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Nitric Oxide in Major Depressive Disorder

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Nitric Oxide: From Research to Therapeutics

Part of the book series: Advances in Biochemistry in Health and Disease ((ABHD,volume 22))

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Abstract

The pathogenesis of mood disorders remains elusive, but it is evident that multiple factors, genetic and environmental, play a crucial role in adult psychopathology and neurobiology. Concerning therapy, a significant proportion of affective disorder patients are partial or non-responders. There has been no breakthrough in finding novel, valuable drug targets since introducing the current marketed antidepressant drugs in the 1950s to the 1980s, which all are based on monoaminergic pharmacological effects. Consequently, there is a pressing need to develop novel treatment strategies—and ultimately understand the aetiology and pathophysiology of affective disorders. Nitric Oxide serves an essential role in the nervous system. It acts as a messenger molecule in several physiological processes, including processes linked to major psychiatric diseases. The present chapter will review the general aspects of the NO system in Major depressive disorder (MDD) and focus on reducing NO production as putative therapeutic agents towards depression.

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References

  1. Olesen J, Leonardi M (2003) The burden of brain diseases in Europe. Eur J Neurol 10(5):471–477

    Article  CAS  PubMed  Google Scholar 

  2. Olesen J, Sobscki P, Truelsen T, Sestoft D, Jonsson B (2008) Cost of disorders of the brain in Denmark. NordJ Psychiatry. 62(2):114–120

    Article  Google Scholar 

  3. Wittchen HU, Jacobi F, Rehm J, Gustavsson A, Svensson M, Jonsson B et al (2011) The size and burden of mental disorders and other disorders of the brain in Europe 2010. Eur Neuropsychopharmacol 21(9):655–679

    Article  CAS  PubMed  Google Scholar 

  4. Olesen J, Gustavsson A, Svensson M, Wittchen HU, Jonsson B, group Cs, et al. The economic cost of brain disorders in Europe. Eur J Neurol. 2012;19(1):155–62.

    Google Scholar 

  5. Gustavsson A, Svensson M, Jacobi F, Allgulander C, Alonso J, Beghi E et al (2011) Cost of disorders of the brain in Europe 2010. Eur Neuropsychopharmacol 21(10):718–779

    Article  CAS  PubMed  Google Scholar 

  6. Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H et al (2003) Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301(5631):386–389

    Article  CAS  PubMed  Google Scholar 

  7. Palmer RM, Ferrige AG, Moncada S (1987) Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327(6122):524–526

    Article  CAS  PubMed  Google Scholar 

  8. Hibbs JB Jr, Taintor RR, Vavrin Z (1987) Macrophage cytotoxicity: role for L-arginine deiminase and imino nitrogen oxidation to nitrite. Science 235(4787):473–476

    Article  CAS  PubMed  Google Scholar 

  9. Bredt DS, Snyder SH (1989) Nitric oxide mediates glutamate-linked enhancement of cGMP levels in the cerebellum. Proc Natl Acad Sci USA 86(22):9030–9033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Garthwaite J, Garthwaite G, Palmer RM, Moncada S (1989) NMDA receptor activation induces nitric oxide synthesis from arginine in rat brain slices. Eur J Pharmacol 172(4–5):413–416

    Article  CAS  PubMed  Google Scholar 

  11. Knott AB, Bossy-Wetzel E (2009) Nitric oxide in health and disease of the nervous system. Antioxid Redox Signal 11(2). https://doi.org/10.1089/ars.2008.234

  12. Oosthuizen F, Wegener G, Harvey BH (2005) Nitric oxide as inflammatory mediator in post-traumatic stress disorder (PTSD): evidence from an animal model. Neuropsychiatr Dis Treat 1(2):109–123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Reif A, Herterich S, Strobel A, Ehlis AC, Saur D, Jacob CP et al (2006) A neuronal nitric oxide synthase (NOS-I) haplotype associated with schizophrenia modifies prefrontal cortex function. Mol Psychiatry 11(3):286–300

    Article  CAS  PubMed  Google Scholar 

  14. Reif A, Jacob CP, Rujescu D, Herterich S, Lang S, Gutknecht L et al (2009) Influence of functional variant of neuronal nitric oxide synthase on impulsive behaviors in humans. Arch Gen Psychiatry 66(1):41–50

    Article  CAS  PubMed  Google Scholar 

  15. Garthwaite J, Charles SL, Chess-Williams R (1988) Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain. Nature 336(6197):385–388

    Article  CAS  PubMed  Google Scholar 

  16. Garthwaite J (2008) Concepts of neural nitric oxide-mediated transmission. Eur J Neurosci 27(11):2783–2802

    Article  PubMed  PubMed Central  Google Scholar 

  17. Guix FX, Uribesalgo I, Coma M, Munoz FJ (2005) The physiology and pathophysiology of nitric oxide in the brain. Prog Neurobiol 76(2):126–152

    Article  CAS  PubMed  Google Scholar 

  18. Blum-Degen D, Heinemann T, Lan J, Pedersen V, Leblhuber F, Paulus W et al (1999) Characterization and regional distribution of nitric oxide synthase in the human brain during normal ageing. Brain Res 834(1–2):128–135

    Article  CAS  PubMed  Google Scholar 

  19. Amitai Y (2010) Physiologic role for “inducible” nitric oxide synthase: a new form of astrocytic-neuronal interface. Glia 58(15):1775–1781

    Article  PubMed  Google Scholar 

  20. Feil R, Kleppisch T (2008) NO/cGMP-dependent modulation of synaptic transmission. Handb Exp Pharmacol 184:529–560

    Article  CAS  Google Scholar 

  21. Kleppisch T, Feil R (2009) cGMP signalling in the mammalian brain: role in synaptic plasticity and behaviour. Handb Exp Pharmacol 191:549–579

    Article  CAS  Google Scholar 

  22. Ding JD, Burette A, Nedvetsky PI, Schmidt HH, Weinberg RJ (2004) Distribution of soluble guanylyl cyclase in the rat brain. J Comp Neurol 472(4):437–448

    Article  CAS  PubMed  Google Scholar 

  23. Jaffrey SR, Erdjument-Bromage H, Ferris CD, Tempst P, Snyder SH (2001) Protein S-nitrosylation: a physiological signal for neuronal nitric oxide. Nat Cell Biol 3(2):193–197

    Article  CAS  PubMed  Google Scholar 

  24. Brenman JE, Chao DS, Gee SH, McGee AW, Craven SE, Santillano DR et al (1996) Interaction of nitric oxide synthase with the postsynaptic density protein PSD-95 and α1-syntrophin mediated by PDZ domains. Cell 84(5):757–767

    Article  CAS  PubMed  Google Scholar 

  25. Nedvetsky PI, Sessa WC, Schmidt HHHW (2002) There’s NO binding like NOS binding: Protein-protein interactions in NO/cGMP signaling. Proc Natl Acad Sci U S A 99(26):16510–16512

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Doucet MV, Harkin A, Dev KK (2012) The PSD-95/nNOS complex: New drugs for depression? Pharmacol Ther 133(2):218–229

