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.
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