The physiological mechanisms by which ingested food terminates eating in animals and humans is unknown. Knowledge about such mechanisms is necessary for the development of effective treatments for the control of eating in clinical conditions, such as obesity and bulimia. This proposal tests the hypothesis that the small intestinal peptide hormone called cholecystokinin (CCK) that is released by food stimuli contacting the surface of the small intestine is one of the physiological mechanisms for ending a meal and eliciting the behaviors characteristic of postprandial satiety in the rat. A radioimmunoassay technique will be used to measure the release of CCK by the intraduodenal infusion of a mixture of fats or by L-phenylalanine. The pattern and quantity of CCK released will be correlated with the inhibition of sham feeding produced by the intraduodenal infusions. The causal nature of this correlation will be investigated by measuring the effect of CCK antagonists, Proglumide and gastric vagotomy, on the satiating effect of the duodenal infusions that release CCK. If the released CCK is shown to inhibit sham feeding, then the satiating effect of released CCK on the termination of a real meal will be determined using the antagonist strategy. In addition to testing the hypothesis that CCK released from the intestine is a physiological satiety signal, experiments are proposed to determine the peripheral site of CCK's satiety effect. A specific binding procedure for CCK will be used to determine the effect of total and selective gastric vagotomy on the CCK binding sites in the pyloric sphincter. This will decide whether the binding sites are on terminal fibers of the vagus nerve or on other elements in the sphincter, i.e., muscle cells or intrinsic neurons of the gut. The final experiment will identify the site in the nucleus tractus solitarius in the medulla that is necessary for the transduction of vagal afferent activity produced by peripheral administration of exogenous CCK or the release of endogenous CCK into information that is used by the central network for the control of feeding to stop eating and initiate postprandial satiety.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH040010-06
Application #
3377865
Study Section
Neurosciences Research Review Committee (BPN)
Project Start
1984-12-01
Project End
1991-11-30
Budget Start
1990-01-01
Budget End
1990-11-30
Support Year
6
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Type
Schools of Medicine
DUNS #
201373169
City
New York
State
NY
Country
United States
Zip Code
10065
Torregrossa, A-M; Davis, J D; Smith, G P (2006) Orosensory stimulation is sufficient and postingestive negative feedback is not necessary for neuropeptide Y to increase sucrose intake. Physiol Behav 87:773-80
Eisen, S; Phillips, R J; Geary, N et al. (2005) Inhibitory effects on intake of cholecystokinin-8 and cholecystokinin-33 in rats with hepatic proper or common hepatic branch vagal innervation. Am J Physiol Regul Integr Comp Physiol 289:R456-R462
Ster, Andrea M; Kowalski, Timothy J; Dube, Michael G et al. (2003) Decreased hypothalamic concentration of neuropeptide Y correlates with onset of hyperphagia in fa/fa rats on postnatal day 12. Physiol Behav 78:517-20
Torregrossa, Ann-Marie; Smith, Gerard P (2003) Two effects of high-fat diets on the satiating potency of cholecystokinin-8. Physiol Behav 78:19-25
Kowalski, Timothy J; Ster, Andrea M; Smith, Gerard P (2002) Increased hypothalamic neuropeptide Y expression in deprived preweanling rats is reversed by intragastric infusion of milk. Physiol Behav 75:425-32
Davis, John D; Smith, Gerard P; McCann, D P (2002) The control of water and sodium chloride intake by postingestional and orosensory stimulation in water-deprived rats. Physiol Behav 75:7-14
Smith, Gerard P (2002) The evolution of an operant ecologist. Appetite 38:166-72
Corp, E S; McQuade, J; Krasnicki, S et al. (2001) Feeding after fourth ventricular administration of neuropeptide Y receptor agonists in rats. Peptides 22:493-9
Eisen, S; Davis, J D; Rauhofer, E et al. (2001) Gastric negative feedback produced by volume and nutrient during a meal in rats. Am J Physiol Regul Integr Comp Physiol 281:R1201-14
Weller, A; Tsitolovskya, L; Smith, G P (2001) Hypertonic glucose preloads act preabsorptively to decrease intake in rats on postnatal day 18. Physiol Behav 72:199-203

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