Effects of interferon-alpha on rhesus monkeys: a nonhuman primate model of cytokine-induced depression.
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/m(2)) 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.
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Winship Cancer Institute, 1365-C Clifton Road, Atlanta, GA 30322, USA.
Jennifer C
JC
Felger
Oyetunde
O
Alagbe
Fang
F
Hu
Deborah
D
Mook
Amanda A
AA
Freeman
Mar M
MM
Sanchez
Ned H
NH
Kalin
Emiliangelo
E
Ratti
Charles B
CB
Nemeroff
Andrew H
AH
Miller
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D000928:Antidepressive Agents; D001522:Behavior, Animal / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D016207:Cytokines; D003863:Depression / Q000139:chemically induced* / Q000188:drug therapy / Q000523:psychology; D005434:Flow Cytometry; D006719:Homovanillic Acid / Q000134:cerebrospinal fluid; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology* / Q000502:physiology / Q000627:therapeutic use; D008253:Macaca mulatta; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D009490:Neurosecretory Systems / Q000187:drug effects; D011863:Radioimmunoassay; D053633:Receptor, Interferon alpha-beta / Q000096:biosynthesis; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects
D000928:Antidepressive Agents; D016207:Cytokines; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D053633:Receptor, Interferon alpha-beta; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D006719:Homovanillic Acid