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Author Notes:

Correspondence: Andrew H. Miller, MD, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Winship Cancer Institute, 1365-C Clifton Rd, 5th floor, Atlanta, GA 30322; Email: amill02@emory.edu

Acknowledgments: The authors would like to express their appreciation for guidance provided by NIMH program staff and investigators including Drs. Linda Brady, Lois Winsky, and Husseini Manji as well as investigators from GSK including Drs. David Trist, Vincenza Di Modugno and Mauro Corsi, and the Mount Sinai School of Medicine including Dr. Dennis Charney.

Finally, the authors would like to thank Kathryn Knowlson, Casie Lyon, Matt Boudreau and Lorraine Smith for technical assistance.

Disclosures: In the past three years, the following authors have consulted to, served on the Speakers’ Bureau, Advisory Board, and/or Board of Directors, have been a grant recipient, and/or owned equity or stock in one or more of the following: JCF: NIMH, NSF.

OA: NIMH

FH: None

DM: None

AAF: NIH

MMS: NIH

NHK: Amgen, AstraZeneca, Bristol-Myers-Squibb, Corcept, CeNeRx Biopharma, Cypress Biosciences, Cyberonics, Forest Laboratories, GlaxoSmithKline, Janssen Pharmaceutica, Johnson and Johnson, Lilly, NIMH, Neurocrine Biosciences, Neuronetics, Pfizer Pharmaceuticals, Promoter Neurosciences, LLC, Sanofi-Syntholabs, Stanley Foundation, Wyeth-Ayerst

ER: GlaxoSmithKline

CBN: Abbott Laboratories, Acadia Pharmaceuticals, American Foundation for Suicide Prevention(AFSP), American Psychiatric Institute for Research and Educations(APIRE), AstraZeneca, BMC-JR LLC, Bristol-Myers-Squibb, CeNeRx, Corcept, Cypress Biosciences, Cyberonics, Eli Lilly, Entrepreneur’s Fund, Forest Laboratories, George West Mental Health Foundation, GlaxoSmithKline, i3 DLN, Janssen/Ortho-McNeil, Janssen Pharmaceutica, Lundbeck, National Alliance for Research on Schizophrenia and Depression, Neuronetics, NIH, NIMH, NFMH, NovaDel Pharma, Otsuka, Pfizer Pharmaceuticals, Quintiles, Reevax, UCB Pharma, Wyeth-Ayerst

AHM: Centocor, GlaxoSmithKline, Janssen Pharmaceutica, NIH, NIMH, Schering Plough Corporation.

Subjects:

Research Funding:

This work was supported by grants from the National Institute of Mental Health (NIH U19MH069056-01; F31 MH073355-01) and the National Science Foundation (NS FSTC9876754).

Keywords:

  • Interferon-alpha
  • HPA-axis
  • proinflammatory cytokines
  • behavior
  • non-human primate
  • animal model
  • dopamine

Effects of Interferon-alpha on Rhesus Monkeys: A Non-Human Primate Model of Cytokine-Induced Depression

Tools:

Journal Title:

Biological Psychiatry

Volume:

Volume 62, Number 11

Publisher:

, Pages 1324-1333

Type of Work:

Article | Post-print: After Peer Review

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 non-human 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 to 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 ACTH, cortisol, and interleukin-6 that tended to diminish after chronic administration, especially in dominant animals. Interestingly, in 3 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.

Copyright information:

© 2007 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported License (http://creativecommons.org/licenses/by-nc-nd/3.0/).

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