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Prelimbic neuronal nitric oxide synthase inhibition exerts antidepressant-like effects independently of BDNF signalling cascades

Published online by Cambridge University Press:  20 March 2019

Vitor Silva Pereira Open the ORCID record for Vitor Silva Pereira [Opens in a new window] ,
Angélica C.D. Romano Suavinha ,
Gregers Wegener  and
Sâmia R.L. Joca
Vitor Silva Pereira*
Affiliation:
Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, 8240 Risskov, Denmark School of Medicine of Ribeirão Preto, Campus USP-Ribeirão Preto, Ribeirão Preto, SP 14040-904, Brazil
Angélica C.D. Romano Suavinha
Affiliation:
Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, Campus USP-Ribeirão Preto, Ribeirão Preto, SP 14040-904, Brazil
Gregers Wegener
Affiliation:
Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, 8240 Risskov, Denmark
Sâmia R.L. Joca
Affiliation:
Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, 8240 Risskov, Denmark Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, Campus USP-Ribeirão Preto, Ribeirão Preto, SP 14040-904, Brazil Aarhus Institute of Advanced Studies (AIAS), Aarhus University, Aarhus, Denmark
*
Author for correspondence: Sâmia R.L. Joca, School of Pharmaceutical Sciences of Ribeirão Preto (FCFRP), University of Sao Paulo (USP), Sao Paulo, Brazil. E-mail: [email protected]
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Abstract

Objectives

NMDA antagonists and nitric oxide synthase (NOS) inhibitors induce antidepressant-like effects and may represent treatment options for depression. The behavioural effects of NMDA antagonists seem to depend on Tyrosine kinase B receptor (TrkB) activation by BDNF and on mechanistic target of rapamycin (mTOR), in the medial prefrontal cortex (mPFC). However, it is unknown whether similar mechanisms are involved in the behavioural effects of NOS inhibitors. Therefore, this work aimed at determining the role of TrkB and mTOR signalling in the prelimbic area of the ventral mPFC (vmPFC-PL) in the antidepressant-like effect of NOS inhibitors.

Methods

Pharmacological treatment with LY235959 or ketamine (NMDA antagonists), NPA or 7-NI (NOS inhibitors), BDNF, K252a (Trk antagonist) and rapamycin (mTOR inhibitor) injected systemically or into vmPFC-PL followed by behavioural assessment.

Results

We found that bilateral injection of BDNF into the vmPFC-PL induced an antidepressant-like effect, which was blocked by pretreatment with K252a and rapamycin. Microinjection of LY 235959 into the vmPFC-PL induced antidepressant-like effect that was suppressed by local rapamycin but not by K252a pretreatment. Microinjection of NPA induced an antidepressant-like effect insensitive to both K252a and rapamycin. Similarly, the antidepressant-like effects of a systemic injection of ketamine or 7-NI were not affected by blockade of mTOR or Trk receptors in the vmPFC-PL.

Conclusion

Our data support the hypothesis that NMDA blockade induces an antidepressant-like effect that requires mTOR but not Trk signalling into the vmPFC-PL. The antidepressant-like effect induced by local NOS inhibition is independent on both Trk and mTOR signalling in the vmPFC-PL.

Keywords

N-methyl-D-aspartate receptorsnitric oxide synthase
Type
Original Article
Information
Acta Neuropsychiatrica , Volume 31 , Issue 3 , June 2019 , pp. 143 - 150
Copyright
© Scandinavian College of Neuropsychopharmacology 2019 

