic neurotransmission. Brain Res Bull 52(6):459–466

    Article  PubMed  Google Scholar 

  • Kume T, Kouchiyama H, Kaneko S, Maeda T, Kaneko S, Akaike A, Shimohama S, Kihara T, Kimura J, Wada K, Koizumi S (1997) BDNF prevents NO mediated glutamate cytotoxicity in cultures cortical neurons. Brain Res 756:200–204

    Article  PubMed  Google Scholar 

  • Lee J, Duan W, Mattson MP (2002) Evidence that brain derived neurotrophic factor is required for basal neurogenesis and mediates, in part, the enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice. J Neurochem 82:1367–1375

    Article  PubMed  Google Scholar 

  • MacKenzie GM, Rose S, Bland-Ward PA, Moore PK, Jenner P, Marsden CD (1994) Time course of inhibition of brain nitric oxide synthase by 7-nitroindazole. Neuroreport 5:1993–1996

    PubMed  Google Scholar 

  • Malberg JE, Duman RS (2003) Cell proliferation in adult hippocampus is decreased by inescapable stress: reversal by fluoxetine treatment. Neuropsychopharmacology 28:1562–1571

    Article  PubMed  Google Scholar 

  • Masood A, Banerji B, Vijayan VK, Ray A (2004) Pharmacological and biochemical studies on the possible role of nitric oxide in stress adaptation in rats. Eur J Pharmacol 493:111–115

    Article  PubMed  Google Scholar 

  • McLeod TM, Lopez-Figueroa AL, Lopez-Figueroa MO (2001) Nitric oxide, stress and depression. Psychopharmacol Bull 35(1):24–41

    PubMed  Google Scholar 

  • Moghaddam B (1993) Stress preferentially increases extraneuronal levels of excitatory amino acids in the prefrontal cortex: comparison to hippocampus and basal ganglia. J Neurochem 60(5):1650–1657

    PubMed  Google Scholar 

  • Naylor GJ, Smith AH, Connelly P (1987) A controlled trial of methylene blue in severe depressive illness. Biol Psychiatry 22(5):657–689

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Padovan CM, Guimarães FS (2004) Antidepressant-like effects of NMDA-receptor antagonist injected into the dorsal hippocampus of rats. Pharmacol Biochem Behav 77(1):15–19

    Article  PubMed  Google Scholar 

  • Padovan CM, Del Bel EA, Guimaraes FS (2000) Behavioral effects in the elevated plus maze of an NMDA antagonist injected into the dorsal hippocampus: influence of restraint stress. Pharmacol Biochem Behav 67(2):325–330

    Article  PubMed  Google Scholar 

  • Paxinos G, Watson C (1997) The rat brain in stereotaxic coordinates, 3rd edn. Academic, San Diego

    Google Scholar 

  • Paul IA, Skolnick P (2003) Glutamate and depression. Clinical and preclinical studies. Ann N Y Acad Sci 1003:250–272

    Article  PubMed  Google Scholar 

  • Petrie RX, Reid IC, Stewart CA (2000) The N-methyl-d-aspartate receptor, synaptic plasticity, and depressive disorder. A critical review. Pharmacol Ther 87:11–25

    Article  PubMed  Google Scholar 

  • Porsolt RD, Le Pichon M, Jalfre M (1977) Depression: a new animal model sensitive to antidepressant treatment. Nature 266:730–732

    Article  PubMed  Google Scholar 

  • Prast H, Philippu A (2001) Nitric oxide as a modulator of neuronal function. Prog Neurobiol 64:51–56

    Article  PubMed  Google Scholar 

  • Rosa AO, Lin J, Calixto JB, Santos AR, Rodrigues AL (2003) Involvement of NMDA receptors and l-arginine-nitric oxide pathway in the antidepressant-like effects of zinc in mice. Behav Brain Res 144(1–2):87–93

