Activities of the Dopaminergic System and Glutathione Antioxidant System in the Hippocampus of Stressed rats

  • N. Popović
  • S. B. Pajović
  • V. Stojiljković
  • A. Todorović
  • S. Pejić
  • I. Pavlović
  • L. GavrilovićEmail author

The effects of chronic restraint stress (CRS, 2 h during 14 days) on gene expression of tyrosine hydroxylase (TH), catechol-O-methyltransferase (COMT), and glutathione peroxidase (GPx) were studied in the rat hippocampus. Changes in the dopamine (DA) concentration and activities of monoamine oxidases (MAO A and MAO B) and GPx in this cerebral structure of chronically stressed rats were also examined. The investigated parameters were quantified using real-time RT-PCR, Western blot analyses, and assay of enzymatic activity. We found that CRS decreased the TH protein level and DA concentration, which probably confirms the statement that de novo synthesis of DA is suppressed under stress conditions. The increased activities of MAO B, as well as the increased level of COMT protein, are believed to be related to intensified DA catabolism conditions. Also, a decreased activity of GPx in the hippocampus of chronically stressed animals was found. The increased enzymatic activity of MAO B negatively correlated with the reduced activity of GPx under the above-mentioned stress conditions. These events in the hippocampus of chronically stressed animals could synergistically cause oxidative damage to the mitochondria.


