Elsevier

Biological Psychiatry

Volume 62, Issue 11, 1 December 2007, Pages 1324-1333
Biological Psychiatry

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

https://doi.org/10.1016/j.biopsych.2007.05.026Get rights and content

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.

Section snippets

Animals

Four male (5–10 kg) and 4 female (5–7 kg), rhesus monkeys (Macaca mulatta), aged 4–6 years, were housed in same-sex, dominate–subordinate pairs either together (n = 6) or individually in adjacent cages (n = 2). Social status (dominant vs. subordinate) was stable throughout the study and was based on experimenter interactions, competition for hand-fed treats, mounting, and occasional aggression. Animals were fed Purina monkey chow twice daily and were maintained on a 7 am–7 pm light–dark cycle.

Behavioral Changes

Repeated-measures ANOVAs indicated that, compared with saline, monkeys treated with IFN-alpha exhibited increased anxiety-like behaviors [F(1,7) = 7.81, p < .05] and decreased environmental exploration [F(1,7) = 10.21, p < .05] with no significant effects of time or a treatment by time interaction (Figure 1A,1B). Post hoc analyses revealed significantly increased anxiety-like behaviors at weeks 1 and 4 (p < .05), whereas exploratory behaviors were not significantly different between IFN-alpha

Discussion

Compared with saline, administration of IFN-alpha to rhesus monkeys was associated with immune, neuroendocrine, and behavioral responses similar to that observed in humans. Behavioral changes included depressive-like huddling behavior (three of eight monkeys), increased anxiety-like behavior, decreased environmental exploration, and alterations in locomotor activity that depended on social status. IFN-alpha administration was also associated with increased plasma ACTH, cortisol, and IL-6, which

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