Scientific Report 2005

Molecular and Integrative Neurosciences

Neurobiology of Feeding and Stress

E.P. Zorrilla, G.F. Koob, A.J. Roberts, K. Inoue,* A. Tabarin,** É. Fekete, Y. Zhao, V. Sabino, P. Cottone, L. O’Dell, S. Chen, G.R. Valdez, R. Lintz, M. Arends, M. Brennan, M. Mattock, M. Hoefer, J. Becker, J. Stampe

* Osaka City University Medical School, Osaka, Japan
** Université de Bordeaux II, USN du Haut-Leveque, Pessac, France

We study the regulation of motivated behavior, such as appetite. In a study fundamental for understanding ingestion, we showed that drinking is an integrated component of meal taking in rats, a finding that redefined what a meal is. Using the meal model, we discovered that leptin and fenfluramine suppress appetite through different behavioral mechanisms, as had been suggested by clinical experience but not reproduced in animal models. The model opens the way for differentiating appetite suppressants according to modes of action and perhaps for identifying those that act as long-term, and not only short-term, signals of energy balance.

One goal of our group is to understand the influence of stress and stress-related peptides, such as corticotropin-releasing factor (CRF) and the urocortins, on motivated behavior. We found that CNS infusion of urocortin 2, a selective CRF₂ receptor agonist, reduced intake of a palatable cafeteria diet, which otherwise promotes overeating, without malaise. Urocortin 2 was more potent than ovine CRF, a preferential CRF₁ receptor agonist, and did not have the anxiogenic-like or stimulant properties of the CRF₁ agonist. Urocortin 2 suppressed appetite via a different mode of action than ovine CRF did, because the peptides had qualitatively different effects on diet self-selection. CNS infusion of urocortin 3, another CRF₂ agonist, also suppressed intake of palatable food without malaise, and hypothalamic CRF₂ receptors were the site of action.

To understand further the role of signaling by members of the CRF/urocortin family in energy balance, we expanded meal-pattern analysis to mice and examined the effects of CRF₁, CRF₂, and urocortin 2 deficiencies on the microstructure of ingestion. The findings support our hypothesis that CRF₁ and CRF₂ pathways participate differentially in the regulation of feeding and support the potential efficacy of CRF₂ agonists as appetite suppressants.

We also studied the relation of scheduled dieting to changes in feeding and stress-related behavior. A history of scheduled, restricted feeding (i.e., eating less than what would be typically eaten in an entire day and predominantly within a single large meal) reduced anxiety-like behavior not only during food restriction but also after the resumption of normal daily intake. The results indicate that scheduled dieting interacts with stress-related neurocircuitry in a manner with implications for the treatment of eating disorders.

Finally, we found that small-molecule, selective CRF₁ receptor antagonists had antistress effects, consistent with the finding that CNS infusion of a novel, selective CRF₁ agonist, stressin-1, had anxiogenic-like effects in animal models. The findings support the therapeutic potential of CRF₁ antagonists for treatment of anxiety.

Publications

Stinus, L., Cador, M., Zorrilla, E.P., Koob, G.F. Buprenorphine and a CRF₁ antagonist block the acquisition of opiate withdrawal-induced conditioned place aversion in rats. Neuropsychopharmacology 30:90, 2005.

Zorrilla, E.P., Inoue, K., Fekete, E.M., Tabarin, A., Valdez, G.R., Koob, G.F. Measuring meals: structure of prandial food and water intake of rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 288:R1450, 2005.

Zorrilla, E.P., Inoue, K., Valdez, G.R., Tabarin, A., Koob, G.F. Leptin and post-prandial satiety: acute central leptin more potently reduces meal frequency than meal size in the rat. Psychopharmacology (Berl.) 177:324, 2005.

Zorrilla, E.P., Koob, G.F. The therapeutic potential of CRF₁ antagonists for anxiety. Expert Opin. Investig. Drugs 13:799, 2004.

Zorrilla, E.P., Reinhardt, L.E., Valdez, G.R., Inoue, K., Rivier, J., Vale, W.W., Koob, G.F. Human urocortin 2, a corticotropin-releasing factor (CRF) agonist, and ovine CRF, a CRF₁ agonist, differentially alter feeding and motor activity. J. Pharmacol. Exp. Ther. 310:1027, 2004.