Obesity is a health problem of grave concern in western nations and the search for effective treatments has yet to come to fruition. The control of food intake and body weight involves peripheral (hormonal) and central (neural) mechanisms. In the brain, the hypothalamic melanocortin (MC) family of peptides is thought to play an important role in the control of food intake. Administration of MC antagonists produce[s] robust increases in food intake, while agonists lead to decreased intake. In addition, central expression of the precursor molecule, pro-opiomelanocortin (POMC), for these peptides is regulated by signals of energy balance, including the adipocyte hormone, leptin. Finally, genetic knockout mice, which lack a specific receptor subtype for these brain melanocortins, overeat and become obese. Together, these data suggest that the melanocortin system plays an important role in the CNS control of food intake and are critical to the maintenance of energy balance. Yet, virtually no analysis [has focused on] the behavioral mechanisms through which the MC peptides might alter food intake. The goal of this proposal is to assess the effects of melanocortins in several categories of ingestive behaviors. In one series of experiments, we will assess whether MC peptides influence pre-ingestive stimuli or appetitive behavior using sophisticated behavioral paradigms. In some studies, we will train rats to make conditioned responses under a food deprivation state and assess whether administration of central MCs lead[s] to similar sensory consequences. In addition, we will assess if MC peptides modulate rats' conditioned responses for stimuli that predict food, in ways similar to food deprivation. In a separate series of experiments, we will assess whether administration of central MCs alters the hedonic value of food. In one experiment, we will measure rats' appetitive responses during oral infusion of sweet solutions. In another experiment, we will assess whether MC peptides influence the ability of a sweet flavor to support conditioned place preference. In a final series of experiments, we will assess whether MC peptides [affect] food intake by influencing post-ingestive learning. We will test whether exposure to foods after central administration of MC peptides changes subsequent conditioned responding to cues that predicted the exposed food. Finally, we will assess whether such changes are post-ingestive, rather than orosensory, by infusing nutritive or nonnutritive solutions directly into the stomachs of the rats. These results will expand our understanding of this critical system for the regulation of food intake and body weight and, hopefully, provide insight into important structures and systems that are downstream of the melanocortins.
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