EXCEED THE SPACE PROVIDED. Obesity accounts for significant morbidity and mortality in the USA, as well as Western societies in general. The development of obesity can often be linked to a consumption of excess calories. Clearly, people eat in response to a variety of stimuli--physiological, environmental, emotional and social. However, improving our understanding of the neural controls of food intake may provide concrete measures by which obesity can be avoided. Meal termination usually begins with the propagation of sensory signals from the gut. For example, both mechanical stimulation of the stomach, and chemical stimulation of the intestine provide negative feedback that contributes to termination of food intake (satiation). Although vagal sensory neurons are known to convey both gastric mechanosensitive and intestinal chemosensitive signals to the brain, little is known about the neurotransmitters and receptors that communicate these signals from the vagus, to and through the brain. Several years ago, we have demonstrated that ionotropic; N-methyl-D-aspartate receptors (NMDA receptors) participate in termination of food intake. Our more recent results indicate that NMDA receptors specifically participate in satiety by altering gastric motor activity. In support of this hypothesis, we have compiled evidence to suggest that NMDA receptors involved in termination of feeding are located in the dorsal hindbrain, where vagal motor fibers from the gastrointestinal tract arise. These motor fibers act to control food intake via muscarinic cholinergic receptors to modulate the rate of gastric emptying. Furthermore, preliminary data from our lab suggest that substance P neurons and/or neurotachyldnin receptors may be important neural substrates for this effect. Accordingly, the specific aims that we have outlined for this renewal application are: 1) to employ physical/chemical ablation to reveal the central and peripheral neural and neurochemical substrates that contribute to increases in meal size induced by systemic MK-801; 2) to utilize a combination of behavioral and physiological techniques to determine the qualitative and quantitative relationships between altered within-meal gastric motor functions and increased food intake evoked by MK-801; and, 3) to make use of computer-assisted monitoring and analysis of meal parameters, in combination with acute and chronic administration of NMDA receptor antagonists, to determine the role of NMDA receptors in control of spontaneous meal size, 24-hour food intake, and body weight. PERFORMANCE SITE ========================================Section End===========================================

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK052849-06
Application #
6824087
Study Section
Special Emphasis Panel (ZRG1-IFCN-2 (01))
Program Officer
Yanovski, Susan Z
Project Start
1998-08-01
Project End
2007-12-31
Budget Start
2005-01-01
Budget End
2005-12-31
Support Year
6
Fiscal Year
2005
Total Cost
$266,814
Indirect Cost
Name
Washington State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
041485301
City
Pullman
State
WA
Country
United States
Zip Code
99164
Campos, Carlos A; Ritter, Robert C (2015) NMDA-type glutamate receptors participate in reduction of food intake following hindbrain melanocortin receptor activation. Am J Physiol Regul Integr Comp Physiol 308:R1-9
Zhao, Huan; Peters, James H; Zhu, Mingyan et al. (2015) Frequency-dependent facilitation of synaptic throughput via postsynaptic NMDA receptors in the nucleus of the solitary tract. J Physiol 593:111-25
Campos, Carlos A; Shiina, Hiroko; Ritter, Robert C (2014) Central vagal afferent endings mediate reduction of food intake by melanocortin-3/4 receptor agonist. J Neurosci 34:12636-45
Campos, Carlos A; Shiina, Hiroko; Silvas, Michael et al. (2013) Vagal afferent NMDA receptors modulate CCK-induced reduction of food intake through synapsin I phosphorylation in adult male rats. Endocrinology 154:2613-25
Campos, Carlos A; Wright, Jason S; Czaja, Krzysztof et al. (2012) CCK-induced reduction of food intake and hindbrain MAPK signaling are mediated by NMDA receptor activation. Endocrinology 153:2633-46
Gallaher, Z R; Ryu, V; Herzog, T et al. (2012) Changes in microglial activation within the hindbrain, nodose ganglia, and the spinal cord following subdiaphragmatic vagotomy. Neurosci Lett 513:31-6
Zhang, Jingchuan; Ritter, Robert C (2012) Circulating GLP-1 and CCK-8 reduce food intake by capsaicin-insensitive, nonvagal mechanisms. Am J Physiol Regul Integr Comp Physiol 302:R264-73
Ritter, Robert C (2011) A tale of two endings: modulation of satiation by NMDA receptors on or near central and peripheral vagal afferent terminals. Physiol Behav 105:94-9
Wright, Jason; Campos, Carlos; Herzog, Thiebaut et al. (2011) Reduction of food intake by cholecystokinin requires activation of hindbrain NMDA-type glutamate receptors. Am J Physiol Regul Integr Comp Physiol 301:R448-55
Ruiter, Marieke; Duffy, Patricia; Simasko, Steven et al. (2010) Increased hypothalamic signal transducer and activator of transcription 3 phosphorylation after hindbrain leptin injection. Endocrinology 151:1509-19

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