Effect of cytokines on the pathogenesis of mood disondens

为了研究细胞因子在情绪障碍发病机制中的作用，我们进行了两个动物实验。(1)据报道，细胞因子作为免疫调节因子之一，控制着大脑下丘脑-垂体-肾上腺轴（HPA轴）的应激反应。抗利尿激素（VP）是室旁核（PVN）内的一种HPA调节肽，关于细胞因子对其影响的报道很少。本研究采用微透析技术，通过显微注射细胞因子、白细胞介素-1 （IL-1β）、肿瘤坏死因子（TNF）、干扰素（IFN），观察大鼠脑PVN中VP的释放情况。我们还研究了白细胞介素-1受体拮抗剂（IL-1Ra）对细胞因子诱导VP释放的影响。雄性Wistar大鼠（8 ~ 10周龄）用聚氨酯（1.4g/kg, ip）麻醉。微透析探针植入PVN，每30分钟采集一次样品。用RIA测定VP。IL-1β和TNF刺激VP释放，IFN不刺激VP释放。预注射IL-1Ra可阻止这些增加。这些结果表明，I1-1β和TNF均通过IL-1R调节HPA轴。(2)将靶向M5毒毒碱受体mRNA的寡核苷酸注入自由行为大鼠的腹侧被盖区6 d。注射M5反义寡核苷酸（oligo）使按压棒材所需的频率比基线水平增加了48%，注射后4-6 d增加最多。与错义寡核苷酸相比，反义寡核苷酸输注减少了腹侧被盖同侧而非对侧的M5受体。因此，与中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起重要作用。

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.