Skip to main content
Log in

Behavioral Symptoms of Anxiety and Depression and Brain Monoamine Contents in Rats after Chronic Intranasal Administration of Interferon-α

  • Published:
Neuroscience and Behavioral Physiology Aims and scope Submit manuscript

The effects of chronic (17 days) intranasal administration of low (50 IU/kg) and intermediate (8000 IU/kg) doses of human interferon-α (IA) on behavioral indicators of anxiety and depression and the monoaminergic system of the brain were studied in rats. Control rats received the same volume of intranasal physiological saline. IA was found to have any ambiguous effects on anxiety levels. Thus, anxiety in the open field test increased after administration of both doses of IA and decreased in the light-dark test and elevated plus maze test after small doses of IA. In the forced swimming test, administration of both doses of IA was followed by an increase in the duration of immobility (a behavioral symptom of depression). Administration of the intermediate (but not the small) dose of IA was followed by increases in the contents of dopamine and its metabolites in the olfactory bulb and decreases in the nucleus accumbens; the noradrenaline content decreased in the prefrontal cortex. It is suggested that these neurochemical changes in the brain may underlie the behavioral symptoms of depression induced by intranasal administration of intermediate doses of IA. Depression-like behavioral symptoms occurring after administration of small doses of IA were evidently not linked with changes in brain monoaminergic systems but could be due to other mechanisms.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. V. S. Kudrin, P. M. Klodt, V. B. Narkevich, I. A. Shipilov, V. I. Poseva, G. M. Molodavkin, and T. A. Voronina, “Behavioral and neurochemical aspects of the antidepressant actions of GSB-106 – a dipeptide fragment of brain-derived neurotrophic factor (BDNF),” Eksperim. Klin. Farmakol., 75, No. 10, 41–45 (2012).

    Google Scholar 

  2. E. V. Loseva, N. A. Loginova, and I. G. Akmaev, “Neuroimmunomodulatory interferon-α and its dose-dependent action on behavior in humans and animals,” Ros. Fiziol. Zh. im. I. M. Sechenova, 95, No. 12, 1397–1406 (2009).

    CAS  Google Scholar 

  3. E. V. Loseva, N. A. Loginova, and I. G. Akmaev, “The role of interferon-α in the regulation of nervous system functions,” Usp. Fiziol. Nauk., 39, No. 2, 31–45 (2008).

    Google Scholar 

  4. E. V. Loseva, N. A. Loginova, L. M. Biryukova, V. N. Mats, and N. V. Pasikova, “Acquisition of feeding conditioned reflexes in young and old rats in controls and after administration of small doses of interferon-α,” Ros. Fiziol. Zh. im. I. M. Sechenova, 93, No. 4, 386–393 (2007).

    CAS  Google Scholar 

  5. E. V. Loseva, N. A. Loginova, V. V. Neklyudov, V. N. Mats, O. V. Kurskaya, and N. V. Pasikova, “Effects of human and rat interferon-α on behavior in rats of different ages and comparison of their amino acid sequence homologies,” Zh. Vyssh. Nerv. Deyat. I. P. Pavlova, 59, No. 4, 461–472 (2009).

    CAS  Google Scholar 

  6. E. V. Loseva, M. V. Mezentseva, L. I. Russu, N. A. Loginova, N. V. Panov, M. N. Shchetvin, and I. A. Suetina, “Suppression of cytokine synthesis in the spleen and brain and minor changes in c-fos expression in the brain in rats given intranasal administration of single-layer carbon nanotubes,” Ros. Nanotekhnol., 11, No. 3–4, 80–86 (2016).

    Google Scholar 

  7. E. V. Loseva, N. V. Pasikova, N. A. Loginova, L. M. Biryukova, and V. N. Mats, “Effects of intranasal administration of small doses of human interferon-α on behavior in rats of different ages,” Zh. Vyssh. Nerv. Deyat. I. P. Pavlova, 57, No. 3, 323–335 (2007).

    CAS  Google Scholar 

  8. E. V. Obraztsova, L. V. Osidak, E. G. Golovacheva, O. I. Afanas’eva, K. K. Mil’kint, E. G. Koroleva, S. A. Tarasov, M. V. Kachanova, V. P. Drinevskii, and I. A. Vasil’eva, “Interferon status in children with acute respiratory infections. Interferon therapy,” Byull. Eksperim. Biol. Med., Supplement Experimental and Clinical Pharmacology of Ultralow Doses of Antibodies to Endogenous Function Regulators, 22–26 (2009).

