Felger Jennifer C, Alagbe Oyetunde, Hu Fang, Mook Deborah, Freeman Amanda A, Sanchez Mar M, Kalin Ned H, Ratti Emiliangelo, Nemeroff Charles B, Miller Andrew H
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Winship Cancer Institute, 1365-C Clifton Road, Atlanta, GA 30322, USA.
Biol Psychiatry. 2007 Dec 1;62(11):1324-33. doi: 10.1016/j.biopsych.2007.05.026. Epub 2007 Aug 2.
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.
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.
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.
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.
干扰素（IFN）-α是一种先天性免疫细胞因子，可导致人类出现高比例的抑郁症状，因此已被用于研究细胞因子对大脑和行为的影响。为建立细胞因子诱导性抑郁的非人灵长类动物模型，我们研究了IFN-α对恒河猴的影响。
八只恒河猴以平衡的方式接受重组人（rHu）-IFN-α（20 MIU/m²）或生理盐水注射，为期4周。定期获取录像行为以及血浆和脑脊液（CSF），以评估行为、神经内分泌、免疫和神经递质参数。此外，还评估了猴外周血单个核细胞（PBMCs）中IFN-α/β受体的表达和活性。
与生理盐水治疗相比，给予IFN-α与焦虑样行为持续增加和环境探索减少有关。此外，IFN-α导致促肾上腺皮质激素（ACTH）、皮质醇和白细胞介素-6的血浆浓度显著升高，长期给药后这些浓度趋于降低，尤其是在占主导地位的动物中。有趣的是，在三只动物中观察到了类似抑郁的蜷缩行为。表现出蜷缩行为的猴子的ACTH血浆浓度显著更高，而多巴胺代谢产物高香草酸的脑脊液浓度更低。发现恒河猴PBMCs表达IFN-α/β受体的mRNA和蛋白质。此外，用rHu-IFN-α处理PBMCs会导致主要的IFN-α诱导信号分子之一STAT1的诱导。
IFN-α在恒河猴中引发了与人类相似的行为、神经内分泌和免疫反应。此外，下丘脑-垂体-肾上腺轴反应和多巴胺代谢的改变可能导致IFN-α诱导的类似抑郁的蜷缩行为。
