The overall aim of the research proposed in this grant is to identify the sites of action and mechanisms through which centrally and peripherally administered bombesin-like peptides affect food intake. Underlying these experiments is the view that bombesin (BBS) interacts with a variety of receptor populations in mammals, mimicking the effects of mammalian peptides such as gastrin releasing peptide (GRP) and neuromedin B (NMB) and that the inhibition of food intake is a physiological action of one or more of these endogenous mammalian peptides. The specific experiments take a number of directions. Utilizing receptor binding techniques and in vitro autoradiography, we propose to identify subpopulations of BBS binding sites for the mammalian peptides GRP and NMB, differentiated by their pharmacological specificity. We will determine the distribution and relative specificity of these BBS receptor subtypes in specific brain regions, the gastrointestinal tract and the spinal cord. We will use general and specific BBS receptor antagonists to identify the role of endogenous BBS-like peptides in the control of food intake and which actions of BBS are likely mediated by different specific receptor subpopulations. We will also use BBS agonist compounds with high degrees of specificity for one or the other receptor subtypes to identify local gastrointestinal actions of BBS-like peptides that may play a role in their ability to inhibit food intake. BBS agonists and antagonists will also be used to identify the mammalian peptides whose behavioral actions exogenous BBS is mimicking. Finally, we will identify the specific anatomical location of BBS receptors in the nucleus tractus solitarius (NTS) and determine the role of these receptors in the inhibition of food intake elicited by either centrally or peripherally administered BBS. Elucidation of this role will enable us to identify the relationship between the inhibition of food intake produced by both routes of administration. This work will also identify brain sites at which other behavioral actions of centrally administered BBS are mediated and the specific receptor subpopulations which may underlie these behavioral actions. Together, these experiments will significantly advance our understanding of the feeding inhibitory actions of BBS-like peptides specifically and brain/gut peptides in general. Our results will also provide a framework for understanding the overall functions of BBS-like peptides in behavior and neuro and gastrointestinal physiology.
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