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The Journal of Neuroscience, May 1, 2000, 20(9):3442-3448
A Novel Selective Melanocortin-4 Receptor Agonist Reduces Food Intake in Rats and Mice without Producing Aversive Consequences
Stephen C. Benoit1, Michael W. Schwartz2, Jennifer L. Lachey1, Mary M. Hagan1, Paul A. Rushing1, Kathleen A. Blake1, Keith A. Yagaloff3, Grazyna Kurylko3, Lucia Franco3, Waleed Danhoo3, and Randy J. Seeley1 1 Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio 45267, 2 University of Washington, Department of Veterans Affairs, Puget Sound Health Care System, Seattle, Washington 98108-1597, and 3 Department of Metabolic Diseases, Hoffmann-La Roche Inc., Nutley, New Jersey 07110
Studies using nonselective agonists and antagonists of melanocortin-3 receptor (MC3R) and MC4R point to the importance of the CNS melanocortin system in the control of food intake. We describe here a novel compound that is highly selective as an agonist at the MC4 receptor but has minimal activity at the MC3 receptor. When administered centrally to rats, this selective agonist increased Fos-like immunoreactivity in the paraventricular nucleus, central nucleus of the amygdala, nucleus of the solitary tract, and area postrema, a pattern of neuronal activation that is similar to that induced by a nonselective MC3/4R agonist. Additionally, it suppresses food intake when administered centrally to rats or peripherally to db/db mice that lack functional leptin receptors via a mechanism that is not accompanied by illness or other nonspecific effects. Conversely, a related compound that is a selective MC4R antagonist potently increased food intake when administered centrally in rats. These results support the hypothesis that the brain MC4R is intimately involved in the control of food intake and body weight and provide evidence that selective activation of MC4R causes anorexia that is not secondary to aversive effects.
Key words: melanocortins; MC4-R; hypothalamus; food intake; taste aversion; c-Fos
Copyright © 2000 Society for Neuroscience 0270-6474/00/2093442-07$05.00/0
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