Cytokine Induced Depression

医学疾病中抑郁症的发生率是一般人群中抑郁症的5-10倍，对治疗依从性、生活质量、发病率和死亡率有显著影响。医学疾病中抑郁症概念化的新发展集中在免疫激活/炎症的潜在作用和促炎细胞因子的相关释放上。已发现促炎细胞因子影响神经生物学功能并诱导抑郁综合征，其与重性抑郁症具有重叠特征。拟议工作的长期目标是进一步了解这种尼古丁诱导的抑郁症的病理生理学和治疗，因为它与医学疾病中的抑郁症有关。为了实现这一目标，我们计划开发一种动物模型，使用恒河猴给予细胞因子，干扰素（IFN）α的干扰素诱导的抑郁症。IFN α是促炎细胞因子（特别是白细胞介素6）的强效诱导剂，并根据剂量在30-50%的患者中导致抑郁症状。此外，IFN α激活促肾上腺皮质激素释放因子（CRF）途径，并已显示导致单胺耗竭， 实验动物（包括恒河猴）。此外，IFN α已被证明改变人类的额-纹状体神经回路，并诱导REM睡眠变化（REM潜伏期减少，REM百分比增加），这与人类和恒河猴动物的抑郁症一致。因此，IFN α治疗提供了一个独特的模型系统，以进一步了解病理生理学和治疗尼古丁诱导的情绪障碍。本研究的具体目的是：1）描述恒河猴对IFN α的神经内分泌、单胺、免疫和行为反应; 2）检查IFN α的治疗效果（逆转IFN α诱导的神经内分泌、单胺、免疫和行为变化的能力）（NK-1拮抗剂），拮抗CRF，或增加单胺神经回路中的神经传递活性。用于实现这些目标的相关技术将包括重复血液和CSF采样、遥测多导睡眠图、microPET和行为分析。 恐惧增强了惊吓和社会互动。这些研究的结果将确定新的目标，以及治疗情绪障碍的药物策略。

Depression in the medically ill occurs 5-10 times more often than depression in the general population and has a significant impact on treatment adherence, quality of life, and morbidity and mortality. New developments in the conceptualization of depression in the medically ill have focused on the potential role of immune activation/inflammation and the associated release of proinflammatory cytokines. Proinflammatory cytokines have been found to influence neurobiologic function and induce a depressive syndrome that has overlapping features with major depression. The long term objective of the proposed work is to further understand the pathophysiology and treatment of this cytokine-induced depression as it relates to depression in the medically ill. To accomplish this goal, we plan to develop an animal model of cytokine-induced depression using rhesus monkeys administered the cytokine, interferon (IFN) alpha. IFN alpha is a potent inducer of proinflammatory cytokines (especially interleukin 6) and leads to depressive symptoms in 30-50% of patients depending on dose. In addition, IFN alpha activates corticotropin releasing factor (CRF) pathways and has been shown to lead to monoamine depletion in laboratory animals (including rhesus monkeys). In addition, IFN alpha has been shown to alter fronto-striatal neurocircuitry in humans and induce REM sleep changes (decreased REM latency, increased REM percentage) consistent with depression in both humans and rhesus animals. Thus, IFN alpha treatment provides a unique model system to further understand the pathophysiology and treatment of cytokine-induced mood disorders. The specific aims of the proposed work are 1) to characterize neuroendocrine, monoamine, immune and behavioral responses of rhesus monkeys to IFN alpha and 2) to examine the therapeutic efficacy (capacity to reverse IFN alpha-induced neuroendocrine, monoamine, immune and behavioral changes) of pharmacologic compounds that antagonize activation of the cytokine network (NK-1 antagonists), antagonize CRF, or increase the activity of neurotransmission in monoamine neurocircuits. Relevant techniques to be used to accomplish these aims will include repeated blood and CSF sampling, telemetric polysomnography, microPET, and behavioral analysis of fear potentiated startle and social interactions. Results from these studies will identify novel targets as well as pharmacologic strategies for treatment of mood disorders in the medically ill.