  9. K. Yu. Sarkisova, M. A. Kulikov, V. S. Kudrin, V. B. Narkevich, I. S. Midzyanovskaya, L. M. Biryukova, A. A. Folomkina, and A. S. Bazyan, “Neurochemical mechanisms of depression-like behavior in WAG/Rij rats,” Zh. Vyssh. Nerv. Deyat. I. P. Pavlova, 63, No. 3, 303–315 (2013).

    Google Scholar 

  10. G. M. Asnis and R. De La Garza, 2nd, “Interferon-induced depression in chronic hepatitis C: a review of its prevalence, risk factors, biology, and treatment approaches,” J. Clin. Gastroenterology, 40, No. 4, 322–335 (2006).

    Article  CAS  Google Scholar 

  11. S. Bhatt, P. Kilambi, P. Patel, N. Patel, A. Panchal, G. Shah, and S. Goswami, “Beneficial effect of aspirin against interferon-β-2b-induced depressive behavior in Sprague Dawley rats,” Clin. Exp. Pharmacol. Physiol. (2016), doi: 10.111/1440-1681.12660.2016.

  12. L. Capuron, G. Neurauter, D. L. Musselman, D. H. Lawson, C. B. Nemeroff, D. Fuchs, and A. H. Miller, “Interferon-alpha-induced changes in tryptophan metabolism. Relationship to depression and paroxetine treatment,” Biol. Psychiatry, 54, No. 9, 906–914 (2003).

    Article  CAS  Google Scholar 

  13. I. E. Cicek, E. Cicek, F. Kayhan, F. Uguz, I. Erayman, S. Kurban, F. H. Yerlikaya, and N. Kaya, “The roles of BDNF, S100B, and oxidative stress in interferon-induced depression and the effect of antidepressant treatment in patients with chronic viral hepatitis: a prospective study,” J. Psychosom. Res., 76, No. 3, 227–232 (2014).

    Article  Google Scholar 

  14. L. Danielyan, S. Beer-Hammer, A. Stolzing, R. Schäfer, G. Siegel, C. Fabian, P. Kahle, T. Biedermann, A. Lourhmati, M. Buadze, A. Novakovic, B. Proksch, C. H. Gleiter, W. H. Frey, 2nd, and M. Schwab, “Intranasal delivery of bone marrow-derived mesenchymal stem cells, macrophages, and microglia to the brain in mouse models of Alzheimer’s and Parkinson’s disease,” Cell Transplant., 23, Suppl. 1, S123–S139 (2014).

    Article  Google Scholar 

  15. R. De La Garza, 2nd and G. M. Asnis, “The non-steroidal anti-inflammatory drug diclofenac sodium attenuates IFN-alpha induced alterations to monoamine turnover in prefrontal cortex and hippocampus,” Brain Res., 977, No. 1, 70–79 (2003).

    Article  Google Scholar 

  16. R. De La Garza, 2nd, G. M. Asnis, E. Pedrosa, C. Stearns, A. L. Migdal, J. F. Reinus, R. Paladugu, and S. Vemulapalli, “Recombinant human interferon-alpha does not alter reward behavior, or neuroimmune and neuroendocrine activation in rats,” Prog. Neuropsychopharmacol. Biol. Psychiatry, 29, No. 5, 781–792 (2005).

    Article  Google Scholar 

  17. M. Dec and A. Puchalski, “Use of oromucosally administered interferon-alpha in the prevention and treatment of animal diseases,” Pol. J. Vet. Sci., 11, No. 2, 175–186 (2008).

    CAS  PubMed  Google Scholar 

  18. S. V. Dhuria, L. R. Hanson, and W. H. Frey, 2nd, “Intranasal delivery to the central nervous system: mechanisms and experimental considerations,” J. Pharm. Sci., 99, No. 4, 1654–1673 (2010).

    Article  CAS  Google Scholar 

  19. O. Dipasquale, E. A. Cooper, J. Tibbie, V. Voon, F. Baglio, G. Baselli, M. Cercignani, and N. A. Harrison, “Interferon-β acutely impairs whole-brain functional connectivity network architecture – A preliminary study,” Brain Behav. Immun., 58, 31–39 (2016).

    Article  CAS  Google Scholar 

  20. A. Dunn, “Effects of cytokines and infections on brain neurochemistry,” J. Clin. Neurosci. Res., 6, No. 1–2, 52–68 (2006).