    Article  PubMed  Google Scholar 

  • Saarelainen T, Hendolin P, Lucas G, Koponen E, Sairanen M, Macdonald E, Agerman K, Haapasalo A, Nawa H, Aloys R, Ernfors P, Castren E (2003) Activation of the TrkB neurotrophin receptor is induced by antidepressant drugs and is required for antidepressant-induced behavioral effects. J Neurosci 23 (1):349–357

    PubMed  Google Scholar 

  • Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R (2003) Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301(5634):805–809

    Article  PubMed  Google Scholar 

  • Segieth J, Fowler L, Whitton P, Pearce B (2000) Nitric oxide-mediated regulation of dopamine release in the hippocampus in vivo. Neuropharmacology 39:571–577

    Article  PubMed  Google Scholar 

  • Seo DO, Rivier C (2001) Microinfusion of a nitric oxide donor in discrete brain regions activates the hypothalamic–pituitary–adrenal axis. J Neuroendocrinol 13(11):925–933

    Article  PubMed  Google Scholar 

  • Sheline YI, Wang PW, Gado M, Csernanski JG (1996) Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci U S A 93:3908–3913

    Article  PubMed  Google Scholar 

  • Sheline YI, Gado MH, Kraemer HC (2003) Untreated depression and hippocampal volume loss. Am J Psychiatry 160(8):1516–1518

    Article  PubMed  Google Scholar 

  • Snyder SH, Ferris CD (2000) Novel neurotransmitters and their psychiatric relevance. Am J Psychiatry 157(11):1738–1751

    Article  PubMed  Google Scholar 

  • Suzuki E, Yagi G, Nakaki T, Kanba S, Asai M (2001) Elevated plasma nitrate levels in depressive states. J Affect Disord 63:221–224

    Article  PubMed  Google Scholar 

  • Titze-de-Almeida R, Lino de Oliveira C, Shida HW, Guimarães FS, Del Bel EA (1994) Midazolan and the N-methyl-d-aspartate (NMDA) receptor antagonist 2-amino-7-phosphono-heptanoic acid (AP-7) attenuate stress-induced expression of c-fos mRNA in the dentate gyrus. Cell Mol Neurobiol 14:373–380

    Article  PubMed  Google Scholar 

  • Volke V, Wegener G, Bourin M, Vasar E (2003) Antidepressant- and anxiolytic-like effects of selective neuronal NOS inhibitor 1-(2-trifluoromethylphenyl)-imidazole in mice. Behav Brain Res 140(1–2):141–147

    Article  PubMed  Google Scholar 

  • Weneger G, Volke V, Rosenberg R (2000) Endogenous nitric oxide decreases hippocampal level of serotonin and dopamine in vivo. Br J Pharmacol 130(3):575–580

    Article  PubMed  Google Scholar 

  • Wegener G, Volke V, Harvey BH, Rosenberg R (2003) Local, but not systemic, administration of serotonergic antidepressants decreases hippocampal nitric oxide synthase activity. Brain Res 959:128–134

    Article  PubMed  Google Scholar 

  • Yildiz F, Erden BF, Ulak G, Utkan T, Gacar N (2000) Antidepressant-like effect of 7-nitroindazole in the forced swimming test in rats. Psychopharmacology (Berl) 149:41–44

    Article  Google Scholar 

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Acknowledgements

The authors acknowledge J.C. de Aguiar and E.L.T. Gomes for their helpful technical assistance and L.B.M. Resstel by edition of the figures. This research was supported by grants from Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (04/01738-4, 02/13197-2) and Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (470402/2004-00).

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  1. Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, 14049-900,, Ribeirão Preto, SP, Brazil

    Sâmia Regiane Lourenço Joca & Francisco Silveira Guimarães

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  1. Sâmia Regiane Lourenço Joca
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  2. Francisco Silveira Guimarães
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Correspondence to Sâmia Regiane Lourenço Joca.

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Joca, S.R.L., Guimarães, F.S. Inhibition of neuronal nitric oxide synthase in the rat hippocampus induces antidepressant-like effects. Psychopharmacology 185, 298–305 (2006). https://doi.org/10.1007/s00213-006-0326-2

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