    Article  CAS  PubMed  Google Scholar 

  27. Osuka K, Watanabe Y, Usuda N, Nakazawa A, Fukunaga K, Miyamoto E et al (2002) Phosphorylation of Neuronal Nitric Oxide Synthase at Ser847 by CaM-KII in the Hippocampus of Rat Brain after Transient Forebrain Ischemia. J Cereb Blood Flow Metab 22(9):1098–1106

    Article  CAS  PubMed  Google Scholar 

  28. Zhou Q-G, Zhu X-H, Nemes AD, Zhu D-Y (2018) Neuronal nitric oxide synthase and affective disorders. IBRO Reports. 5:116–132

    Article  PubMed  PubMed Central  Google Scholar 

  29. Jaffrey SR, Snowman AM, Eliasson MJL, Cohen NA, Snyder SH (1998) CAPON: A protein associated with neuronal nitric oxide synthase that regulates its interactions with PSD95. Neuron 20(1):115–124

    Article  CAS  PubMed  Google Scholar 

  30. Fang M, Jaffrey SR, Sawa A, Ye K, Luo X, Snyder SH (2000) Dexras1: A G protein specifically coupled to neuronal nitric oxide synthase via CAPON. Neuron 28(1):183–193

    Article  CAS  PubMed  Google Scholar 

  31. Jaffrey SR, Benfenati F, Snowman AM, Czernik AJ, Snyder SH (2002) Neuronal nitric-oxide synthase localization mediated by a ternary complex with synapsin and CAPON. Proc Natl Acad Sci U S A 99(5):3199–3204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Riccio A, Alvania RS, Lonze BE, Ramanan N, Kim T, Huang Y et al (2006) A Nitric Oxide Signaling Pathway Controls CREB-Mediated Gene Expression in Neurons. Mol Cell 21(2):283–294

    Article  CAS  PubMed  Google Scholar 

  33. Hara MR, Agrawal N, Kim SF, Cascio MB, Fujimuro M, Ozeki Y et al (2005) S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding. Nat Cell Biol 7(7):665–674

    Article  CAS  PubMed  Google Scholar 

  34. Ghasemi M, Claunch J, Niu K (2019) Pathologic role of nitrergic neurotransmission in mood disorders. Prog Neurobiol 173:54–87

    Article  CAS  PubMed  Google Scholar 

  35. Hara MR, Snyder SH (2007) Cell Signaling and Neuronal Death. Annu Rev Pharmacol Toxicol 47(1):117–141

    Article  CAS  PubMed  Google Scholar 

  36. Spiers JG, Chen H-JC, Bourgognon J-M, Steinert JR. Dysregulation of stress systems and nitric oxide signaling underlies neuronal dysfunction in Alzheimer’s disease. Free Radical Biology and Medicine. 2019;134:468–83.

    Google Scholar 

  37. Yuste JE, Tarragon E, Campuzano CM, Ros-Bernal F. Implications of glial nitric oxide in neurodegenerative diseases. Frontiers in cellular neuroscience. 2015;9(322).

    Google Scholar 

  38. Bernstein HG, Stanarius A, Baumann B, Henning H, Krell D, Danos P et al (1998) Nitric oxide synthase-containing neurons in the human hypothalamus: reduced number of immunoreactive cells in the paraventricular nucleus of depressive patients and schizophrenics. Neurosci 83(3):867–875

    Article  CAS  Google Scholar 

  39. Bernstein HG, Heinemann A, Krell D, Mawrin C, Bielau H, Danos P et al (2002) Further immunohistochemical evidence for impaired NO signaling in the hypothalamus of depressed patients. Ann N Y Acad Sci 973:91–93

    Article  CAS  PubMed  Google Scholar 

  40. Xing G, Chavko M, Zhang LX, Yang S, Post RM (2002) Decreased calcium-dependent constitutive nitric oxide synthase (cNOS) activity in prefrontal cortex in schizophrenia and depression. Schizophr Res 58(1):21–30

    Article  PubMed  Google Scholar 

  41. Karolewicz B, Szebeni K, Stockmeier CA, Konick L, Overholser JC, Jurjus G et al (2004) Low nNOS protein in the locus coeruleus in major depression. J Neurochem 91(5):1057–1066

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Oliveira RM, Guimaraes FS, Deakin JF (2008) Expression of neuronal nitric oxide synthase in the hippocampal formation in affective disorders. Braz J Med Biol Res 41(4):333–341

    Article  CAS  PubMed  Google Scholar 

  43. Gao S, Zhang T, Jin L, Liang D, Fan G, Song Y et al (2019) CAPON Is a Critical Protein in Synaptic Molecular Networks in the Prefrontal Cortex of Mood Disorder Patients and Contributes to Depression-Like Behavior in a Mouse Model. Cereb Cortex 29(9):3752–3765

    Article  PubMed  Google Scholar 

  44. Kim YK, Paik JW, Lee SW, Yoon D, Han C, Lee BH (2006) Increased plasma nitric oxide level associated with suicide attempt in depressive patients. Prog Neuropsychopharmacol Biol Psychiatry 30(6):1091–1096

    Article  CAS  PubMed  Google Scholar 

  45. Lee BH, Lee SW, Yoon D, Lee HJ, Yang JC, Shim SH et al (2006) Increased plasma nitric oxide metabolites in suicide attempters. Neuropsychobiology 53(3):127–132

    Article  CAS  PubMed  Google Scholar 

  46. Suzuki E, Yagi G, Nakaki T, Kanba S, Asai M (2001) Elevated plasma nitrate levels in depressive states. J Affect Disord 63(1–3):221–224

    Article  CAS  PubMed  Google Scholar 

  47. Herken H, Gurel A, Selek S, Armutcu F, Ozen ME, Bulut M et al (2007) Adenosine deaminase, nitric oxide, superoxide dismutase, and xanthine oxidase in patients with major depression: impact of antidepressant treatment. Arch Med Res 38(2):247–252

    Article  CAS  PubMed  Google Scholar 

  48. Suzuki E, Yoshida Y, Shibuya A, Miyaoka H (2003) Nitric oxide involvement in depression during interferon-alpha therapy. Int J Neuropsychopharmacol 6(4):415–419

    Article  CAS  PubMed  Google Scholar 

  49. Srivastava N, Barthwal MK, Dalal PK, Agarwal AK, Nag D, Seth PK et al (2002) A study on nitric oxide, beta-adrenergic receptors and antioxidant status in the polymorphonuclear leukocytes from the patients of depression. J Affect Disord 72(1):45–52

    Article  CAS  PubMed  Google Scholar 

  50. Wallerath T, Gath I, Aulitzky WE, Pollock JS, Kleinert H, Förstermann U (1997) Identification of the NO synthase isoforms expressed in human neutrophil granulocytes, megakaryocytes and platelets. Thromb Haemost 77(1):163–167

    Article  CAS  PubMed  Google Scholar 

  51. Chrapko WE, Jurasz P, Radomski MW, Lara N, Archer SL, Le Melledo JM (2004) Decreased platelet nitric oxide synthase activity and plasma nitric oxide metabolites in major depressive disorder. Biol Psychiatry 56(2):129–134

    Article  CAS  PubMed  Google Scholar 

  52. Chrapko W, Jurasz P, Radomski MW, Archer SL, Newman SC, Baker G et al (2006) Alteration of decreased plasma NO metabolites and platelet NO synthase activity by paroxetine in depressed patients. Neuropsychopharmacol 31(6):1286–1293

    Article  CAS  Google Scholar 

  53. Loeb E, El Asmar K, Trabado S, Gressier F, Colle R, Rigal A, et al. Nitric Oxide Synthase activity in major depressive episodes before and after antidepressant treatment: Results of a large case-control treatment study. Psychological Medicine. 2020:1–10.

