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Decreased levels of kynurenic acid in prefrontal cortex in a genetic animal model of depression

Published online by Cambridge University Press:  13 July 2016

Xi-Cong Liu ,
Sophie Erhardt ,
Michel Goiny ,
Göran Engberg  and
Aleksander A. Mathé
Xi-Cong Liu
Affiliation:
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
Sophie Erhardt
Affiliation:
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
Michel Goiny
Affiliation:
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
Göran Engberg*
Affiliation:
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
Aleksander A. Mathé
Affiliation:
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
*
Göran Engberg, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden. Tel: +46 703526717; Fax: +46 703526717; E-mail: [email protected]
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Abstract

Objective

There is a growing interest in the role of kynurenine pathway and tryptophan metabolites in the pathophysiology of depression. In the present study, the metabolism of tryptophan along the kynurenine pathway was analysed in a rat model of depression.

Methods

Kynurenic acid (KYNA) and 3-hydroxykynurenine (3-HK) were measured by high-performance liquid chromatography (HPLC) in prefrontal cortex (PFC) and frontal cortex (FC) in a rat model of depression, the Flinders Sensitive Line (FSL) and their controls, the Flinders Resistant Line (FRL) rats. In addition, KYNA was also measured in hippocampus, striatum and cerebellum.

Results

KYNA levels were reduced in the PFC of FSL rats compared with FRL rats, but did not differ with regard to the FC, hippocampus, striatum or cerebellum. 3-HK levels in PFC and FC, representing the activity of the microglial branch of the kynurenine pathway, did not differ between the FSL and FRL strains.

Conclusion

Our results suggest an imbalanced metabolism of the kynurenine pathway in the PFC of FSL rats.

Keywords

3-hydroxykynureninedepressionFlinders Sensitive Line ratkynurenic acid
Type
Original Articles
Information
Acta Neuropsychiatrica , Volume 29 , Issue 1 , February 2017 , pp. 54 - 58
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Copyright
© Scandinavian College of Neuropsychopharmacology 2016 

