Effect of cytokines on the pathogenesis of mood disondens

为探讨细胞因子在心境障碍发病机制中的作用，进行了两个动物实验：(1)细胞因子是免疫调节因子之一，控制脑内下丘脑-垂体-肾上腺轴(HPA轴)的应激反应。加压素(VP)是室旁核(PVN)内调节HPA的多肽之一，有关细胞因子对其影响的报道较少。本研究采用微透析技术，观察了大鼠脑下丘脑室旁核内微量注射细胞因子白介素1β、肿瘤坏死因子和干扰素对VP释放的影响。我们还观察了白细胞介素1受体拮抗剂(IL-1ra)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。将微透析探头植入PVN，每30分钟采集标本一次。IL-1β和肿瘤坏死因子可促进VP的释放，而IFN不能刺激VP的释放，而IL-1ra可抑制VP的释放。这些结果表明，I1-1β和肿瘤坏死因子都通过IL-1R调节HPA轴。(2)将针对M5受体基因的寡核苷酸注入自由行为大鼠的腹侧被盖区6d，进行下丘脑外侧刺激训练。注射M5反义寡核苷酸可使压棒所需的频率比基线水平增加48%，最大的增加发生在输注后4-6天。与错义寡核苷酸相比，反义寡核苷酸注射减少了同侧腹侧被盖的M5受体，但不减少对侧的M5受体。因此，与中脑边缘多巴胺神经元相关的M5受体似乎在脑刺激奖赏中起着重要作用。

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.