    Google Scholar 

  54. Ali-Sisto T, Tolmunen T, Viinamäki H, Mäntyselkä P, Valkonen-Korhonen M, Koivumaa-Honkanen H et al (2018) Global arginine bioavailability ratio is decreased in patients with major depressive disorder. J Affect Disord 229:145–151

    Article  CAS  PubMed  Google Scholar 

  55. Boger RH, Diemert A, Schwedhelm E, Luneburg N, Maas R, Hecher K (2009) The Role of Nitric Oxide Synthase Inhibition by Asymmetric Dimethylarginine in the Pathophysiology of Preeclampsia. Gynecol Obstet Invest 69(1):1–13

    Article  PubMed  Google Scholar 

  56. Boger RH, Maas R, Schulze F, Schwedhelm E (2009) Asymmetric dimethylarginine (ADMA) as a prospective marker of cardiovascular disease and mortality-An update on patient populations with a wide range of cardiovascular risk. Pharmacol Res 60(6):7

    Article  Google Scholar 

  57. Boger RH, Sullivan LM, Schwedhelm E, Wang TJ, Maas R, Benjamin EJ et al (2009) Plasma asymmetric dimethylarginine and incidence of cardiovascular disease and death in the community. Circulation 119(12):1592–1600

    Article  PubMed  PubMed Central  Google Scholar 

  58. McEvoy MA, Schofield P, Smith W, Agho K, Mangoni AA, Soiza RL et al (2013) Serum methylarginines and incident depression in a cohort of older adults. J Affect Disord 151(2):493–499

    Article  CAS  PubMed  Google Scholar 

  59. Ozden A, Angelos H, Feyza A, Elizabeth W, John P (2020) Altered plasma levels of arginine metabolites in depression. J Psychiatr Res 120:21–28

    Article  PubMed  Google Scholar 

  60. Selley ML (2004) Increased (E)-4-hydroxy-2-nonenal and asymmetric dimethylarginine concentrations and decreased nitric oxide concentrations in the plasma of patients with major depression. J Affect Disord 80(2–3):249–256

    Article  CAS  PubMed  Google Scholar 

  61. Das I, Khan NS, Puri BK, Hirsch SR (1996) Elevated endogenous nitric oxide synthase inhibitor in schizophrenic plasma may reflect abnormalities in brain nitric oxide production. Neurosci Lett 215(3):209–211

    Article  CAS  PubMed  Google Scholar 

  62. Arlt S, Schulze F, Eichenlaub M, Maas R, Lehmbeck JT, Schwedhelm E et al (2008) Asymmetrical dimethylarginine is increased in plasma and decreased in cerebrospinal fluid of patients with Alzheimer’s disease. Dement Geriatr Cogn Disord 26(1):58–64

    Article  CAS  PubMed  Google Scholar 

  63. Nasyrova RF, Moskaleva PV, Vaiman EE, Shnayder NA, Blatt NL, Rizvanov AA (2020) Genetic Factors of Nitric Oxide’s System in Psychoneurologic Disorders. Int J Mol Sci 21(5):1604

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Yu YW, Chen TJ, Wang YC, Liou YJ, Hong CJ, Tsai SJ (2003) Association analysis for neuronal nitric oxide synthase gene polymorphism with major depression and fluoxetine response. Neuropsychobiology 47(3):137–140

    Article  CAS  PubMed  Google Scholar 

  65. Buttenschon HN, Mors O, Ewald H, McQuillin A, Kalsi G, Lawrence J et al (2004) No association between a neuronal nitric oxide synthase (NOS1) gene polymorphism on chromosome 12q24 and bipolar disorder. AmJMedGenetB NeuropsychiatrGenet. 124(1):73–75

    Google Scholar 

  66. Okumura T, Kishi T, Okochi T, Ikeda M, Kitajima T, Yamanouchi Y et al (2010) Genetic association analysis of functional polymorphisms in neuronal nitric oxide synthase 1 gene (NOS1) and mood disorders and fluvoxamine response in major depressive disorder in the Japanese population. Neuropsychobiology 61(2):57–63

    Article  CAS  PubMed  Google Scholar 

  67. Wigner P, Czarny P, Synowiec E, Bijak M, Białek K, Talarowska M et al (2018) Variation of genes involved in oxidative and nitrosative stresses in depression. Eur Psychiat 48(1):38–48

    Article  Google Scholar 

  68. Sullivan PF, de Geus EJ, Willemsen G, James MR, Smit JH, Zandbelt T et al (2009) Genome-wide association for major depressive disorder: a possible role for the presynaptic protein piccolo. Mol Psychiatry 14(4):359–375

    Article  CAS  PubMed  Google Scholar 

  69. Galecki P, Maes M, Florkowski A, Lewinski A, Galecka E, Bienkiewicz M et al (2011) Association between inducible and neuronal nitric oxide synthase polymorphisms and recurrent depressive disorder. J Affect Disord 129(1–3):175–182

    Article  CAS  PubMed  Google Scholar 

  70. Montesanto A, Crocco P, Tallaro F, Pisani F, Mazzei B, Mari V et al (2013) Common polymorphisms in nitric oxide synthase (NOS) genes influence quality of aging and longevity in humans. Biogerontology 14(2):177–186

    Article  CAS  PubMed  Google Scholar 

  71. Sarginson JE, Deakin JFW, Anderson IM, Downey D, Thomas E, Elliott R et al (2014) Neuronal Nitric Oxide Synthase (NOS1) Polymorphisms Interact with Financial Hardship to Affect Depression Risk. Neuropsychopharmacol 39(12):2857–2866

    Article  CAS  Google Scholar 

  72. Gałecki P, Gałecka E, Maes M, Chamielec M, Orzechowska A, Bobińska K et al (2012) The expression of genes encoding for COX-2, MPO, iNOS, and sPLA2-IIA in patients with recurrent depressive disorder. J Affect Disord 138(3):360–366

    Article  PubMed  Google Scholar 

  73. Gałecki P, Maes M, Florkowski A, Lewiński A, Gałecka E, Bieńkiewicz M et al (2010) An inducible nitric oxide synthase polymorphism is associated with the risk of recurrent depressive disorder. Neurosci Lett 486(3):184–187

    Article  PubMed  Google Scholar 

  74. Lawford BR, Morris CP, Swagell CD, Hughes IP, Young RM, Voisey J (2013) NOS1AP is associated with increased severity of PTSD and depression in untreated combat veterans. J Affect Disord 147(1–3):87–93