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References

1. WHO (2018) Depression – Fact Sheet Geneva: World Health Organization; Available at http://www.who.int/news-room/fact-sheets/detail/depression. Accessed March 22, 2018.Google Scholar
2. Hindmarch, I (2002) Beyond the monoamine hypothesis: mechanisms, molecules and methods. Eur Psychiatry 17(Suppl 3):294–299.Google Scholar
3. Browne, CA Lucki, I (2013) Antidepressant effects of ketamine: mechanisms underlying fast-acting novel antidepressants. Front Pharmacol 4, 161, https://doi.org/10.3389/fphar.2013.00161.Google Scholar
4. RaS Trullas, R Skolnick, P (1990) Functional antagonists at the NMDA receptor complex exhibit antidepressant actions. European Journal of Pharmacology 185, 1–10.Google Scholar
5. Zarate, CA Jr. Machado-Vieira, R (2017) Ketamine: translating mechanistic discoveries into the next generation of glutamate modulators for mood disorders. Mol Psychiatry 22, 324–327.Google Scholar
6. 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, 351–354.Google Scholar
7. 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, 856–864.Google Scholar
8. 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, 959–964.Google Scholar
9. 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, 754–761.Google Scholar
10. Pereira, VS Hiroaki-Sato, VA (2018) A brief history of antidepressant drug development: from tricyclics to beyond ketamine. Acta Neuropsychiatr 30, 307–322 doi:10.1017/neu.2017.39.Google Scholar
11. Autry, AE, Adachi, M, Nosyreva, E, Na, ES, Los, MF, Cheng, PF, Kavalali, ET Monteggia, LM (2011) NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 475, 91–95.Google Scholar
12. Lepack, AE, Fuchikami, M, Dwyer, JM, Banasr, M Duman, RS (2014) BDNF release is required for the behavioral actions of ketamine. Int J Neuropsychopharmacol 18, pyu033, https://doi.org/10.1093/ijnp/pyu033.Google Scholar
13. Martinowich, K Lu, B (2008) Interaction between BDNF and serotonin: role in mood disorders. Neuropsychopharmacology 33, 73–83.Google Scholar
14. Minichiello, L (2009) TrkB signalling pathways in LTP and learning. Nat Rev Neurosci 10, 850–860.Google Scholar
15. Guix, FX, Uribesalgo, I, Coma, M Munoz, FJ (2005) The physiology and pathophysiology of nitric oxide in the brain. Prog Neurobiol 76, 126–152.Google Scholar
16. Dhir, A Kulkarni, SK (2011) Nitric oxide and major depression. Nitric Oxide 24, 125–131.Google Scholar
17. Joca, SRL, Ferreira, FR Guimarães, FS (2007) Modulation of stress consequences by hippocampal monoaminergic, glutamatergic and nitrergic neurotransmitter systems. Stress 10, 227–249.Google Scholar
18. Calabrese, V, Mancuso, C, Calvani, M, Rizzarelli, E, Butterfield, DA Stella, AM (2007) Nitric oxide in the central nervous system: neuroprotection versus neurotoxicity. Nat Rev Neurosci 8, 766–775.Google Scholar
19. Harkin, AJ, Bruce, KH, Craft, B Paul, IA (1999) Nitric oxide synthase inhibitors have antidepressant-like properties in mice. 1. Acute treatments are active in the forced swim test. Eur J Pharmacol 372, 207–213.Google Scholar
20. Yildiz, F, Erden, BF, Ulak, G, Utkan, T Gacar, N (2000) Antidepressant-like effect of 7-nitroindazole in the forced swimming test in rats. Psychopharmacol (Berl) 149, 41–44.Google Scholar
21. Wegener, G Volke, V (2010) Nitric oxide synthase inhibitors as antidepressants. Pharmaceuticals 3, 273–299.Google Scholar
22. Pereira, VS, Romano, A, Wegener, G Joca, SR (2015) Antidepressant-like effects induced by NMDA receptor blockade and NO synthesis inhibition in the ventral medial prefrontal cortex of rats exposed to the forced swim test. Psychopharmacology 232, 2263. https://doi.org/10.1007/s00213-014-3853-2.Google Scholar
23. Hiroaki-Sato, VA, Sales, AJ, Biojone, C Joca, SR (2014) Hippocampal nNOS inhibition induces an antidepressant-like effect: involvement of 5HT1A receptors. Behav Pharmacol 25, 187–196.Google Scholar
24. Diniz, CR, Casarotto, PC Joca, SR (2016) NMDA-NO signaling in the dorsal and ventral hippocampus time-dependently modulates the behavioral responses to forced swimming stress. Behav Brain Res 307, 126–136.Google Scholar
25. Yazir, Y, Utkan, T Aricioglu, F (2012) Inhibition of neuronal nitric oxide synthase and soluble guanylate cyclase prevents depression-like behaviour in rats exposed to chronic unpredictable mild stress. Basic Clin Pharmacol Toxicol 111, 154–160.Google Scholar
