NEURAL SUBSTRATES OF PEPTIDE INDUCED SATIETY

描述：(改编自申请人的摘要) 此应用程序是竞争续订的修订版 旨在定义神经机制的研究计划，通过 胃肠肽，尤其是CCK，减少进食 摄取并最终了解这些底物是如何参与的 在食物摄入的生理学和病理学上。CCK由 肠道粘膜I细胞，对肠道中的营养物质作出反应。 我们发现外源性CCK和肠道内注入的营养物质 通过作用于类似的(如果不是完全相同的)辣椒素来减少食物摄入量 敏感的迷走神经纤维。此外，外源激素减少摄食 CCK和肠道营养输注被受体拮抗剂阻断 作用于CCKA，但不作用于CCKB受体。这些结果表明， 外周CCK受体与小型无髓迷走神经感觉神经元 通过外源性CCK参与减少食物摄入量 肠道营养素。他们还表明，内源性CCK在 肠道营养素在减少食物摄入量中的重要作用。 尽管现在已经知道辣椒素敏感的迷走神经纤维 为了减少CCK和肠道营养素的摄入量，我们 不知道用来传递饱腹感的神经递质(S) 从迷走神经纤维到大脑的信号。此外，我们不知道如何 其他胃肠肽可能参与迷走神经的激活 肠壁中的感觉纤维。我们最近的研究表明 谷氨酸作用于NMDA受体，可能参与传递 从迷走神经到大脑的饱腹感信号。另外，我们还有一些证据 降钙素基因相关肽可能参与启动饱腹感信号 在迷走神经的肠道末端。最后，我们几乎没有 了解CCK可能如何应对饮食变化以改变 饱腹感信号的灵敏度。然而，我们最近的结果表明， 适应某些饮食，特别是高脂肪饮食，可能会导致明显的 对CCK和其他饱腹感信号的反应减弱。因此， 提议的实验旨在：1)使用颅内注射 与肠道输注一起评估患者的参与度 谷氨酸能传递在CCK和CCK减少食物中的作用 肠道营养素；2)使用行为、药理和生化 肠道降钙素基因相关肽参与迷走神经活动的研究进展 导致食物摄入量的减少和3)使用饮食控制， 行为测试，免疫组织化学和生化技术 评估膳食中大量营养素在改变对疾病的反应中的作用 外源性CCK及内源性CCK参与 对肠道营养的反应性改变。

DESCRIPTION: (Adapted From The Applicant's Abstract) This application is a revised version for a competitive renewal of a research program aimed at defining the neuromechanisms through which gastrointestinal peptides especially cholecystokinin, CCK, reduce food intake and ultimately to appreciate how these substrates are involved in the physiology and pathology of food intake. CCK is released by intestinal mucosal I cells, in response to nutrients in the intestine. We discovered that exogenous CCK and intestinally infused nutrients reduce food intake by acting on similar, if not identical, capsacin sensitive, vagal fibers. Furthermore, reduction of feeding by exogenous CCK and intestinal nutrient infusions is blocked by receptor antagonist acting at CCKA but not CCKB receptors. These results suggest that peripheral CCK receptors and small unmyelinated vagal sensory neurons participate in the reduction of food intake by exogenous CCK and intestinal nutrients. They also suggest that endogenous CCK plays an important role in reduction of food intake by intestinal nutrients. Although it is now known that capsaicin sensitive vagal fibers mediate the reduction of food intake by both CCK and intestinal nutrients, we do not know the neurotransmitter(s) used to communicate these satiety signals from vagal fibers to the brain. Furthermore, we do not know how other gastrointestinal peptides may participate in activation of vagal sensory fibers in the intestinal wall. Our recent work suggests that glutamate, acting at NMDA receptors, may be involved in transmitting satiety signals from the vagus to brain. Also, we have some evidence that the peptide, CGRP, may participate in initiating satiety signals at the intestinal end of the vagus. Finally, we have little understanding of how CCK may respond to dietary changes to alter sensitivity of satiety signals. However, our recent results suggest that adaptation to certain diets, notably high fat diets, may cause marked reduction of response to CCK and other satiety signals. Therefore, the experiments proposed are designed to: 1) use intracranial injections together with intestinal infusions to evaluate the participation of glutamatergic transmission in the reduction of food by CCK and intestinal nutrients; 2) use behavioral, pharmacological and biochemical approaches to assess participation of gut CGRP in vagal activation leading to reduction of food intake and 3) to use dietary manipulations, behavioral testing, immunohistochemical and biochemical techniques to assess the role of dietary macronutrients in altering responsiveness to exogenous CCK and to evaluate participation of endogenous CCK in alterations of responsiveness to intestinal nutrients.