    Article  CAS  Google Scholar 

  21. G. Dusheiko, “Side effects of alpha interferon in chronic hepatitis,” Hepatology, 26, No. 3, Suppl. 1, 112S–121S (1997).

  22. B. Fahey, B. Hickey, D. Kelleher, A. M. O’Dwyer, and S. M. O’Mara, “The widely-used antiviral drug interferon-alpha induces depressive-and anxiogenic-like effects in healthy rats,” Behav. Brain Res., 182, No. 1, 80–87 (2007).

    Article  CAS  Google Scholar 

  23. J. C. Felger, O. Alagbe, F. Hu, D. Mook, A. A. Freeman, M. M. Sanchez, N. H. Kalin, E. Ratti, C. B. Nemeroff, and A. H. Miller, “Effects of interferon-alpha on rhesus monkeys: a nonhuman primate model of cytokine-induced depression,” Biol. Psychiatry, 62, No. 11, 1324–1333 (2007).

    Article  CAS  Google Scholar 

  24. J. C. Felger, L. Li, P. J. Marvar, B. J. Woolwine, D. G. Harrison, C. L. Raison, and A. H. Miller, “Tyrosine metabolism during interferon-alpha administration: Association with fatigue and CSF dopamine concentrations,” Brain Behav. Immun., 31, 153–160 (2013).

    Article  CAS  Google Scholar 

  25. C. W. Fischer, A. Eskelund, D. P. Budac, S. Tillmann, N. Liebenberg, B. Elfving, and G. Wegener, “Interferon-alpha treatment induces depression-like behaviour accompanied by elevated hippocampal quinolinic acid levels in rats,” Behav. Brain Res., 293, 166–172 (2015).

    Article  CAS  Google Scholar 

  26. L. Gao, S. Yu, Q. Chen, Z. Duan, J. Zhou, C. Mao, D. Yu, W. Zhu, J. Nie, and Y. Hou, “A randomized controlled trial of low-dose recombinant human interferons alpha-2b nasal spray to prevent acute viral respiratory infections in military recruits,” Vaccine, 28, No. 28, 4445–4451 (2010).

    Article  CAS  Google Scholar 

  27. S. G. Helton and F. W. Lohoff, “Serotonin pathway polymorphisms and the treatment of major depressive disorder and anxiety disorders,” Pharmacogenomics, 16, No. 5, 541–553 (2015).

    Article  CAS  Google Scholar 

  28. C. Hoyo-Becerra, A. Huebener, M. Trippler, M. Lutterbeck, Z. J. Liu, K. Truebner, T. Bajanowski, G. Gerken, D. M. Hermann, and J. F. Schlaak, “Concomitant interferon-alpha stimulation and TLR3 activation induces neuronal expression of depression-related genes that are elevated in the brain of suicidal persons,” PLoS One, 8, No. 12, e83149 (2013).

    Article  Google Scholar 

  29. J. Ishikawa, A. Ishikawa, and S. Nakamura, “Interferon-alpha reduces the density of monoaminergic axons in the rat brain,” Neuroreport, 18, No. 2, 137–140 (2007).

    Article  CAS  Google Scholar 

  30. O. A. Kalyoncu, D. Tan, H. Mirsal, O. Pektas, and M. Beyazyurek, “Major depressive disorder with psychotic features induced by interferon-alpha treatment for hepatitis C in a polydrug abuser,” J. Psychopharmacology, 19, No. 1, 102–105 (2005).

    Article  Google Scholar 

  31. M. Kamata, H. Higuchi, M. Yoshimoto, K. Yoshida, and T. Shimizu, “Effect of single intracerebroventricular injection of alpha-interferon on monoamine concentrations in the rat brain,” Eur. Neuropsychopharmacol., 10, No. 2, 129–132 (2000).

    Article  CAS  Google Scholar 

  32. J. Kaufman, C. DeLorenzo, S. Choudhury, and R. V. Parsey, “The 5-HT1A receptor in major depressive disorder,” Eur. Neuropsychopharmacol., 26, No. 3, 397–410 (2016).

    Article  CAS  Google Scholar 

  33. C. Kiank, J. P. Zeden, S. Drude, G. Domanska, G. Fusch, W. Otten, and C. Schuett, “Psychological stress-induced, IDO1-dependent tryptophan catabolism: implications on immunosuppression in mice and humans,” PLoS One, 5, No. 7, e11825 (2010).