26. 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, 400–412.Google Scholar
27. Joca, SR, Ferreira, FR Guimaraes, FS (2007) Modulation of stress consequences by hippocampal monoaminergic, glutamatergic and nitrergic neurotransmitter systems. Stress 10, 227–249.Google Scholar
28. Biojone, C, Casarotto, PC, Joca, SR Castren, E (2015) Interplay between nitric oxide and brain-derived neurotrophic factor in neuronal plasticity. CNS Neurol Disord Drug Targets 14, 979–987.Google Scholar
29. Stanquini, LA, Biojone, C, Guimaraes, FS Joca, SR (2018) Repeated treatment with nitric oxide synthase inhibitor attenuates learned helplessness development in rats and increases hippocampal BDNF expression. Acta Neuropsychiatr 30, 127–136.Google Scholar
30. Liebenberg, N, Joca, S Wegener, G (2015) Nitric oxide involvement in the antidepressant-like effect of ketamine in the Flinders sensitive line rat model of depression. Acta Neuropsychiatr 27, 90–96.Google Scholar
31. Harraz, MM, Tyagi, R, Cortes, P Snyder, SH (2016) Antidepressant action of ketamine via mTOR is mediated by inhibition of nitrergic Rheb degradation. Mol Psychiatry 21, 313–319.Google Scholar
32. Myers-Schulz, B Koenigs, M (2011) Functional anatomy of ventromedial prefrontal cortex: implications for mood and anxiety disorders. Molecular Psychiatry 17, 132–141.Google Scholar
33. Kilkenny, C, Browne, WJ, Cuthill, IC, Emerson, M Altman, DG (2010) Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol 8, e1000412, https://doi.org/10.1371/journal.pbio.1000412.Google Scholar
34. Porsolt, RD, Le Pichon, M Jalfre, M (1977) Depression: a new animal model sensitive to antidepressant treatments. Nature 266, 730–732.Google Scholar
35. Joca, SR Guimaraes, FS (2006) Inhibition of neuronal nitric oxide synthase in the rat hippocampus induces antidepressant-like effects. Psychopharmacol (Berl) 185, 298–305.Google Scholar
36. Kirkedal, C, Wegener, G, Moreira, F, Joca, SRL Liebenberg, N (2017) A dual inhibitor of FAAH and TRPV1 channels shows dose-dependent effect on depression-like behaviour in rats. Acta Neuropsychiatr 29, 324–329.Google Scholar
37. Scopinho, AA, Scopinho, M, Lisboa, SF, Correa, FM, Guimaraes, FS Joca, SR (2010) Acute reversible inactivation of the ventral medial prefrontal cortex induces antidepressant-like effects in rats. Behav Brain Res 214, 437–442.Google Scholar
38. Benveniste, M Mayer, ML (1991) Structure-activity analysis of binding kinetics for NMDA receptor competitive antagonists: the influence of conformational restriction. Br J Pharmacol 104, 207–221.Google Scholar
39. Casarotto, PC, Santos, PC, Lucas, GA, Biojone, C, Pobbe, RL, Vilela-Costa, HH, Joca, SR, Guimaraes, FS Zangrossi, H Jr. (2015) BDNF-TRKB signaling system of the dorsal periaqueductal gray matter is implicated in the panicolytic-like effect of antidepressant drugs. Eur Neuropsychopharmacol 25, 913–922.Google Scholar
40. Silva, M, Aguiar, DC, Diniz, CR, Guimaraes, FS Joca, SR (2012) Neuronal NOS inhibitor and conventional antidepressant drugs attenuate stress-induced fos expression in overlapping brain regions. Cell Mol Neurobiol 32, 443–453.Google Scholar
41. 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.Google Scholar
42. Sairanen, M, Lucas, G, Ernfors, P, Castren, M Castren, E (2005) Brain-derived neurotrophic factor and antidepressant drugs have different but coordinated effects on neuronal turnover, proliferation, and survival in the adult dentate gyrus. J Neurosci 25, 1089–1094.Google Scholar
43. Saarelainen, T, Hendolin, P, Lucas, G, Koponen, E, Sairanen, M, MacDonald, E, Agerman, K, Haapasalo, A, Nawa, H, Aloyz, 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, 349–357.Google Scholar
44. Li, Y, Luikart, BW, Birnbaum, S, Chen, J, Kwon, CH, Kernie, SG, Bassel-Duby, R Parada, LF (2008) TrkB regulates hippocampal neurogenesis and governs sensitivity to antidepressive treatment. Neuron 59, 399–412.Google Scholar
45. Hoeffer, CA Klann, E (2010) mTOR signaling: at the crossroads of plasticity, memory and disease. Trends Neurosci 33, 67–75.Google Scholar
46. Yoon, SC, Seo, MS, Kim, SH, Jeon, WJ, Ahn, YM, Kang, UG Kim, YS (2008) The effect of MK-801 on mTOR/p70S6K and translation-related proteins in rat frontal cortex. Neurosci Lett 434, 23–28.Google Scholar