    Article  CAS  PubMed  Google Scholar 

  75. Cheah SY, Lawford BR, Young RM, Morris CP, Voisey J (2015) Association of NOS1AP variants and depression phenotypes in schizophrenia. J Affect Disord 188:263–269

    Article  CAS  PubMed  Google Scholar 

  76. Ikenouchi-Sugita A, Yoshimura R, Kishi T, Umene-Nakano W, Hori H, Hayashi K et al (2011) Three polymorphisms of the eNOS gene and plasma levels of metabolites of nitric oxide in depressed Japanese patients: a preliminary report. Hum Psychopharmacol Clin Exp 26(7):531–534

    Article  CAS  Google Scholar 

  77. Moraes-Neto TB, Scopinho AA, Biojone C, Corrêa FMA, Resstel LBM (2014) Involvement of dorsal hippocampus glutamatergic and nitrergic neurotransmission in autonomic responses evoked by acute restraint stress in rats. Neurosci 258:364–373

    Article  CAS  Google Scholar 

  78. Echeverry MB, Guimaraes FS, Del Bel EA (2004) Acute and delayed restraint stress-induced changes in nitric oxide producing neurons in limbic regions. Neurosci 125(4):981–993

    Article  CAS  Google Scholar 

  79. Zhou QG, Zhu LJ, Chen C, Wu HY, Luo CX, Chang L et al (2011) Hippocampal neuronal nitric oxide synthase mediates the stress-related depressive behaviors of glucocorticoids by downregulating glucocorticoid receptor. J Neurosci 31(21):7579–7590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Wegener G, Harvey BH, Bonefeld B, Muller HK, Volke V, Overstreet DH et al (2010) Increased stress-evoked nitric oxide signalling in the Flinders sensitive line (FSL) rat: a genetic animal model of depression. Int J Neuropsychopharmacol 13(4):461–473

    Article  CAS  PubMed  Google Scholar 

  81. Filipović D, Todorović N, Bernardi RE, Gass P (2017) Oxidative and nitrosative stress pathways in the brain of socially isolated adult male rats demonstrating depressive- and anxiety-like symptoms. Brain Struct Funct 222(1):1–20

    Article  PubMed  Google Scholar 

  82. Brown GC, Neher JJ (2010) Inflammatory Neurodegeneration and Mechanisms of Microglial Killing of Neurons. Mol Neurobiol 41(2):242–247

    Article  CAS  PubMed  Google Scholar 

  83. Brown GC, Vilalta A (2015) How microglia kill neurons. Brain Res 1628:288–297

    Article  CAS  PubMed  Google Scholar 

  84. Munhoz CD, García-Bueno B, Madrigal JLM, Lepsch LB, Scavone C, Leza JC (2008) Stress-induced neuroinflammation: mechanisms and new pharmacological targets. Braz J Med Biol Res 41:1037–1046

    Article  CAS  PubMed  Google Scholar 

  85. Wang Y, Ni J, Zhai L, Gao C, Xie L, Zhao L et al (2019) Inhibition of activated astrocyte ameliorates lipopolysaccharide- induced depressive-like behaviors. J Affect Disord 242:52–59

    Article  CAS  PubMed  Google Scholar 

  86. Gądek-Michalska A, Tadeusz J, Rachwalska P, Bugajski J (2013) Cytokines, prostaglandins and nitric oxide in the regulation of stress-response systems. Pharmacological reports : PR. 65(6):1655–1662

    Article  PubMed  Google Scholar 

  87. Gądek-Michalska A, Tadeusz J, Bugajski A, Bugajski J (2019) Chronic Isolation Stress Affects Subsequent Crowding Stress-Induced Brain Nitric Oxide Synthase (NOS) Isoforms and Hypothalamic-Pituitary-Adrenal (HPA) Axis Responses. Neurotox Res 36(3):523–539

    Article  PubMed  PubMed Central  Google Scholar 

  88. Rivier C (1998) Role of Nitric Oxide and Carbon Monoxide in Modulating the ACTH Response to Immune and Nonimmune Signals. NeuroImmunoModulation 5(3–4):203–213

    Article  CAS  PubMed  Google Scholar 

  89. Gądek-Michalska A, Tadeusz J, Rachwalska P, Spyrka J, Bugajski J (2012) Effect of repeated restraint on homotypic stress-induced nitric oxide synthases expression in brain structures regulating HPA axis. Pharmacological reports : PR. 64(6):1381–1390

    Article  PubMed  Google Scholar 

  90. Vernet D, Bonavera JJ, Swerdloff RS, Gonzalez-Cadavid NF, Wang C (1998) Spontaneous Expression of Inducible Nitric Oxide Synthase in the Hypothalamus and Other Brain Regions of Aging Rats*. Endocrinology 139(7):3254–3261

    Article  CAS  PubMed  Google Scholar 

  91. Dinerman JL, Dawson TM, Schell MJ, Snowman A, Snyder SH (1994) Endothelial nitric oxide synthase localized to hippocampal pyramidal cells: implications for synaptic plasticity. Proc Natl Acad Sci USA 91(10):4214–4218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Sparrow JR (1994) Inducible nitric oxide synthase in the central nervous system. J Mol Neurosci 5(4):219–229

    Article  CAS  PubMed  Google Scholar 

  93. Tanda K, Nishi A, Matsuo N, Nakanishi K, Yamasaki N, Sugimoto T et al (2009) Abnormal social behavior, hyperactivity, impaired remote spatial memory, and increased D1-mediated dopaminergic signaling in neuronal nitric oxide synthase knockout mice. Mol Brain 2(1):19

    Article  PubMed  PubMed Central  Google Scholar 

  94. Weitzdoerfer R, Hoeger H, Engidawork E, Engelmann M, Singewald N, Lubec G et al (2004) Neuronal nitric oxide synthase knock-out mice show impaired cognitive performance. Nitric Oxide 10(3):130–140

    Article  CAS  PubMed  Google Scholar 

  95. Nelson RJ, Demas GE, Huang PL, Fishman MC, Dawson VL, Dawson TM et al (1995) Behavioural abnormalities in male mice lacking neuronal nitric oxide synthase. Nature 378(6555):383–386

    Article  CAS  PubMed  Google Scholar 

  96. Bilbo SD, Hotchkiss AK, Chiavegatto S, Nelson RJ (2003) Blunted stress responses in delayed type hypersensitivity in mice lacking the neuronal isoform of nitric oxide synthase. J Neuroimmunol 140(1–2):41–48

    Article  CAS  PubMed  Google Scholar 

  97. Juch M, Smalla KH, Kahne T, Lubec G, Tischmeyer W, Gundelfinger ED et al (2009) Congenital lack of nNOS impairs long-term social recognition memory and alters the olfactory bulb proteome. Neurobiol Learn Mem 92(4):469–484

    Article  PubMed  Google Scholar 

  98. Zhou QG, Hu Y, Hua Y, Hu M, Luo CX, Han X et al (2007) Neuronal nitric oxide synthase contributes to chronic stress-induced depression by suppressing hippocampal neurogenesis. J Neurochem 103(5):1843–1854

