Effects of Interferon-Alpha on Rhesus Monkeys: A Nonhuman Primate Model of Cytokine-Induced Depression

Jennifer C. Felger, Oyetunde Alagbe, Fang Hu, Deborah Mook, Amanda A. Freeman, Mar M. Sanchez, Ned H. Kalin, Emiliangelo Ratti, Charles Nemeroff, Andrew H. Miller

Research output: Contribution to journalArticle

137 Citations (Scopus)

Abstract

Background: Interferon (IFN)-alpha is an innate immune cytokine that causes high rates of depression in humans and therefore has been used to study the impact of cytokines on the brain and behavior. To establish a nonhuman primate model of cytokine-induced depression, we examined the effects of IFN-alpha on rhesus monkeys. Methods: Eight rhesus monkeys were administered recombinant human (rHu)-IFN-alpha (20 MIU/m2) or saline for 4 weeks in counterbalanced fashion, and videotaped behavior, as well as plasma and cerebrospinal fluid (CSF), were obtained at regular intervals to assess behavioral, neuroendocrine, immune, and neurotransmitter parameters. Additionally, expression and activity of IFN-alpha/beta receptors in monkey peripheral blood mononuclear cells (PBMCs) were assessed. Results: Compared with saline treatment, IFN-alpha administration was associated with persistent increases in anxiety-like behaviors and decreases in environmental exploration. In addition, IFN-alpha induced significant increases in plasma concentrations of corticotropin (ACTH), cortisol, and interleukin-6 that tended to diminish after chronic administration, especially in dominant animals. Interestingly, in three animals, depressive-like, huddling behavior was observed. Monkeys that displayed huddling behavior exhibited significantly higher plasma concentrations of ACTH and lower CSF concentrations of the dopamine metabolite homovanillic acid. Rhesus monkey PBMCs were found to express mRNA and protein for the IFN-alpha/beta receptor. Moreover, treatment of PBMCs with rHu-IFN-alpha led to induction of STAT1, one of the primary IFN-alpha-induced signaling molecules. Conclusions: IFN-alpha evoked behavioral, neuroendocrine, and immune responses in rhesus monkeys that are similar to humans. Moreover, alterations in hypothalamic-pituitary-adrenal axis responses and dopamine metabolism may contribute to IFN-alpha-induced depressive-like huddling behavior.

Original languageEnglish
Pages (from-to)1324-1333
Number of pages10
JournalBiological Psychiatry
Volume62
Issue number11
DOIs
StatePublished - Dec 1 2007
Externally publishedYes

Fingerprint

Macaca mulatta
Interferon-alpha
Primates
Depression
Cytokines
Interferon alpha-beta Receptor
Adrenocorticotropic Hormone
Blood Cells
Haplorhini
Cerebrospinal Fluid
Dopamine
Homovanillic Acid
Neurotransmitter Agents
Hydrocortisone
Interleukin-6
Anxiety
Messenger RNA
Brain

Keywords

  • Animal model
  • behavior
  • dopamine
  • HPA axis
  • interferon-alpha
  • nonhuman primate
  • proinflammatory cytokines

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

Felger, J. C., Alagbe, O., Hu, F., Mook, D., Freeman, A. A., Sanchez, M. M., ... Miller, A. H. (2007). Effects of Interferon-Alpha on Rhesus Monkeys: A Nonhuman Primate Model of Cytokine-Induced Depression. Biological Psychiatry, 62(11), 1324-1333. https://doi.org/10.1016/j.biopsych.2007.05.026

Effects of Interferon-Alpha on Rhesus Monkeys : A Nonhuman Primate Model of Cytokine-Induced Depression. / Felger, Jennifer C.; Alagbe, Oyetunde; Hu, Fang; Mook, Deborah; Freeman, Amanda A.; Sanchez, Mar M.; Kalin, Ned H.; Ratti, Emiliangelo; Nemeroff, Charles; Miller, Andrew H.

In: Biological Psychiatry, Vol. 62, No. 11, 01.12.2007, p. 1324-1333.

Research output: Contribution to journalArticle

Felger, JC, Alagbe, O, Hu, F, Mook, D, Freeman, AA, Sanchez, MM, Kalin, NH, Ratti, E, Nemeroff, C & Miller, AH 2007, 'Effects of Interferon-Alpha on Rhesus Monkeys: A Nonhuman Primate Model of Cytokine-Induced Depression', Biological Psychiatry, vol. 62, no. 11, pp. 1324-1333. https://doi.org/10.1016/j.biopsych.2007.05.026
Felger, Jennifer C. ; Alagbe, Oyetunde ; Hu, Fang ; Mook, Deborah ; Freeman, Amanda A. ; Sanchez, Mar M. ; Kalin, Ned H. ; Ratti, Emiliangelo ; Nemeroff, Charles ; Miller, Andrew H. / Effects of Interferon-Alpha on Rhesus Monkeys : A Nonhuman Primate Model of Cytokine-Induced Depression. In: Biological Psychiatry. 2007 ; Vol. 62, No. 11. pp. 1324-1333.
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AU - Freeman, Amanda A.

AU - Sanchez, Mar M.

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