In humans, dogs and, under appropriate circumstances, rats, the ingestion of food elicits increases in the secretion of the hypothalamic-pituitary- adrenal (HPA) axis. The hormonal and neural pathways linking these events have not been established although they are thought to involve brain-gut peptides such as vasoactive intestinal peptide (VIP), chlocystokinin (CCK), and gastrin releasing peptide (GRP), all of which have been shown to simulate the HPA axis when administered either centrally or peripherally the hypothesis on which the proposed studied are based is that the brain-gut peptides VIP, CCK and/or GRP act either/or both peripherally and centrally to mediate/modulate feeding-induced HPA secretion; that these peptides, acting at multiple receptors, interact with a) each other, b) leptin and c) stress/obesity in such mediation/modulation. In order to test this hypothesis we intend to:
Specific Aim 1 -establish the brain site(s) at which CCK, bombesin/GRP and VIP mediate/modulate feeding-induced HPA secretion via stereotaxic administration of specific receptor antagonists;
Specific Aim 2 - further characterize interactions of the multiple receptors for CCK/gastrin, GRP/NMB (neuromedin B) and VIP in regulating feeding-induced HPA secretion;
Specific Aim 3 -establish the role of leptin in the mediation of peptide (CCK, VIP and bombesin)- and feeding-induced HPA secretion via co- administration of leptin to fasted animals;
and Specific Aim 4 -examine the influence of brain-gut peptides in modulating HPA secretion during stress induced feeding and anorexia, using tail- pinch and isolation/crowding models of stress. Given the importance of these hormones of the HPA axis in regulating the responses of the body to stress and the apparent regulation of HPA axial function by the timing of food ingestion, an understanding of the mechanisms through which food ingestion alters HPA axial function is critical to our understanding of the body's response to stress.
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