    Article  CAS  PubMed  Google Scholar 

  99. Sugimoto K, Iadecola C (2002) Effects of aminoguanidine on cerebral ischemia in mice: comparison between mice with and without inducible nitric oxide synthase gene. Neurosci Lett 331(1):25–28

    Article  CAS  PubMed  Google Scholar 

  100. Akasaka S, Nomura M, Nishii H, Fujimoto N, Ueta Y, Tsutsui M et al (2006) The hypothalamo-pituitary axis responses to lipopolysaccharide-induced endotoxemia in mice lacking inducible nitric oxide synthase. Brain Res 1089(1):1–9

    Article  CAS  PubMed  Google Scholar 

  101. De Luca G, Di Giorgio RM, Macaione S, Calpona PR, Di Paola ED, Costa N et al (2006) Amino acid levels in some brain areas of inducible nitric oxide synthase knock out mouse (iNOS−/−) before and after pentylenetetrazole kindling. Pharmacol Biochem Behav 85(4):804–812

    Article  PubMed  Google Scholar 

  102. Kawano T, Kunz A, Abe T, Girouard H, Anrather J, Zhou P et al (2007) iNOS-Derived NO and Nox2-Derived Superoxide Confer Tolerance to Excitotoxic Brain Injury through Peroxynitrite. J Cereb Blood Flow Metab 27(8):1453–1462

    Article  CAS  PubMed  Google Scholar 

  103. Montezuma K, Biojone C, Lisboa SF, Cunha FQ, Guimaraes FS, Joca SR (2012) Inhibition of iNOS induces antidepressant-like effects in mice: pharmacological and genetic evidence. Neuropharmacol 62(1):485–491

    Article  CAS  Google Scholar 

  104. Lisboa SF, Gomes FV, Silva AL, Uliana DL, Camargo LHA, Guimarães FS, et al. Increased Contextual Fear Conditioning in iNOS Knockout Mice: Additional Evidence for the Involvement of Nitric Oxide in Stress-Related Disorders and Contribution of the Endocannabinoid System. Int J Neuropsychopharmacol. 2015;18(8).

    Google Scholar 

  105. Dere E, De Souza Silva MA, Topic B, Fiorillo C, Li J-S, Sadile AG et al (2002) Aged endothelial nitric oxide synthase knockout mice exhibit higher mortality concomitant with impaired open-field habituation and alterations in forebrain neurotransmitter levels. Genes, Brain and Behav 1(4):204–213

    Article  CAS  Google Scholar 

  106. Frisch C, Dere E, Silva MADS, Gödecke A, Schrader J, Huston JP (2000) Superior Water Maze Performance and Increase in Fear-Related Behavior in the Endothelial Nitric Oxide Synthase-Deficient Mouse Together with Monoamine Changes in Cerebellum and Ventral Striatum. J Neurosci 20(17):6694–6700

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Hopper RA, Garthwaite J (2006) Tonic and Phasic Nitric Oxide Signals in Hippocampal Long-Term Potentiation. J Neurosci 26(45):11513–11521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Jefferys D, Funder J (1996) Nitric oxide modulates retention of immobility in the forced swimming test in rats. Eur J Pharmacol 295(2–3):131–135

    Article  PubMed  Google Scholar 

  109. Harkin AJ, Bruce KH, Craft B, Paul IA. Nitric oxide synthase inhibitors have antidepressant-like properties in mice. 1. Acute treatments are active in the forced swim test. European Journal of Pharmacology. 1999;372(3):207–13.

    Google Scholar 

  110. 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(4):274–281

    Article  CAS  PubMed  Google Scholar 

  111. Gigliucci V, Buckley KN, Nunan J, O’Shea K, Harkin A (2010) A role for serotonin in the antidepressant activity of NG-Nitro-L-arginine, in the rat forced swimming test. Pharmacol Biochem Behav 94(4):524–533

    Article  CAS  PubMed  Google Scholar 

  112. Karolewicz B, Bruce KH, Lee B, Paul IA. Nitric oxide synthase inhibitors have antidepressant-like properties in mice. 2. Chronic treatment results in downregulation of cortical beta-adrenoceptors. European Journal of Pharmacology. 1999;372(3):215–20.

    Google Scholar 

  113. 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  CAS  PubMed  Google Scholar 

  114. Joca SR, Guimaraes FS (2006) Inhibition of neuronal nitric oxide synthase in the rat hippocampus induces antidepressant-like effects. Psychopharmacology 185(3):298–305

    Article  CAS  PubMed  Google Scholar 

  115. 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(3):443–453

    Article  CAS  PubMed  Google Scholar 

  116. Sales AJ, Hiroaki-Sato VA, Joca SR (2017) Participation of hippocampal nitric oxide synthase and soluble guanylate cyclase in the modulation of behavioral responses elicited by the rat forced swimming test. Behav Pharmacol 28(1):19–29

    Article  CAS  PubMed  Google Scholar 

  117. 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(3):127–136

    Article  PubMed  Google Scholar 

  118. 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(3):154–160

    CAS  PubMed  Google Scholar 

  119. Palumbo ML, Fosser NS, Rios H, Zubilete MAZ, Guelman LR, Cremaschi GA et al (2007) Loss of hippocampal neuronal nitric oxide synthase contributes to the stress-related deficit in learning and memory. J Neurochem 102(1):261–274

    Article  CAS  PubMed  Google Scholar 

  120. Heiberg IL, Wegener 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(1–2):479–484

    Article  CAS  PubMed  Google Scholar 

  121. 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(13):2263–2273

    Article  CAS  PubMed  Google Scholar 

  122. Pereira VS, Suavinha A, Wegener G, Joca SRL (2019) Prelimbic neuronal nitric oxide synthase inhibition exerts antidepressant-like effects independently of BDNF signalling cascades. Acta Neuropsychiatr. 31(3):143–150

    Article  PubMed  Google Scholar 

  123. Frey C, Narayanan K, McMillan K, Spack L, Gross SS, Masters BS, et al. L-thiocitrulline. A stereospecific, heme-binding inhibitor of nitric-oxide synthases. J Biol Chem. 1994;269(42):26083–91.

