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Nitric oxide involvement in the antidepressant-like effect of ketamine in the Flinders sensitive line rat model of depression

  • Nico Liebenberg (a1), Sâmia Joca (a2) and Gregers Wegener (a1) (a3)
Abstract
Objective

We investigated whether the nitric oxide (NO) precursor, l-arginine, can prevent the antidepressant-like action of the fast-acting antidepressant, ketamine, in a genetic rat model of depression, and/or induce changes in the glutamate (Glu)/N-methyl-d-aspartate receptor (NMDAR)/NO/cyclic guanosine monophosphate (cGMP) signalling pathway. Hereby it was evaluated whether the NO signalling system is involved in the antidepressant mechanism of ketamine.

Methods

Flinders sensitive line (FSL) rats received single i.p. injections of ketamine (15 mg/kg) with/without pre-treatment (30 min prior) with l-arginine (500 mg/kg). Depression-like behaviour was assessed in the forced swim test (FST) in terms of immobility, and the activation state of the Glu/NMDAR/NO/cGMP pathway was evaluated ex vivo in the frontal cortex and hippocampus regions in terms of total constitutive NOS (cNOS) activity and cGMP concentration.

Results

l-Arginine pre-treatment prevented the antidepressant-like effect of ketamine in the FST, as well as a ketamine-induced increase in cGMP levels in the frontal cortex and hippocampus of FSL rats. Ketamine reduced cNOS activity only in the hippocampus, and this effect was not reversed by l-arginine.

Conclusion

Both the behavioural and molecular results from this study indicate an involvement for the NO signalling pathway in the antidepressant action of ketamine. Although not easily interpretable, these findings broaden our knowledge of effects of ketamine on the NO system.

