| Interferon (IFN)-alpha is a cytokine of the innate immune response that is used to treat viral infections and cancers. Although an effective treatment strategy, IFN-alpha is notorious for causing behavioral disturbances including depression, and therefore has been used to study the effects of cytokines on the brain and behavior. Acutely, IFN-alpha stimulates the hypothalamic pituitary adrenal (HPA)-axis in humans, likely reflecting activation of central corticotropin-releasing factor pathways. Additionally, IFN-alpha has been shown to alter concentrations of monoamines and their metabolites in humans and rodents including both serotonin and dopamine (DA).; To further explore the mechanisms of INF-alpha-induced behavioral alterations, I endeavored to develop an animal model of IFN-alpha administration in rhesus monkeys. Using Western blot, flow cytometry, and RT-PCR techniques, I first established that monkeys express IFN-alpha receptors (IFNAR1) in peripheral blood mononuclear cells and that these receptors are active (phosphorylate STAT1) in the presence of IFN-alpha, similar to humans. Additionally, IFNAR1 expression in the monkey brain was confirmed using RT-PCR. I also conducted a proof of concept study that determined the effects of IFN-alpha on neuroendocrine and immune activation, sleep alterations, and behavioral disturbance in these animals. Based on these findings, a systematic series of studies was performed to assess the impact of 4 weeks of IFN-alpha (20 MIU/m2) and saline administration on behavior, neuroendocrine responses, immune activation and neurotransmitters in 8 monkeys.; Compared to saline treatment, IFN-alpha administration was associated with persistent increases in anxiety-like behaviors and decreases in environmental exploration. IFN-alpha also induced significant increases in plasma concentrations of adrenocorticotropic hormone (ACTH), cortisol, and intefeukin-6, an effect that diminished after chronic administration in dominant but not subordinate monkeys. Interestingly, depressive-like huddling behavior was observed in 3 animals. Monkeys that displayed huddling behavior exhibited higher plasma ACTH and lower cerebrospinal fluid homovanillic acid (DA metabolite) concentrations. Therefore, alterations in HPA-axis responses and DA metabolism may contribute to IFN-alpha-induced depressive-like huddling behavior.; Taken together, these studies indicate that IFN-alpha-evoked behavioral, neuroendocrine, and immune responses in rhesus monkeys are similar to that in humans, and that the administration of IFN-alpha to these animals is a valid model of cytokine-induced depression. |