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References

1. Zarate, CA, 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;63:856–864.Google Scholar
2. Abdallah, CG, Averill, LA, Krystal, JH. Ketamine as a promising prototype for a new generation of rapid-acting antidepressants. Ann N Y Acad Sci 2015;1344:66–77.Google Scholar
3. Berman, RM, Cappiello, A, Anand, A et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 2000;47:351–354.Google Scholar
4. Skolnick, P, Layer, RT, Popik, P, Nowak, G, Paul, IA, Trullas, R. Adaptation of N-methyl-D-aspartate (NMDA) receptors following antidepressant treatment: implications for the pharmacotherapy of depression. Pharmacopsychiatry 1996;29:23–26.Google Scholar
5. Najjar, S, Pearlman, DM, Alper, K, Najjar, A, Devinsky, O. Neuroinflammation and psychiatric illness. J Neuroinflammation 2013;10:43.CrossRefGoogle ScholarPubMed
6. Schwarcz, R, Bruno, JP, Muchowski, PJ, Wu, H-Q. Kynurenines in the mammalian brain: when physiology meets pathology. Nat Rev Neurosci 2012;13:465–477.Google Scholar
7. Bogdanov, VB, Bogdanova, OV, Koulchitsky, SV et al. Behavior in the open field predicts the number of KCl-induced cortical spreading depressions in rats. Behav Brain Res 2013;236:90–93.Google Scholar
8. Jiménez-Vasquez, PA, Overstreet, DH, Mathé, AA. Neuropeptide Y in male and female brains of Flinders Sensitive Line, a rat model of depression. Effects of electroconvulsive stimuli. J Psychiatr Res 2000;34:405–412.Google Scholar
9. Glowinski, J, Iversen, LL. Regional studies of catecholamines in the rat brain. I. The disposition of [3H]norepinephrine, [3H]dopamine and [3H]dopa in various regions of the brain. J Neurochem 1966;13:655–669.Google Scholar
10. Agudelo, LZ, Femenía, T, Orhan, F et al. Skeletal muscle PGC-1α1 modulates kynurenine metabolism and mediates resilience to stress-induced depression. Cell 2014;159:33–45.Google Scholar
11. Ceresoli-Borroni, G, Guidetti, P, Amori, L, Pellicciari, R, Schwarcz, R. Perinatal kynurenine 3-hydroxylase inhibition in rodents: pathophysiological implications. J Neurosci Res 2007;85:845–854.Google Scholar
12. Notarangelo, FM, Wilson, EH, Horning, KJ et al. Evaluation of kynurenine pathway metabolism in Toxoplasma gondii-infected mice: implications for schizophrenia. Schizophr Res 2014;152:261–267.Google Scholar
13. El Khoury, A, Gruber, SH, Mørk, A, Mathé, AA. Adult life behavioral consequences of early maternal separation are alleviated by escitalopram treatment in a rat model of depression. Prog Neuropsychopharmacol Biol Psychiatry 2006;30:535–540.Google Scholar
14. Hansson, AC, Rimondini, R, Heilig, M, Mathé, AA, Sommer, WH. Dissociation of antidepressant-like activity of escitalopram and nortriptyline on behaviour and hippocampal BDNF expression in female rats. J Psychopharmacol (Oxford) 2011;25:1378–1387.Google Scholar
15. Musazzi, L, Mallei, A, Tardito, D et al. Early-life stress and antidepressant treatment involve synaptic signaling and Erk kinases in a gene-environment model of depression. Psychiatr Res 2010;44:511–520.Google Scholar
16. Piubelli, C, Vighini, M, Mathé, AA, Domenici, E, Carboni, L. Escitalopram modulates neuron-remodelling proteins in a rat gene-environment interaction model of depression as revealed by proteomics. Part I: genetic background. Int J Neuropsychopharmacol 2011;14:796–833.Google Scholar
17. Piubelli, C, Vighini, M, Mathé, AA, Domenici, E, Carboni, L. Escitalopram affects cytoskeleton and synaptic plasticity pathways in a rat gene-environment interaction model of depression as revealed by proteomics. Part II: environmental challenge. Int J Neuropsychopharmacol 2011;14:834–855.Google Scholar
18. Shrestha, SS, Pine, DS, Luckenbaugh, DA et al. Antidepressant effects on serotonin 1A/1B receptors in the rat brain using a gene x environment model. Neurosci Lett 2014;559:163–168.Google Scholar
19. Overstreet, DH, Friedman, E, Mathé, AA, Yadid, G. The Flinders Sensitive Line rat: a selectively bred putative animal model of depression. Neurosci Biobehav Rev 2005;29:739–759.Google Scholar
20. Ryan, B, Musazzi, L, Mallei, A et al. Remodelling by early-life stress of NMDA receptor-dependent synaptic plasticity in a gene-environment rat model of depression. Int J Neuropsychopharmacol 2009;12:553–559.Google Scholar
