The control of gastric motility and emptying following a meal is mediated by both hormonal and neural pathways.
The aim of this proposal is to establish a role for cholecystokinin (CCK) in mediating changes in motility and emptying in response to duodenal stimulation, and investigate its pathways and mechanisms of action. In particular, the role of visceral afferent pathways in mediating changes in gastroduodenal motility induced by CCK and duodenal stimulants will be studied. Changes in gastroduodenal motility and gastric emptying in response to duodenal perfusion with protein, soya bean trypsin inhibitor, acid and glucose and duodenal distension and exogenous will be determined in anesthetized rats. Intraluminal pressure in the gastric corpus, antrum and duodenum will be measured using a multilumen catheter for perfused side hole manometry in combination with a sleeve sensor to simultaneously measure pyloric pressure. Gastric emptying studies will be carried out in conscious rats fitted with gastric fistulas using the double sampling technique. The role of CCK will be determined using a specific receptor antagonist and by immunoneutralization with a CCK monclonal antibody binding. The afferent pathways by which duodenal stimulation and CCK act will be studied using direct application of the sensory neurotoxin, capsaicin, to the vagus, coeliac/superior mesenteric ganglion or duodenum. Local administration of capsaicin to a peripheral nerve in adult animals produces an impairment of afferent C-fiber function and a long-lasting insensitivity to stimulation by physiological, electrical or chemical means. The mechanism of action of CCK will be assessed in electrophysiological recordings of vagal afferent fibers mediating intestinal mechano- and chemoreceptor discharge. The response of these afferents to duodenal stimulation will be studied in the presence of CCK, CCK receptor blockade or CCK immunoneutralization. There is abundant evidence that CCK acts in the periphery to inhibit food intake and alter feeding behaviors. There is evidence that this may be secondary to changes in gastrointestinal motility and transit. The elucidation of the pathway and mechanism of action of CCK on the gastrointestinal tract will contribute to a better understanding of postpostprandial events and consequently eating disorders.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First Independent Research Support & Transition (FIRST) Awards (R29)
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General Medicine A Subcommittee 2 (GMA)
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University of California Los Angeles
Schools of Medicine
Los Angeles
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de La Serre, Claire B; de Lartigue, Guillaume; Raybould, Helen E (2015) Chronic exposure to low dose bacterial lipopolysaccharide inhibits leptin signaling in vagal afferent neurons. Physiol Behav 139:188-94
Ronveaux, Charlotte C; de Lartigue, Guillaume; Raybould, Helen E (2014) Ability of GLP-1 to decrease food intake is dependent on nutritional status. Physiol Behav 135:222-9
de Lartigue, Guillaume; Barbier de la Serre, Claire; Espero, Elvis et al. (2012) Leptin resistance in vagal afferent neurons inhibits cholecystokinin signaling and satiation in diet induced obese rats. PLoS One 7:e32967
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Otis, Jessica P; Raybould, Helen E; Carey, Hannah V (2011) Cholecystokinin activation of central satiety centers changes seasonally in a mammalian hibernator. Gen Comp Endocrinol 171:269-74
Lee, Jennifer; Martin, Elizabeth; Paulino, Gabriel et al. (2011) Effect of ghrelin receptor antagonist on meal patterns in cholecystokinin type 1 receptor null mice. Physiol Behav 103:181-7
Liou, Alice P; Lu, Xinping; Sei, Yoshitatsu et al. (2011) The G-protein-coupled receptor GPR40 directly mediates long-chain fatty acid-induced secretion of cholecystokinin. Gastroenterology 140:903-12
Liou, Alice P; Sei, Yoshitatsu; Zhao, Xilin et al. (2011) The extracellular calcium-sensing receptor is required for cholecystokinin secretion in response to L-phenylalanine in acutely isolated intestinal I cells. Am J Physiol Gastrointest Liver Physiol 300:G538-46
Raybould, Helen E (2010) Gut chemosensing: interactions between gut endocrine cells and visceral afferents. Auton Neurosci 153:41-6
De Lartigue, Guillaume; Dimaline, Rod; Varro, Andrea et al. (2010) Cocaine- and amphetamine-regulated transcript mediates the actions of cholecystokinin on rat vagal afferent neurons. Gastroenterology 138:1479-90

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