    Article  Google Scholar 

  34. I. J. Kopin, K. S. Bankiewicz, and J. Harvey-White, “Assessment of brain dopamine metabolism from plasma HVA and MHPG during debrisoquin treatment: validation in monkeys treated with MPTP,” Neuropsychopharmacology, 1, No. 2, 119–125 (1988).

    Article  CAS  Google Scholar 

  35. M. Kosel, A. Bilkei-Gorzo, R. Zawatzky, A. Zimmer, and T. E. Schlaepfer, “Pegylated human interferon-alpha 2a does not induce depression-associated changes in mice,” Psychiatry Res., 185, No. 1–2, 243–247 (2011).

    Article  CAS  Google Scholar 

  36. D. Kugel, G. Kochs, K. Obojes, J. Roth, G. P. Kobinger, D. Kobasa, O. Haller, P. Staeheli, and V. von Messling, “Intranasal administration of alpha interferon reduces seasonal influenza A virus morbidity in ferrets,” J. Virol., 83, No. 8, 3843–3851 (2009).

    Article  CAS  Google Scholar 

  37. K. Kuter, W. Kolasiewicz, K. Golembiowska, A. Dziubina, G. Schulze, K. Berghauzen, J. Wardas, and K. Ossowska, “Partial lesion of the dopaminergic innervation of the ventral striatum induces ‘depressive-like’ behavior of rats,” Pharmacol. Rep., 63, No. 6, 1383–1392 (2011).

    Article  CAS  Google Scholar 

  38. N. Mayr, J. Zeitlhofer, L. Deecke, E. Fritz, H. Ludwig, and H. Gisslinger, “Neurological function during long-term therapy with recombinant interferon alpha,” J. Neuropsych. Clin. Neurosci., 11, No. 3, 343–348 (1999).

    Article  CAS  Google Scholar 

  39. S. Mehta, S. Mukherjee, D. Balasubramanian, and A. Chowdhary, “Evaluation of neuroimmunomodulatory activity of recombinant human interferon-α,” Neuroimmunomodulation, 21, No. 5, 250–256 (2014).

    Article  CAS  Google Scholar 

  40. E. Palazidou, “The neurobiology of depression,” Br. Med. Bull., 101, 127–145 (2012).

    Article  CAS  Google Scholar 

  41. C. L. Raison, A. S. Borisov, B. J. Woolwine, B. Massung, G. Vogt, and A. H. Miller, “Interferon-alpha effects on diurnal hypothalamic-pituitary-adrenal axis activity: relationship with proinflammatory cytokines and behavior,” Mol. Psychiatry, 15, No. 5, 535–547 (2010).

    Article  CAS  Google Scholar 

  42. C. L. Raison, L. Capuron, and A. H. Miller, “Cytokines sing the blues: inflammation and the pathogenesis of depression,” Trends Immunol., 27, No. 1, 24–31 (2006).

    Article  CAS  Google Scholar 

  43. C. L. Raison, M. Demetrashvili, L. Capuron, and A. H. Miller, “Neuropsychiatric adverse effects of interferon-alpha: recognition and management,” CNS Drugs, 19, No. 2, 105–123 (2005).

    Article  CAS  Google Scholar 

  44. J. Reichen, L. Bianchi, P. C. Frei, P. J. Mal, D. Lavanchy, and M. Schmid, “Efficacy of steroid withdrawal and low-dose interferon treatment in chronic active hepatitis. Results of a randomized multicenter trial. Swiss Association for the Study of the Liver,” J. Hepatol., 20, No. 2, 168–174 (1994).

    Article  CAS  Google Scholar 

  45. C. Reyes-Vázquez, B. Prieto-Gómez, and N. Dafny, “Interferon modulates central nervous system function,” Brain Res., 1442, 76–89 (2012).

    Article  Google Scholar 

  46. A. B. Richards and E. Sherwood (inventors), Amarillo Biosciences, Inc. (assignee), United States Patent 6036949, “Treatment of fibromyalgia with low interferon doses.”

  47. Y. Rotman, B. B. Borg, A. Soza, J. J. Feld, A. A. Modi, R. Loomba, G. Lutchman, E. Rivera, E. Doo, M. G. Ghany, T. Heller, A. U. Neumann, T. J. Liang, and J. H. Hoofnagle, “Low-and standard-dose peginterferon alfa-2a for chronic hepatitis C, genotype 2 or 3: efficacy, tolerability, viral kinetics and cytokine response,” Aliment. Pharmacol. Ther., 31, No. 9, 1018–1027 (2010).

