Depression and Immunity: Behavioral and CNS Mechanisms

描述（由申请人提供）：大多数研究者假设，在抑郁症患者中发现的免疫异常继发于脑功能的改变，特别是在涉及免疫功能调节的区域和系统中。尽管如此，尽管有证据表明抗抑郁药治疗可使临床人群的免疫功能正常化，但这一假设尚未得到广泛验证。拟议的研究将使用Flinders Sensitive Line（FSL）抑郁症遗传大鼠模型来测试大脑单胺能系统的改变有助于抑郁症相关免疫功能异常的假设。该项目建立在令人兴奋的最新数据的基础上，这些数据显示FSL大鼠体内1型免疫反应显着降低。拟议的研究有两个具体目标。第一个源于以前的工作表明，长期抗抑郁治疗与三环类或阿托伐他汀特异性抗抑郁药正常化的行为和神经化学异常的FSL大鼠。在拟议的研究中，FSL和对照大鼠将接受抗抑郁药地昔帕明和舍曲林的长期治疗。预期这些处理可使FSL动物的行为和免疫异常正常化。第二个目的将测试的假设，慢性脑室内输注去甲肾上腺素或5-羟色胺，地昔帕明和舍曲林的药理学目标，分别将正常化的FSL和FRL株之间的行为和免疫学差异。这些实验将同时评价（a）抗抑郁药对行为的作用部位和对免疫功能的假设作用（即中枢或外周），（B）特定单胺能系统在调节1型免疫应答中可能发挥更大作用的程度，和（c）脑单胺慢性升高的免疫调节作用。总的来说，这些研究建立在令人兴奋的新数据基础上，它们被设计为描述源自大脑并最终改变特定免疫细胞功能的无缝影响链过程的初始步骤。由于FSL大鼠已经被确立为抑郁症的有效模型，因此这些研究产生的数据有望阐明临床抑郁症患者对身体疾病的易感性增加的综合生物学过程。

DESCRIPTION (provided by applicant): Most investigators hypothesize that immunological abnormalities that have been identified in depressed individuals are secondary to alterations in brain function, particularly in regions and systems that are implicated in the regulation of immune function. Nonetheless, this hypothesis has not been broadly tested despite evidence that immune function is normalized by antidepressant treatment in clinical populations. The proposed research will use the Flinders Sensitive Line (FSL) genetic rat model of depression to test the hypothesis that alterations in brain monoaminergic systems contribute to depression-related abnormalities of immune function. This project builds on exciting recent data showing markedly reduced in vivo type 1 immune responses in FSL rats. Two specific aims comprise the proposed research. The first stems from previous work showing that chronic antidepressant treatment with tricyclic or serotonin-specific antidepressants normalizes behavioral and neurochemical abnormalities in the FSL rats. In the proposed studies, FSL and control rats will receive chronic treatment with the antidepressants desipramine and sertraline. These treatments are expected to normalize behavioral and immunological abnormalities in the FSL animals. The second aim will test the hypothesis that chronic intracerebroventricular infusion of norepinephrine or serotonin, the pharmacological targets of desipramine and sertraline, respectively, will normalize behavioral and immunological differences between the FSL and FRL strains. These experiments will simultaneously evaluate (a) the site of action for antidepressant effects on behavior and hypothesized effects on immune function (i.e. central or peripheral), (b) the extent to which a specific monoaminergic system may play a greater role in regulating type 1 immune responses, and (c) the immunomodulatory effects of chronic elevations in brain monoamines. Collectively, these studies build on exciting new data, and they are designed as initial steps in the process of describing a seamless chain of influence originating in the brain and culminating in altered function of specific immunological cells. Because the FSL rat has already been established as a valid model for depression, the data generated from these studies promise to illuminate the integrated biological processes that produce increased vulnerability to physical illness in the clinically depressed