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.

通过两项动物实验研究细胞因子对情绪障碍发病机制的影响。(1)据报道细胞因子是免疫调节因子之一,控制着下丘脑-垂体-肾上腺轴(HPA轴)的应激反应。关于细胞因子对加压素 (VP) 的影响的报道很少，加压素是室旁核 (PVN) 内的 HPA 调节肽之一。在这项研究中，我们检查了 VP 的释放。我们还利用微透析技术在大鼠脑部 PVN 中显微注射细胞因子、白细胞介素 1 (IL-1β)、肿瘤坏死因子 (TNF)、干扰素 (IFN)。 IL-1Ra)对细胞因子诱导的VP释放的影响用尿烷(1.4g/kg，腹腔注射)麻醉雄性Wistar大鼠(8-10周龄)。将探针植入 PVN，并每 30 分钟收集一次样品，通过 RIA 测量。VP 释放受 IL-1β 和 TNF 刺激，但 VP 不受 IFN 刺激。IL-1Ra 预注射可防止这些增加。这些结果表明I1-1β和TNF均通过IL-1R调节HPA轴。(2)将靶向M5毒蕈碱受体mRNA的寡核苷酸注入腹侧6天。训练自由行为的大鼠的被盖区，接受 M5 反义寡核苷酸（oligo）输注进行侧下丘脑刺激，使按杠所需的频率比基线水平增加了 48%，最大增加发生在 4-6 天后。与错义寡核苷酸相比，反义寡核苷酸输注可减少同侧腹侧被盖的 M5 受体，但不会减少对侧。与中脑边缘多巴胺神经元相关的毒蕈碱受体似乎在大脑刺激奖励中很重要。