47. Rantamaki, T Yalcin, I (2016) Antidepressant drug action – from rapid changes on network function to network rewiring. Prog Neuropsychopharmacol Biol Psychiatry 64, 285–292.Google Scholar
48. Lu, B, Nagappan, G, Guan, X, Nathan, PJ Wren, P (2013) BDNF-based synaptic repair as a disease-modifying strategy for neurodegenerative diseases. Nat Rev Neurosci 14, 401–416.Google Scholar
49. Yin, JB, Wu, HH, Dong, YL, Zhang, T, Wang, J, Zhang, Y, Wei, YY, Lu, YC, Wu, SX, Wang, W Li, YQ (2014) Neurochemical properties of BDNF-containing neurons projecting to rostral ventromedial medulla in the ventrolateral periaqueductal gray. Front Neural Circuits 8, 137, https://doi.org/10.3389/fncir.2014.00137 Google Scholar
50. Altar, CA, Boylan, CB, Fritsche, M, Jackson, C, Hyman, C Lindsay, RM (1994) The neurotrophins NT-4/5 and BDNF augment serotonin, dopamine, and GABAergic systems during behaviorally effective infusions to the substantia nigra. Exp Neurol 130, 31–40.Google Scholar
51. Gardier, AM (2013) Antidepressant activity: contribution of brain microdialysis in knock-out mice to the understanding of BDNF/5-HT transporter/5-HT autoreceptor interactions. Frontiers in pharmacology 4, 98.Google Scholar
52. Sartim, AG, Guimaraes, FS Joca, SR (2016) Antidepressant-like effect of cannabidiol injection into the ventral medial prefrontal cortex-Possible involvement of 5-HT1A and CB1 receptors. Behav Brain Res 303, 218–227.Google Scholar
53. Koike, H, Iijima, M Chaki, S (2011) Involvement of AMPA receptor in both the rapid and sustained antidepressant-like effects of ketamine in animal models of depression. Behav Brain Res 224, 107–111.Google Scholar
54. Ignacio, ZM, Reus, GZ, Arent, CO, Abelaira, HM, Pitcher, MR Quevedo, J (2015) New perspectives on the involvement of mTOR in depression as well as in the action of antidepressant drugs. Br J Clin Pharmacol 82, 1280–1290.Google Scholar
55. Akinfiresoye, L Tizabi, Y (2013) Antidepressant effects of AMPA and ketamine combination: role of hippocampal BDNF, synapsin, and mTOR. Psychopharmacology (Berl) 230, 291–298.Google Scholar
56. Sanacora, G Schatzberg, AF (2015) Ketamine: promising path or false prophecy in the development of novel therapeutics for mood disorders? Neuropsychopharmacol 40, 259–267.Google Scholar
57. Zanos, P, Moaddel, R, Morris, PJ, Georgiou, P, Fischell, J, Elmer, GI, Alkondon, M, Yuan, P, Pribut, HJ, Singh, NS, Dossou, KS, Fang, Y, Huang, XP, Mayo, CL, Wainer, IW, Albuquerque, EX, Thompson, SM, Thomas, CJ, Zarate, CA Jr. Gould, TD (2016) NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature 533, 481–486.Google Scholar
58. du Jardin, KG, Liebenberg, N, Cajina, M, Muller, HK, Elfving, B, Sanchez, C Wegener, G (2017) S-ketamine mediates its acute and sustained antidepressant-like activity through a 5-HT1B receptor dependent mechanism in a genetic rat model of depression. Front Pharmacol 8, 978, https://doi.org/10.3389/fphar.2017.00978.Google Scholar
59. du Jardin, KG, Muller, HK, Elfving, B, Dale, E, Wegener, G Sanchez, C (2016) Potential involvement of serotonergic signaling in ketamine’s antidepressant actions: a critical review. Prog Neuropsychopharmacol Biol Psychiatry 71, 27–38.Google Scholar
60. Popp, S, Behl, B, Joshi, JJ, Lanz, TA, Spedding, M, Schenker, E, Jay, TM, Svenningsson, P, Caudal, D, Cunningham, JI, Deaver, D Bespalov, A(2016) In search of the mechanisms of ketamine’s antidepressant effects: How robust is the evidence behind the mTor activation hypothesis. F1000Research 5, 634.Google Scholar
61. 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 USA 99, 3282–3287.Google Scholar
62. Harkin, A, Connor, TJ, Burns, MP Kelly, JP (2004) Nitric oxide synthase inhibitors augment the effects of serotonin re-uptake inhibitors in the forced swimming test. Eur Neuropsychopharmacol 14, 274–281.Google Scholar
63. Burgdorf, J, Zhang, XL, Nicholson, KL, Balster, RL, Leander, JD, Stanton, PK, Gross, AL, Kroes, RA Moskal, JR (2013) GLYX-13, a NMDA receptor glycine-site functional partial agonist, induces antidepressant-like effects without ketamine-like side effects. Neuropsychopharmacol 38, 729–742.Google Scholar
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