    Google Scholar 

  124. Wiesinger H (2001) Arginine metabolism and the synthesis of nitric oxide in the nervous system. Prog Neurobiol 64(4):365–391

    Article  CAS  PubMed  Google Scholar 

  125. Zomkowski AD, Hammes L, Lin J, Calixto JB, Santos AR, Rodrigues AL (2002) Agmatine produces antidepressant-like effects in two models of depression in mice. NeuroReport 13(4):387–391

    Article  CAS  PubMed  Google Scholar 

  126. Aricioglu F, Altunbas H (2003) Is agmatine an endogenous anxiolytic/antidepressant agent? Ann N Y Acad Sci 1009:136–140

    Article  CAS  PubMed  Google Scholar 

  127. Li YF, Gong ZH, Cao JB, Wang HL, Luo ZP, Li J (2003) Antidepressant-like effect of agmatine and its possible mechanism. Eur J Pharmacol 469(1–3):81–88

    Article  CAS  PubMed  Google Scholar 

  128. Krass M, Wegener G, Vasar E, Volke V (2008) Antidepressant-like effect of agmatine is not mediated by serotonin. Behav Brain Res 188(2):324–328

    Article  CAS  PubMed  Google Scholar 

  129. Halaris A, Zhu H, Feng Y, Piletz JE (1999) Plasma agmatine and platelet imidazoline receptors in depression. Ann N Y Acad Sci 881:445–451

    Article  CAS  PubMed  Google Scholar 

  130. Halaris A, Piletz JE (2001) Imidazoline receptors: possible involvement in the pathophysiology and treatment of depression. Hum Psychopharmacol Clin Exp 16(1):65–69

    Article  CAS  Google Scholar 

  131. Halaris A, Piletz JE (2003) Relevance of imidazoline receptors and agmatine to psychiatry: a decade of progress. Ann N Y Acad Sci 1009:1–20

    Article  CAS  PubMed  Google Scholar 

  132. Taksande BG, Kotagale NR, Tripathi SJ, Ugale RR, Chopde CT (2009) Antidepressant like effect of selective serotonin reuptake inhibitors involve modulation of imidazoline receptors by agmatine. Neuropharmacol 57(4):415–424

    Article  CAS  Google Scholar 

  133. Ogawa T, Kimoto M, Watanabe H, Sasaoka K (1987) Metabolism of NG, NG-and NG, N’G-dimethylarginine in rats. Arch Biochem Biophys 252(2):526–537

    Article  CAS  PubMed  Google Scholar 

  134. 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(2):90–96

    Article  PubMed  Google Scholar 

  135. Doucet MV, Levine H, Dev KK, Harkin A (2013) Small-molecule inhibitors at the PSD-95/nNOS interface have antidepressant-like properties in mice. Neuropsychopharmacol 38(8):1575–1584

    Article  CAS  Google Scholar 

  136. Tillmann S, Pereira VS, Liebenberg N, Christensen AK, Wegener G (2017) ZL006, a small molecule inhibitor of PSD-95/nNOS interaction, does not induce antidepressant-like effects in two genetically predisposed rat models of depression and control animals. PLoS ONE 12(8):e0182698

    Article  PubMed  PubMed Central  Google Scholar 

  137. Doucet MV, O’Toole E, Connor T, Harkin A (2015) Small-molecule inhibitors at the PSD-95/nNOS interface protect against glutamate-induced neuronal atrophy in primary cortical neurons. Neurosci 301:421–438

    Article  CAS  Google Scholar 

  138. Finkel MS, Laghrissi-Thode F, Pollock BG, Rong J (1996) Paroxetine is a novel nitric oxide synthase inhibitor. Psychopharmacol Bull 32(4):653–658

    CAS  PubMed  Google Scholar 

  139. 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(1):128–134

    Article  CAS  PubMed  Google Scholar 

  140. Musazzi L, Treccani G, Mallei A, Popoli M (2013) The action of antidepressants on the glutamate system: regulation of glutamate release and glutamate receptors. Biol Psychiatry 73(12):1180–1188

    Article  CAS  PubMed  Google Scholar 

  141. Chanrion B, Mannoury la Cour C, Bertaso F, Lerner-Natoli M, Freissmuth M, Millan MJ, et al. Physical interaction between the serotonin transporter and neuronal nitric oxide synthase underlies reciprocal modulation of their activity. Proc Natl Acad Sci U S A. 2007;104(19):8119–24.

    Google Scholar 

  142. Harkin A, Connor TJ, Walsh M, St John N, Kelly JP (2003) Serotonergic mediation of the antidepressant-like effects of nitric oxide synthase inhibitors. Neuropharmacol 44(5):616–623

    Article  CAS  Google Scholar 

  143. 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(3):187–196

    Article  CAS  PubMed  Google Scholar 

  144. Jesse CR, Bortolatto CF, Savegnago L, Rocha JB, Nogueira CW (2008) Involvement of L-arginine-nitric oxide-cyclic guanosine monophosphate pathway in the antidepressant-like effect of tramadol in the rat forced swimming test. Prog Neuropsychopharmacol Biol Psychiatry 32(8):1838–1843

    Article  CAS  PubMed  Google Scholar 

  145. Dhir A, Kulkarni SK (2007) Involvement of nitric oxide (NO) signaling pathway in the antidepressant action of bupropion, a dopamine reuptake inhibitor. Eur J Pharmacol 568(1–3):177–185

    Article  CAS  PubMed  Google Scholar 

  146. Ghasemi M, Sadeghipour H, Mosleh A, Sadeghipour HR, Mani AR, Dehpour AR (2008) Nitric oxide involvement in the antidepressant-like effects of acute lithium administration in the mouse forced swimming test. Eur Neuropsychopharmacol 18(5):323–332

    Article  CAS  PubMed  Google Scholar 

  147. Ferreira FR, Oliveira AM, Dinarte AR, Pinheiro DG, Greene LJ, Silva WA Jr et al (2012) Changes in hippocampal gene expression by 7-nitroindazole in rats submitted to forced swimming stress. Genes Brain Behav 11(3):303–313

    Article  CAS  PubMed  Google Scholar 

  148. Chiavegatto S, Dawson VL, Mamounas LA, Koliatsos VE, Dawson TM, Nelson RJ (2001) Brain serotonin dysfunction accounts for aggression in male mice lacking neuronal nitric oxide synthase. Proc Natl Acad Sci USA 98(3):1277–1281

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Kuhn DM, Aretha CW, Geddes TJ (1999) Peroxynitrite inactivation of tyrosine hydroxylase: Mediation by sulfhydryl oxidation, not tyrosine nitration. J Neurosci 19(23):10289–10294

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Smith JC, Whitton PS (2000) Nitric oxide modulates N-methyl-D-aspartate-evoked serotonin release in the raphe nuclei and frontal cortex of the freely moving rat. Neurosci Lett 291(1):5–8

    Article  CAS  PubMed  Google Scholar 

  151. Trabace L, Kendrick KM (2000) Nitric oxide can differentially modulate striatal neurotransmitter concentrations via soluble guanylate cyclase and peroxynitrite formation. J Neurochem 75(4):1664–1674

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Segieth J, Pearce B, Fowler L, Whitton PS (2001) Regulatory role of nitric oxide over hippocampal 5-HT release in vivo. Naunyn Schmiedebergs ArchPharmacol. 363(3):302–306

    Article  CAS  Google Scholar 

  154. Wegener G, Volke V, Rosenberg R. Endogenous nitric oxide decreases the release of serotonin in the hippocampus: An in vivo microdialysis study. Nord J Psychiat. 2000;54(2):87-.

