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Effect of cytokines on the pathogenesis of mood disondens

细胞因子对情绪障碍发病机制的影响

基本信息

批准号：
10470202
负责人：
KANBA Shigenobu
金额：
$ 2.94万
依托单位：
Yamanashi Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2000
项目状态：
已结题

项目摘要

Two animal experiments were performed for investigating the effect of cytokines on the pathogenesis of mood disorder.(1) It is reported that cytokine, one of immune modulating factors, controls the stress response of hypothalamo-pituitary-adrenal axis (HPA axis) in the brain. There are few reports about the effects of cytokines on the vasopressin (VP), which is one of the HPA regulating peptide within the paraventricular nucleus (PVN). In this study, we examined the VP release by the microinjection of cytokines, interleukin-1 (IL-1β), tumor necrosis factor (TNF), interferon (IFN), in the PVN in the rat brain with the microdialysis technique. We also examined the effect of the interleukin-1 receptor antagonist (IL-1Ra) on the cytokine induced VP release. Male Wistar rats (8〜10 weeks old) were anesthetized with urethane (1.4g/kg, ip). Microdialysis probe was implanted into the PVN and samples were collected every 30 minutes. VP was measured by RIA.VP release was stimulated by the IL-1β and TNF, but VP not by IFN.These increases were prevented by the IL-1Ra pre-injection. These results indicate that I1-1β and TNF both regulate HPA axis through IL-1R.(2) Oligonucleotides targeting M5 muscarinic receptor mRNA were infused for 6 d into the ventral tegmental area of freely behaving rats trained to bar-press for lateral hypothalamic stimulation. M5 antisense oligonucleotide (oligo) infusions increased the frequency required for bar pressing by 48% over baseline levels, with the largest increases occurring after 4-6 d of infusion. Antisense oligo infusions decreased M5 receptors on the ipsilateral, but not the contralateral, side of the ventral tegmentum, as compared with a missense oligo. Therefore, M5 muscarinic receptors associated with mesolimbic dopamine neurons seem to be important in brain-stimulation reward.

本研究通过两个动物实验探讨了细胞因子在心境障碍发病机制中的作用。(1)细胞因子作为一种免疫调节因子，控制着脑内下丘脑-垂体-肾上腺轴（HPA轴）的应激反应。室旁核（PVN）内HPA调节肽之一的加压素（VP）在细胞因子作用下的研究较少。本研究应用微透析技术，观察了大鼠脑内PVN微量注射细胞因子白细胞介素-1（IL-1β）、肿瘤坏死因子（TNF）、干扰素（IFN）对VP释放的影响。我们还研究了白细胞介素-1受体拮抗剂（IL-1 Ra）对细胞因子诱导的VP释放的影响。雄性Wistar大鼠（8 ~ 10周龄）用乌拉坦（1.4g/kg，ip）麻醉。将微透析探针植入PVN中，每30分钟收集样品。结果表明，IL-1β和TNF可刺激VP释放，而IFN对VP释放无明显影响，IL-1 Ra可抑制VP释放。提示I1-1β和TNF均通过IL-1 R调节HPA轴。(2)靶向M5毒蕈碱受体mRNA的寡核苷酸注入到自由行为的大鼠的腹侧被盖区6天，训练大鼠进行下丘脑外侧刺激的压杆。M5反义寡核苷酸（oligo）输注使压杆所需的频率比基线水平增加了48%，最大增加发生在输注4-6天后。与错义寡核苷酸相比，反义寡核苷酸输注降低了同侧腹侧被盖上的M5受体，但对侧没有。因此，与中脑边缘多巴胺神经元相关的M5毒蕈碱受体似乎在脑刺激奖励中很重要。