21. Hascup, KN, Hascup, ER, Stephens, ML et al. Resting glutamate levels and rapid glutamate transients in the prefrontal cortex of the Flinders Sensitive Line rat: a genetic rodent model of depression. Neuropsychopharmacology 2011;36:1769–1777.Google Scholar
22. Gómez-Galán, M, De Bundel, D, Van Eeckhaut, A, Smolders, I, Lindskog, M. Dysfunctional astrocytic regulation of glutamate transmission in a rat model of depression. Mol Psychiatry 2013;18:582–594.Google Scholar
23. Kocki, T, Wnuk, S, Kloc, R, Kocki, J, Owe-Larsson, B, Urbanska, EM. New insight into the antidepressants action: modulation of kynurenine pathway by increasing the kynurenic acid/3-hydroxykynurenine ratio. J Neural Transm 2012;119:235–243.Google Scholar
24. Josefsson, T, Lindwall, M, Archer, T. Physical exercise intervention in depressive disorders: meta-analysis and systematic review. Scand J Med Sci Sports 2014;24:259–272.Google Scholar
25. Bjørnebekk, A, Mathé, AA, Brené, S. The antidepressant effects of running and escitalopram are associated with levels of hippocampal NPY and Y1 receptor but not cell proliferation in a rat model of depression. Hippocampus 2010;20:820–828.Google Scholar
26. Bay-Richter, C, Linderholm, KR, Lim, CK et al. A role for inflammatory metabolites as modulators of the glutamate N-methyl-D-aspartate receptor in depression and suicidality. Brain Behav Immun 2015;43:110–117.Google Scholar
27. Negrón-Oyarzo, I, Aboitiz, F, Fuentealba, P. Impaired functional connectivity in the prefrontal cortex: a mechanism for chronic stress-induced neuropsychiatric disorders. Neural Plast 2016; doi: 10.1155/2016/7539065 [Epub 2016 January 19].Google Scholar
28. Johnstone, T, van Reekum, CM, Urry, HL, Kalin, NH, Davidson, RJ. Failure to regulate: counterproductive recruitment of top-down prefrontal-subcortical circuitry in major depression. J Neurosci 2007;27:8877–8884.Google Scholar
29. Liu, X, Sun, G, Zhang, X et al. Relationship between the prefrontal function and the severity of the emotional symptoms during a verbal fluency task in patients with major depressive disorder: a multi-channel NIRS study. Prog Neuropsychopharmacol Biol Psychiatry 2014;54:114–121.Google Scholar
30. Dutta, A, McKie, S, Deakin, JF. Resting state networks in major depressive disorder. Psychiatry Res 2014;224:139–151.Google Scholar
31. Beggiato, S, Tanganelli, S, Fuxe, K, Antonelli, T, Schwarcz, R, Ferraro, L. Endogenous kynurenic acid regulates extracellular GABA levels in the rat prefrontal cortex. Neuropharmacology 2014;82:11–18.Google Scholar
32. Guillemin, GJ, Smith, DG, Smythe, GA, Armati, PJ, Brew, BJ. Expression of the kynurenine pathway enzymes in human microglia and macrophages. Adv Exp Med Biol 2003;527:105–112.Google Scholar
33. Sellgren, CM, Kegel, ME, Bergen, SE et al. A genome-wide association study of kynurenic acid in cerebrospinal fluid: implications for psychosis and cognitive impairment in bipolar disorder. Mol Psychiatry 2015; doi: 10.1038/mp.2015.186 [Epub ahead of print].Google Scholar
34. Parrott, JM, O’Connor, JC. Kynurenine 3-monooxygenase: an influential mediator of neuropathology. Front Psychiatry 2015;6:116.Google Scholar
35. Furtado, M, Katzman, MA. Examining the role of neuroinflammation in major depression. Psychiatry Res 2015;229:27–36.Google Scholar
36. Friedman, EM, Irwin, MR, Overstreet, DH. Natural and cellular immune responses in Flinders Sensitive and Resistant Line rats. Neuropsychopharmacology 1996;15:314–322.CrossRefGoogle ScholarPubMed
37. Caldwell, CL, Irwin, M, Lohr, J. Reduced natural killer cell cytotoxicity in depression but not in schizophrenia. Biol Psychiatry 1991;30:1131–1138.Google Scholar
38. Carboni, L, Becchi, S, Piubelli, C et al. Early-life stress and antidepressants modulate peripheral biomarkers in a gene-environment rat model of depression. Prog Neuropsychopharmacol Biol Psychiatry 2010;34:1037–1048.Google Scholar
39. Strenn, N, Suchankova, P, Nilsson, S et al. Expression of inflammatory markers in a genetic rodent model of depression. Behav Brain Res 2015;281:348–357.Google Scholar