    Google Scholar 

  155. Strasser A, McCarron RM, Ishii H, Stanimirovic D, Spatz M (1994) L-arginine induces dopamine release from the striatum in vivo. NeuroReport 5(17):2298–2300

    Article  CAS  PubMed  Google Scholar 

  156. Asano S, Matsuda T, Nakasu Y, Maeda S, Nogi H, Baba A (1997) Inhibition by nitric oxide of the uptake of [3H]serotonin into rat brain synaptosomes. JpnJ Pharmacol. 75(2):123–128

    Article  CAS  Google Scholar 

  157. Bryan-Lluka LJ, Papacostas MH, Paczkowski FA, Wanstall JC (2004) Nitric oxide donors inhibit 5-hydroxytryptamine (5-HT) uptake by the human 5-HT transporter (SERT). Br J Pharmacol 143(1):63–70

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Lu Y, Simpson KL, Weaver KJ, Lin RC (2010) Coexpression of serotonin and nitric oxide in the raphe complex: cortical versus subcortical circuit. Anat Rec (Hoboken) 293(11):1954–1965

    Article  PubMed  Google Scholar 

  159. Manji HK, Moore GJ, Rajkowska G, Chen G (2000) Neuroplasticity and cellular resilience in mood disorders. Mol Psychiatry 5(6):578–593

    Article  CAS  PubMed  Google Scholar 

  160. Manji HK, Drevets WC, Charney DS (2001) The cellular neurobiology of depression. NatMed. 7(5):541–547

    CAS  Google Scholar 

  161. Levy MJF, Boulle F, Steinbusch HW, van den Hove DLA, Kenis G, Lanfumey LJP (2018) Neurotrophic factors and neuroplasticity pathways in the pathophysiology and treatment of depression. 235(8):2195–2220

    CAS  Google Scholar 

  162. Leal G, Bramham CR, Duarte CB. Chapter Eight - BDNF and Hippocampal Synaptic Plasticity. In: Litwack G, editor. Vitam Horm. 104: Academic Press; 2017. p. 153–95.

    Google Scholar 

  163. 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(5):3282–3287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Pinnock SB, Herbert J (2008) Brain-derived neurotropic factor and neurogenesis in the adult rat dentate gyrus: interactions with corticosterone. Eur J Neurosci 27(10):2493–2500

    Article  PubMed  PubMed Central  Google Scholar 

  165. Salehpour M, Khodagholi F, Zeinaddini Meymand A, Nourshahi M, Ashabi G (2017) Exercise training with concomitant nitric oxide synthase inhibition improved anxiogenic behavior, spatial cognition, and BDNF/P70S6 kinase activation in 20-month-old rats. Appl Physiol Nutr Metab 43(1):45–53

    Article  PubMed  Google Scholar 

  166. Xiong H, Yamada K, Han D, Nabeshima T, Enikolopov G, Carnahan J et al (1999) Mutual regulation between the intercellular messengers nitric oxide and brain-derived neurotrophic factor in rodent neocortical neurons. 11(5):1567–1576

    CAS  Google Scholar 

  167. Silva Pereira V, Elfving B, Joca SRL, Wegener G (2017) Ketamine and aminoguanidine differentially affect Bdnf and Mtor gene expression in the prefrontal cortex of adult male rats. Eur J Pharmacol 815:304–311

    Article  PubMed  Google Scholar 

  168. Joca S, Biojone C, Casarotto P, Montezuma K, Cunha F, Guimaraes F (2012) BDNF-TrkB signaling is involved in the antidepressant-like effect induced by genetic deletion of iNOS. Int J Neuropsychopharmacol 15:44–45

    Google Scholar 

  169. Yuen EC, Gunther EC, Bothwell M (2000) Nitric oxide activation of TrkB through peroxynitrite. 11(16):3593–3597

    CAS  Google Scholar 

  170. Kolarow R, Kuhlmann CR, Munsch T, Zehendner C, Brigadski T, Luhmann HJ et al (2014) BDNF-induced nitric oxide signals in cultured rat hippocampal neurons: time course, mechanism of generation, and effect on neurotrophin secretion. Front Cell Neurosci 8(323):323

    PubMed  PubMed Central  Google Scholar 

  171. 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(8):979–987

    Article  CAS  PubMed  Google Scholar 

  172. Cheng A, Wang S, Cai J, Rao MS, Mattson MP (2003) Nitric oxide acts in a positive feedback loop with BDNF to regulate neural progenitor cell proliferation and differentiation in the mammalian brain. DevBiol. 258(2):319–333

    CAS  Google Scholar 

  173. Mizoguchi Y, Kato TA, Seki Y, Ohgidani M, Sagata N, Horikawa H et al (2014) Brain-derived neurotrophic factor (BDNF) induces sustained intracellular Ca2+ elevation through the up-regulation of surface transient receptor potential 3 (TRPC3) channels in rodent microglia. J Biol Chem 289(26):18549–18555

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Cai C-Y, Chen C, Zhou Y, Han Z, Qin C, Cao B et al (2018) PSD-95-nNOS Coupling Regulates Contextual Fear Extinction in the Dorsal CA3. Sci Rep 8(1):12775

    Article  PubMed  PubMed Central  Google Scholar 

  175. Manucha W (2017) Mitochondrial dysfunction associated with nitric oxide pathways in glutamate neurotoxicity. Clínica e Investigación en Arteriosclerosis. 29(2):92–97

    Article  PubMed  Google Scholar 

  176. Sunico CR, Portillo F, Gonzalez-Forero D, Moreno-Lopez B (2005) Nitric-oxide-directed synaptic remodeling in the adult mammal CNS. J Neurosci 25(6):1448–1458

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Joca SR, Guimaraes FS, Del-Bel E (2007) Inhibition of nitric oxide synthase increases synaptophysin mRNA expression in the hippocampal formation of rats. Neurosci Lett 421(1):72–76

    Article  CAS  PubMed  Google Scholar 

  178. Nikonenko I, Boda B, Steen S, Knott G, Welker E, Muller D. PSD-95 promotes synaptogenesis and multiinnervated spine formation through nitric oxide signaling. 2008;183(6):1115–27.

    Google Scholar 

  179. Gray WP, Cheung A. Chapter Four - Nitric Oxide Regulation of Adult Neurogenesis. In: Litwack G, editor. Vitam Horm. 96: Academic Press; 2014. p. 59–77.

    Google Scholar 

  180. Chong CM, Ai N, Ke M, Tan Y, Huang Z, Li Y et al (2018) Roles of Nitric Oxide Synthase Isoforms in Neurogenesis. Mol Neurobiol 55(3):2645–2652

    Article  CAS  PubMed  Google Scholar 

  181. Duman RS, Malberg J, Nakagawa S (2001) Regulation of Adult Neurogenesis by Psychotropic Drugs and Stress. J Pharmacol Exp Ther 299(2):401–407

    CAS  PubMed  Google Scholar 

  182. Duman RS, Nakagawa S, Malberg J (2001) Regulation of Adult Neurogenesis by Antidepressant Treatment. Neuropsychopharmacol 25(6):836–844

    Article  CAS  Google Scholar 

  183. Spalding KL, Bergmann O, Alkass K, Bernard S, Salehpour M, Huttner HB et al (2013) XDynamics of hippocampal neurogenesis in adult humans. Cell 153(6):X1219–X1227

    Article  Google Scholar 

  184. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S et al (2003) Requirement of Hippocampal Neurogenesis for the Behavioral Effects of Antidepressants. Science 301(5634):805–809

