Visceral illness refers to the nausea, dimunition of appetite and reduced food intake that contributes significantly to the morbidity and mortality of a wide range of clinical problems including cancer, AIDS, ingestion of toxins, and chemotherapy. Visceral illness can be modeled experimentally in animals using toxic doses of lithium chloride (LiCi). Although the syndrome of LiCi induces visceral illness is well characterized, the neurochemical systems that mediate the effects of this agent in the central nervous system are largely unknown and unexplored. We have recently accumulated evidence to support a role of for the brain-gut peptide glucagon-like-peptide-1 (7-36) amide (GLP-1) in mediating the effects of LiCi-induced visceral illness in the CNS. GLP-1 is a product of preproglucagon made in intestinal mucosal cells and in discrete population of neurons in the caudal brainstem. These neurons project primarily to the hypothalamus and GLP-1 receptors have been identified both in the hypothalamus and in the caudal brainstem. A variety of behavioral, physiological and neural effects of LiCi can be reproduced by administration of GLP-1 into the third cerebral ventricle. Additionally, some markers of LiCi-induced visceral illness are blocked by administration of a potent GLP-1 receptor antagonist into the CNS. These data have led to the guiding hypothesis of this proposal: the effects of LiCi induced toxicity, and perhaps other forms of visceral illness, are mediated by activation of CNS GLP-1 receptors. To test this hypothesis, we propose to 1) Assess whether a receptor antagonist for GLP-1 can ameliorate the effects of peripheral LiCi on a broad spectrum of markers of visceral illness in the rodent. 2) Assess the effect of LiCi on these markers of visceral illness in transgenic mice with null mutation of the GLP-1 receptor. 3) Localize the GLP-1 receptor population that signals GLP-1 and LiCi-induced visceral illness. 4) Identify the source of GLP-1(peripheral vs CNS) involved in transmitting LiCi induced visceral illness. 5) Assess whether the effects of other causes of visceral illness are transmitted by GLP-1 in the CNS. The experiments outlined in this proposal are critical to our understanding of the neural systems that are responsible for visceral illness. Understanding these systems is and important first step in devising therapeutic strategies for the many and varied clinical situations complicated by visceral illness.
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