Cytokine Induced Depression

内科疾病患者抑郁的发生率是普通人群的5-10倍，并对治疗依从性、生活质量、发病率和死亡率产生重大影响。内科疾病患者抑郁症概念化的新进展主要集中在免疫激活/炎症的潜在作用以及相关的促炎细胞因子的释放上。前炎性细胞因子已被发现影响神经生物功能，并诱发抑郁症综合征，其特征与主要抑郁症重叠。这项拟议工作的长期目标是进一步了解这种细胞因子诱导的抑郁症的病理生理学和治疗，因为它与内科疾病患者的抑郁症有关。为了实现这一目标，我们计划建立一种细胞因子诱导抑郁的动物模型，使用给予细胞因子干扰素(干扰素)α的恒河猴。干扰素α是促炎细胞因子(尤其是白介素6)的有效诱导剂，根据剂量的不同，30-50%的患者会出现抑郁症状。此外，干扰素α激活促肾上腺皮质激素释放因子(CRF)途径，并已被证明导致单胺消耗。 实验动物(包括恒河猴)。此外，干扰素α已被证明可以改变人类的额纹状体神经回路，并在人类和恒河猴动物中诱导与抑郁症一致的REM睡眠变化(REM潜伏期缩短，REM百分比增加)。因此，干扰素α治疗为进一步了解细胞因子诱导的情绪障碍的病理生理学和治疗提供了一个独特的模型系统。这项拟议工作的具体目的是1)表征恒河猴对干扰素α的神经内分泌、单胺类、免疫和行为反应，以及2)检测药物化合物的治疗效果(逆转干扰素α诱导的神经内分泌、单胺类、免疫和行为变化的能力)，这些药物化合物可以拮抗细胞因子网络(NK-1拮抗剂)的激活，拮抗CRF，或增加单胺类神经回路中神经传递的活性。实现这些目标的相关技术将包括重复的血液和脑脊液采样、遥测多导睡眠图、MicroPET和行为分析 恐惧加强了惊吓和社交互动。这些研究的结果将确定治疗内科疾病患者情绪障碍的新靶点和药理策略。

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.