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Copyright
This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited.
Corresponding author
Nico Liebenberg, Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Risskov, Denmark. Tel: +45 4252 0521; Fax: +45 7847 1124; E-mail: nico.liebenberg@clin.au.dk
References
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1. Berman, RM, Cappiello, A, Anand, A et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47:351354.
2. Zarate, CA Jr, Singh, JB, Carlson, PJ et al. A randomized trial of an N-methyl-d-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 2006;63:856864.
3. Fond, G, Loundou, A, Rabu, C et al. Ketamine administration in depressive disorders: a systematic review and meta-analysis. Psychopharmacology 2014;231:36633676.
4. McGirr, A, Berlim, MT, Bond, DJ, Fleck, MP, Yatham, LN, Lam, RW. A systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials of ketamine in the rapid treatment of major depressive episodes. Psychol Med 2014;10:112.
5. Duman, RS, Li, N, Liu, RJ, Duric, V, Aghajanian, G. Signaling pathways underlying the rapid antidepressant actions of ketamine. Neuropharmacology 2012;62:3541.
6. Maeng, S, Zarate, CA Jr., Du, J et al. Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol Psychiatry 2008;63:349352.
7. Li, N, Lee, B, Liu, RJ et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 2010;329:959964.
8. Christopherson, KS, Hillier, BJ, Lim, WA, Bredt, DS. PSD-95 assembles a ternary complex with the N-methyl-d-aspartic acid receptor and a bivalent neuronal NO synthase PDZ domain. J Biol Chem 1999;274:2746727473.
9. Suzuki, E, Yagi, G, Nakaki, T, Kanba, S, Asai, M. Elevated plasma nitrate levels in depressive states. J Affect Disord 2001;63:221224.
10. Heiberg, IL, Wegener, G, Rosenberg, R. Reduction of cGMP and nitric oxide has antidepressant-like effects in the forced swimming test in rats. Behav Brain Res 2002;134:479484.
11. Wegener, G, Volke, V, Harvey, BH, Rosenberg, R. Local but not systemic, administration of serotonergic antidepressants decreases hippocampal nitric oxide synthase activity. Brain Res 2003;959:128134.
12. Jefferys, D, Funder, J. Nitric oxide modulates retention of immobility in the forced swimming test in rats. Eur J Pharmacol 1996;295:131135.
13. 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. Eur J Pharmacol 1999;372:207213.
14. Hiroaki-Sato, VA, Sales, AJ, Biojone, C, Joca, SR. Hippocampal nNOS inhibition induces an antidepressant-like effect: involvement of 5HT1A receptors. Behav Pharmacol 2014;25:187196.
15. Yazir, Y, Utkan, T, Aricioglu, F. 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 2012;111:154160.
16. Montezuma, K, Biojone, C, Lisboa, SF, Cunha, FQ, Guimaraes, FS, Joca, SR. Inhibition of iNOS induces antidepressant-like effects in mice: pharmacological and genetic evidence. Neuropharmacology 2012;62:485491.
17. Jesse, CR, Bortolatto, CF, Savegnago, L, Rocha, JB, Nogueira, CW. Involvement of l-arginine-nitric oxide-cyclic guanosine monophosphate pathway in the antidepressant-like effect of tramadol in the rat forced swimming test. Prog Neuro-Psychopharmacol Biol Psychiatry 2008;32:18381843.
18. Donato, F, de Gomes, MG, Goes, AT et al. Hesperidin exerts antidepressant-like effects in acute and chronic treatments in mice: possible role of l-arginine-NO-cGMP pathway and BDNF levels. Brain Res Bull 2014;104:1926.
19. Freitas, AE, Moretti, M, Budni, J et al. NMDA receptors and the l-arginine-nitric oxide-cyclic guanosine monophosphate pathway are implicated in the antidepressant-like action of the ethanolic extract from Tabebuia avellanedae in mice. J Med Food 2013;16:10301038.
20. Zhang, GF, Wang, N, Shi, JY et al. Inhibition of the l-arginine-nitric oxide pathway mediates the antidepressant effects of ketamine in rats in the forced swimming test. Pharmacol, Biochem Behav 2013;110:812.
21. Moretti, M, Freitas, AE, Budni, J, Fernandes, SC, Balen Gde, O, Rodrigues, AL. Involvement of nitric oxide-cGMP pathway in the antidepressant-like effect of ascorbic acid in the tail suspension test. Behav Brain Res 2011;225:328333.
22. Krass, M, Wegener, G, Vasar, E, Volke, V. The antidepressant action of imipramine and venlafaxine involves suppression of nitric oxide synthesis. Behav Brain Res 2011;218:5763.
23. Padovan, CM, Guimaraes, FS. Antidepressant-like effects of NMDA-receptor antagonist injected into the dorsal hippocampus of rats. Pharmacol Biochem Behav 2004;77:1519.
24. Joca, SR, Guimaraes, FS. Inhibition of neuronal nitric oxide synthase in the rat hippocampus induces antidepressant-like effects. Psychopharmacology 2006;185:298305.
25. Overstreet, DH, Friedman, E, Mathe, AA, Yadid, G. The Flinders sensitive line rat: a selectively bred putative animal model of depression. Neurosci Biobehav Rev 2005;29:739759.
26. Overstreet, DH, Wegener, G. The Flinders sensitive line rat model of depression: 25 years and still producing. Pharmacol Rev 2013;65:143155.
27. Garcia, LS, Comim, CM, Valvassori, SS et al. Acute administration of ketamine induces antidepressant-like effects in the forced swimming test and increases BDNF levels in the rat hippocampus. Prog Neuro-Psychopharmacol Biol Psychiatry 2008;32:140144.
28. Cryan, JF, Markou, A, Lucki, I. Assessing antidepressant activity in rodents: recent developments and future needs. Trends Pharmacol Sci 2002;23:238245.
29. Demady, DR, Jianmongkol, S, Vuletich, JL, Bender, AT, Osawa, Y. Agmatine enhances the NADPH oxidase activity of neuronal NO synthase and leads to oxidative inactivation of the enzyme. Mol Pharmacol 2001;59:2429.
30. Parsons, MP, Raymond, LA. Extrasynaptic NMDA receptor involvement in central nervous system disorders. Neuron 2014;82:279293.
31. Liu, DD, Yang, Q, Li, ST. Activation of extrasynaptic NMDA receptors induces LTD in rat hippocampal CA1 neurons. Brain Res Bull 2013;93:1016.
32. Yashiro, K, Philpot, BD. Regulation of NMDA receptor subunit expression and its implications for LTD, LTP, and metaplasticity. Neuropharmacology 2008;55:10811094.
33. Moghaddam, B, Adams, B, Verma, A, Daly, D. Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci: the Official Journal of the Society for Neuroscience 1997;17:29212927.
34. Perrine, SA, Ghoddoussi, F, Michaels, MS, Sheikh, IS, McKelvey, G, Galloway, MP. Ketamine reverses stress-induced depression-like behavior and increased GABA levels in the anterior cingulate: an 11.7T 1H-MRS study in rats. Prog Neuro-Psychopharmacol Biol Psychiatry 2014;51:915.
35. Wegener, G, Harvey, BH, Bonefeld, B et al. Increased stress-evoked nitric oxide signalling in the Flinders sensitive line (FSL) rat: a genetic animal model of depression. Int J Neuropsychopharmacol/Official Scientific Journal of the Collegium Internationale Neuropsychopharmacologicum 2010;13:461473.
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Acta Neuropsychiatrica
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