    Article  CAS  Google Scholar 

  48. Yu. K. Sarkisova, I. S. Midzianovskaia, and M. A. Kulikov, “Depressive-like behavioral alterations and c-fos expression in the dopaminergic brain regions in WAG/Rij rats with genetic absence epilepsy,” Behav. Brain Res., 144, No. 1–2, 211–226 (2003).

    Article  CAS  Google Scholar 

  49. Yu. K. Sarkisova and M. A. Kulikov, “Behavioral characteristics of WAG/Rij rats susceptible and non-susceptible to audiogenic seizures,” Behav. Brain Res., 166, No. 1, 9–18 (2006).

    Article  Google Scholar 

  50. K. Sarkisova and G. van Luijtelaar, “The WAG/Rij strain: a genetic animal model of absence epilepsy with comorbidity of depression. Review article,” Prog. Neuropsychopharmacol. Biol. Psychiatry, 35, 854–876 (2011).

    Article  CAS  Google Scholar 

  51. H. Shuto, Y. Kataoka, T. Horikawa, N. Fujihara, and R. Oishi, “Repeated interferon-alpha administration inhibits dopaminergic neural activity in the mouse brain,” Brain Res., 747, No. 2, 348–351 (1997).

    Article  CAS  Google Scholar 

  52. J. W. Slaton, T. Karahima, P. Perrotte, K. Inoue, S. J. Kim, J. Izawa, D. Kedar, D. J. McConkey, R. Millikan, P. Sweeney, C. Yoshikawa, T. Shuin, and C. P. Dinney, “Treatment with low-dose interferon-alpha restores the balance between matrix metalloproteinase-9 and E-cadherin expression in human transitional cell carcinoma of the bladder,” Clin. Cancer Res., 7, No. 9, 2840–2853 (2001).

    CAS  PubMed  Google Scholar 

  53. S. Sockalingam, P. S. Links, and S. E. Abbey, “Suicide risk in hepatitis C and during interferon-alpha therapy: a review and clinical update,” J. Viral. Hepat., 18, No. 3, 153–160 (2011).

    Article  CAS  Google Scholar 

  54. B. M. Spruijt and W. H. van Hooff Gispen, “Ethology and neurobiology of grooming behavior,” Physiol. Rev., 72, 825–853 (1992).

    Article  CAS  Google Scholar 

  55. M. M. Wen, “Olfactory targeting through intranasal delivery of biopharmaceutical drugs to the brain -current development,” Discov. Med., 11, No. 61, 497–503 (2011).

    PubMed  Google Scholar 

  56. M. C. Wichers, G. Kenis, G. H. Koek, G. Robaeys, N. A. Nicolson, and M. Maes, “Interferon-alpha-induced depressive symptoms are related to changes in the cytokine network but not to cortisol,” J. Psychosom. Res., 62, No. 2, 207–214 (2007).

    Article  Google Scholar 

  57. J. P. Yang, H. J. Liu, S. M. Cheng, Z. L. Wang, X. Cheng, H. X. Yu, and X. F. Liu, “Direct transport of VEGF from the nasal cavity to brain,” Neurosci. Lett., 449, No. 2 108–111 (2009).

    Article  CAS  Google Scholar 

  58. L. S. Zheng, S. Hitoshi, N. Kaneko, K. Takao, T. Miyakawa, Y. Tanaka, H. Xia, U. Kalinke, K. Kudo, S. Kanba, K. Ikenaka, and K. Sawamoto, “Mechanisms for interferon-α-induced depression and neural stem cell dysfunction,” Stem Cell Rep., 3, No. 1, 73–84 (2014).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to E. V. Loseva.

Additional information

P. M. Klodt is deceased.

Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 103, No. 4, pp. 417–431, April, 2017.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Loseva, E.V., Loginova, N.A., Sarkisova, K.Y. et al. Behavioral Symptoms of Anxiety and Depression and Brain Monoamine Contents in Rats after Chronic Intranasal Administration of Interferon-α. Neurosci Behav Physi 48, 954–962 (2018). https://doi.org/10.1007/s11055-018-0655-8

Download citation

  • Received:

  • Revised:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11055-018-0655-8

Keywords

Navigation