dopamine glutathione peroxidase chronic restraint stress hippocampus gene expression 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Y. C. Tse, I. Montoya, A. S. Wong, et al., “A longitudinal study of stress-induced hippocampal volume changes in mice that are susceptible or resilient to chronic social defeat,” Hippocampus, 24, 1120-1128 (2014).CrossRefGoogle Scholar
  2. 2.
    B. S. McEwen and A. M. Magarinos, “Stress effects on morphology and function of the hippocampus,” Ann. N.Y. Acad. Sci., 821, 271-284 (1997).CrossRefGoogle Scholar
  3. 3.
    Xh Li, Jx Chen, Gx Yue, et al., “Gene expression profile of the hippocampus of rats subjected to chronic immobilization stress,” PLoS One, 8, No. 3, e57621 (2013).CrossRefGoogle Scholar
  4. 4.
    A. Ahmad, N. Rasheed, K. Chand, et al., “Restraint stress-induced central monoaminergic & oxidative changes in rats & their prevention by novel Ocimum sanctum compounds,” Indian J. Med. Res., 135, No. 4, 548-554 (2012).Google Scholar
  5. 5.
    C. Nunes, R. M. Barbosa, L. Almeida, and J. Laranjinha, “Nitric oxide and DOPAC-induced cell death: from GSH depletion to mitochondrial energy crisis,” Mol. Cell Neurosci., 48, No. 1, 94-103 (2011).CrossRefGoogle Scholar
  6. 6.
    L. Gavrilovic, N. Spasojevic, and S. Dronjak, “Subsequent stress increases gene expression of catecholamine synthetic enzymes in cardiac ventricles of chronic-stressed rats,” Endocrine, 37, 425-429 (2010).CrossRefGoogle Scholar
  7. 7.
    N. Popović, S. B. Pajović, V. Stojiljković, et al., “Prefrontal catecholaminergic turnover and antioxidant defense system of chronically stressed rats,” Folia Biol., 65, No. 1, 43-54 (2017).CrossRefGoogle Scholar
  8. 8.
    G. D. Gamaro, M. B. Michalowski, D. H. Catelli, et al., “Effect of repeated restraint stress on memory in different tasks,” Braz. J. Med. Biol. Res., 32, No. 3, 341-347 (1999).CrossRefGoogle Scholar
  9. 9.
    K. S. Kim and P. L. Han, “Optimization of chronic stress paradigms using anxiety- and depression-like behavioral parameters,” J. Neurosci. Res., 83, No. 3, 497-507 (2006).CrossRefGoogle Scholar
  10. 10.
    L. Gavrilović, V. Stojiljković, J. Kasapović, et al., “Treadmill exercise does not change gene expression of adrenal catecholamine biosynthetic enzymes in chronically stressed rats,” Ann. Acad. Bras. Cienc., 85, No. 3, 999-1012 (2013).CrossRefGoogle Scholar
  11. 11.
    T. M. Stich, “Determination of protein covalently bound to agarose supports using bicinchoninic acid,” Ann. Biochem., 191, 343-346 (1990).CrossRefGoogle Scholar
  12. 12.
    U. K. Laemmli, “Cleavage of structural proteins during the assembly of the head of bacteriophage T4,” Nature, 227, 680-685 (1970).CrossRefGoogle Scholar
  13. 13.
    M. Zhou and N. Panchuk-Voloshina, “A one-step fluorometric method for the continuous measurement of monoamine oxidase activity,” Analyt. Biochem., 253, No. 2, 169-174 (1997).CrossRefGoogle Scholar
  14. 14.
    V. Stojiljković, A. Todorović, S. Pejić, et al., “Antioxidant status and lipid peroxidation in small intestinal mucosa of children with celiac disease,” Clin. Biochem., 42, Nos. 13/14, 1431-1437 (2009).CrossRefGoogle Scholar
  15. 15.
    M. Bortolato, K. Chen, and J. C. Shih, “Monoamine oxidase inactivation: from pathophysiology to therapeutics,” Adv. Drug. Deliv. Rev., 60, 1527-1533 (2008).CrossRefGoogle Scholar
  16. 16.
    A. M. Cesura and A. Pletscher, “The new generation of monoamine oxidase inhibitors,” Prog. Drug. Res., 38, 171-297 (1992).Google Scholar
  17. 17.
    J. Knoll, “(-)Deprenyl (selegiline): past, present and future,” Neurobiology, 8, 179-199 (2000).Google Scholar
  18. 18.
    T. Müller, “Catechol-O-methyltransferase inhibitors in Parkinson’s disease,” Drugs, 75, No. 2, 157-174 (2015).CrossRefGoogle Scholar
  19. 19.
    V. Nilakantan, X. Zhou, G. Hilton, et al., “Hierarchical change in antioxidant enzyme gene expression and activity in acute cardiac rejection: role of inducible nitric oxide synthase,” Mol. Cell Biochem., 270, Nos. 1/2, 39-47 (2005).CrossRefGoogle Scholar
  20. 20.
    M. Hsu, B. Srinivas, J. Kumar, et al., “Glutathione depletion resulting in selective mitochondrial complex I inhibition in dopaminergic cells is via an NO-mediated pathway not involving peroxynitrite: implications for Parkinson’s disease,” J. Neurochem., 92, 1091-1103 (2005).CrossRefGoogle Scholar
  21. 21.
    J. E. Duda, B. I. Giasson, Q. Chen, et al., “Widespread nitration of pathological inclusions in neurodegenerative synucleinopathies,” Am. J. Pathol., 157, 1439-1445 (2000).CrossRefGoogle Scholar
  22. 22.
    B. I. Giasson, J. E. Duda, I. V. Murray, et al., “Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions,” Science, 290, 985-989 (2000).CrossRefGoogle Scholar
  23. 23.
    P. Klivenyi, O. A. Andreassen, R. J. Ferrante, et al., “Inhibition of neuronal nitric oxide synthase protects against MPTP toxicity,” NeuroReport, 11, 1265-1268 (2000).CrossRefGoogle Scholar
  24. 24.
    Watanabe Y, Kato H, Araki T, “Protective action of neuronal nitric oxide synthase inhibitor in the MPTP mouse model of Parkinson’s disease,” Metab. Brain Dis., 23, 51-69 (2008).CrossRefGoogle Scholar
  25. 25.
    H. Yokoyama, S. Takagi, Y. Watanabe, et al., “Role of reactive nitrogen and reactive oxygen species against MPTP neurotoxicity in mice,” J. Neural Transm., 115, 831-842 (2008).CrossRefGoogle Scholar
  26. 26.
    T. Alexander, C. E. Sortwell, C. D. Sladek, et al., “Comparison of neurotoxicity following repeated administration of L-dopa, D-dopa and dopamine to embryonic mesencephalic dopamine neurons in cultures derived from Fisher 344 and Sprague–Dawley donors,” Cell Transplant., 6, 309-315 (1997).CrossRefGoogle Scholar
  27. 27.
    F. Filloux and J. J. Townsend, “Pre- and postsynaptic neurotoxic effects of dopamine demonstrated by intrastriatal injection,” Exp. Neurol., 119, 79-88 (1993).CrossRefGoogle Scholar
  28. 28.
    T. G. Hastings, D. A. Lewis, and M. J. Zigmond, “Role of oxidation in the neurotoxic effects of intrastriatal dopamine injections,” Proc. Natl. Acad. Sci. USA, 93, 1956-1961 (1996).CrossRefGoogle Scholar
  29. 29.
    P. P. Michel and F. Hefti, “Toxicity of 6-hydroxydopamine and dopamine for dopaminergic neurons in culture,” J. Neurosci. Res., 26, 428-435 (1990).CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • N. Popović
    • 1
  • S. B. Pajović
    • 1
  • V. Stojiljković
    • 1
  • A. Todorović
    • 1
  • S. Pejić
    • 1
  • I. Pavlović
    • 1
  • L. Gavrilović
    • 1
    Email author
  1. 1.Institute of Nuclear Sciences “Vinča”, Laboratory of Molecular Biology and EndocrinologyUniversity of BelgradeBelgradeSerbia

Personalised recommendations