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 neurotachykinin 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.
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