    Article  CAS  PubMed  Google Scholar 

  185. Ehninger D, Kempermann G (2008) Neurogenesis in the adult hippocampus. Cell Tissue Res 331(1):243–250

    Article  PubMed  Google Scholar 

  186. Romero-Grimaldi C, Moreno-López B, Estrada C (2008) Age-dependent effect of nitric oxide on subventricular zone and olfactory bulb neural precursor proliferation. J Comp Neurol 506(2):339–346

    Article  CAS  PubMed  Google Scholar 

  187. Shariful Islam ATM, Kuraoka A, Kawabuchi M (2003) Morphological basis of nitric oxide production and its correlation with the polysialylated precursor cells in the dentate gyrus of the adult guinea pig hippocampus. Anat Sci Int 78(2):98–103

    Article  Google Scholar 

  188. Luo C-X, Jin X, Cao C-C, Zhu M-M, Wang B, Chang L et al (2010) BIdirectional Regulation of Neurogenesis by Neuronal Nitric Oxide Synthase Derived from Neurons and Neural Stem Cells. 28(11):2041–2052

    CAS  PubMed  Google Scholar 

  189. Matarredona ER, Murillo-Carretero M, Moreno-López B, Estrada C (2004) Nitric oxide synthesis inhibition increases proliferation of neural precursors isolated from the postnatal mouse subventricular zone. Brain Res 995(2):274–284

    Article  CAS  PubMed  Google Scholar 

  190. Zhu XJ, Hua Y, Jiang J, Zhou QG, Luo CX, Han X et al (2006) Neuronal nitric oxide synthase-derived nitric oxide inhibits neurogenesis in the adult dentate gyrus by down-regulating cyclic AMP response element binding protein phosphorylation. Neurosci 141(2):827–836

    Article  CAS  Google Scholar 

  191. Packer MA, Stasiv Y, Benraiss A, Chmielnicki E, Grinberg A, Westphal H et al (2003) Nitric oxide negatively regulates mammalian adult neurogenesis. Proc Natl Acad Sci U S A 100(16):9566–9571

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Park S-Y, Kang M-J, Han J-SJMN. Neuronal NOS Induces Neuronal Differentiation Through a PKCα-Dependent GSK3β Inactivation Pathway in Hippocampal Neural Progenitor Cells. 2017;54(7):5646–56.

    Google Scholar 

  193. Islam ATMS, Kuraoka A, Kawabuchi MJASI (2003) Morphological basis of nitric oxide production and its correlation with the polysialylated precursor cells in the dentate gyrus of the adult guinea pig hippocampus. 78(2):98–103

    CAS  Google Scholar 

  194. Izumi Y, Zorumski CF (1993) Nitric oxide and long-term synaptic depression in the rat hippocampus. NeuroReport 4(9):1131–1134

    CAS  PubMed  Google Scholar 

  195. Zorumski CF, Izumi Y (1993) Nitric oxide and hippocampal synaptic plasticity. Biochem Pharmacol 46(5):777–785

    Article  CAS  PubMed  Google Scholar 

  196. Hölscher C (1997) Nitric oxide, the enigmatic neuronal messenger: its role in synaptic plasticity. Trends Neurosci 20(7):298–303

    Article  PubMed  Google Scholar 

  197. Hardingham N, Dachtler J, Fox K (2013) The role of nitric oxide in pre-synaptic plasticity and homeostasis. Front Cell Neurosci 7(190):190

    CAS  PubMed  PubMed Central  Google Scholar 

  198. Nikonenko I, Nikonenko A, Mendez P, Michurina TV, Enikolopov G, Muller D (2013) Nitric oxide mediates local activity-dependent excitatory synapse development. 110(44):E4142–E4151

    CAS  Google Scholar 

  199. Rabinovich D, Yaniv Shiri P, Alyagor I, Schuldiner O (2016) Nitric Oxide as a Switching Mechanism between Axon Degeneration and Regrowth during Developmental Remodeling. Cell 164(1):170–182

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Ribeiro DE, Roncalho AL, Glaser T, Ulrich H, Wegener G, Joca S (2019) P2X7 Receptor Signaling in Stress and Depression. Int J Mol Sci 20(11):2778

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Miller AH, Maletic V, Raison CL (2009) Inflammation and Its Discontents: The Role of Cytokines in the Pathophysiology of Major Depression. Biol Psychiatry 65(9):732–741

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Suneson K, Lindahl J, Chamli Hårsmar S, Söderberg G, Lindqvist D (2021) Inflammatory Depression—Mechanisms and Non-Pharmacological Interventions. Int J Mol Sci 22(4):1640

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Dantzer R, Kelley KW (2007) Twenty years of research on cytokine-induced sickness behavior. Brain Behav Immun 21:153–160

    Article  CAS  PubMed  Google Scholar 

  204. Liu JJ, Wei YB, Strawbridge R, Bao Y, Chang S, Shi L et al (2020) Peripheral cytokine levels and response to antidepressant treatment in depression: a systematic review and meta-analysis. Mol Psychiatry 25(2):339–350

    Article  CAS  PubMed  Google Scholar 

  205. Yuan Z, Chen Z, Xue M, Zhang J, Leng L (2020) Application of antidepressants in depression: A systematic review and meta-analysis. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia. 80:169–181

    Article  CAS  PubMed  Google Scholar 

  206. Inserra A, Mastronardi CA, Rogers G, Licinio J, Wong M-L (2019) Neuroimmunomodulation in Major Depressive Disorder: Focus on Caspase 1, Inducible Nitric Oxide Synthase, and Interferon-Gamma. Mol Neurobiol 56(6):4288–4305

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study was financed by Aarhus University Research Foundation (AUFF starting grant to SJ), and Independent Research Fund Denmark (grant 8020-00310B to GW).

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Authors and Affiliations

  1. Department of Clinical Medicine, Aarhus University, Aarhus, Denmark

    Gregers Wegener

  2. Department of Biomedicine, Aarhus University, Aarhus, Denmark

    Sâmia R. L. Joca

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  1. Gregers Wegener
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Correspondence to Gregers Wegener .

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Editors and Affiliations

  1. Department of Pharmacology, Hamdard Institute of Medical Sciences and Research, Hamdard University, New Delhi, India

    Arunabha Ray

  2. Department of Pharmacology, Vallabhbhai Patel Chest Institute, University of Delhi, New Delhi, India

    Kavita Gulati

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GW reports having received lecture/consultancy fees/research support from H. Lundbeck A/S, Servier SA, Astra Zeneca AB, Eli Lilly A/S, Sun Pharma Pty Ltd, Pfizer Inc, Shire A/S, HB Pharma A/S, Alkermes Inc, Mundipharma International Ltd., J&J Inc., and Jannsen Pharma A/S. SJ reports no conflicts of interest.

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Wegener, G., Joca, S.R.L. (2023). Nitric Oxide in Major Depressive Disorder. In: Ray, A., Gulati, K. (eds) Nitric Oxide: From Research to Therapeutics. Advances in Biochemistry in Health and Disease, vol 22. Springer, Cham. https://doi.org/10.1007/978-3-031-24778-1_15

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