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Scientific Report 2004


Neuropharmacology




Neurobiology of Feeding and Stress


E.P. Zorrilla, G.F. Koob, A.J. Roberts, K. Inoue,* A. Tabarin,** É. Fekete, Y. Zhao, S.A. Chen, G.R. Valdez, R. Lintz, M. Arends, M. Brennan, M. Mattock, M. Hoefer

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

We study the neural regulation of motivated behavior, with a focus on feeding and food reward. For these studies, we developed mathematical approaches that reveal the temporal structures that underlie burstlike behavior, such as feeding that occurs in discrete meals. Coupling these methods with classic neuropharmacologic approaches has shed light on the microstructure of appetitive behavior. In a study fundamental for understanding ingestion, we showed that prandial drinking (i.e., drinking with a meal) is an integrated component of spontaneous meal taking in rats. We found that regulation of this type of drinking can be behaviorally and neuropharmacologically distinguished from nonprandial drinking on the basis of the qualitatively different effects of hunger, leptin, and fenfluramine.

Using this approach, we discovered changes in the microstructure and circadian regulation of meal patterning and drug taking during transition to heroin dependence. Temporal changes were contemporaneous with or even preceded the onset of traditionally defined dependence. We hypothesize that the changes reflect independent motivational measures of dependence. Similar analyses are being extended to other models of drug dependence.

A focus of our group is to understand the influence of stress and stress-related neuropeptides, such as corticotropin-releasing factor (CRF) and the urocortins, on motivated behavior. Recently, we found that CNS infusion of urocortin 2, a selective agonist of type 2 CRF (CRF2) receptors, dose-dependently facilitates satiation. Compared with untreated rats, rats treated with the agonist ate smaller and briefer meals more slowly without changes in meal frequency. Urocortin 2 induced expression of Fos protein, an activational marker, in brain regions that process visceral sensory information and regulate autonomic and neuroendocrine function; regions similar to those involved in rats given recognized appetite suppressants. The effects of urocortin 2 on feeding and neuroactivational responses qualitatively differed from those that occurred after CNS infusion of CRF and urocortin 1, ligands with affinity for CRF1 receptors, suggesting distinct CRF1- and CRF2-mediated anorectic pathways. We hypothesize that these pathways participate differentially in the feeding-related effects of stress specifically and in the regulation of energy balance generally.

To better understand the role of CRF receptor signaling in the regulation of feeding, we expanded meal-pattern analysis to mice. We are examining the effects of CRF1 and CRF2 deficiency on the microstructure of spontaneous ingestion and after treatment with stressors and drugs. Finally, we found that novel small molecule–selective CRF1 receptor antagonists and peptide-selective CRF2 receptor agonists have anxiolytic-like effects, supporting the hypothesis that activation of CRF1 and CRF2 receptors exerts opposing stresslike and anti-stresslike effects, respectively, in the brain.

Publications

Inoue, K., Valdez, G.R., Reyes, T.M., Reinhardt, L.E., Tabarin, A., Rivier, J., Vale, W.W., Sawchenko, P.E., Koob, G.F., Zorrilla, E.P. Human urocortin II, a selective agonist for the type 2 corticotropin-releasing factor receptor, decreases feeding and drinking in the rat. J. Pharmacol. Exp. Ther. 305:385, 2003.

Inoue, K., Zorrilla, E.P., Tabarin, A., Valdez, G.R., Iwasaki, S., Kiriike, N., Koob, G.F. Reduction of anxiety after restricted feeding in the rat: implication for eating disorders. Biol. Psychiatry 55:1075, 2004.

Valdez, G.R., Zorrilla, E.P., Rivier, J., Vale, W.W., Koob, G.F. Locomotor suppressive and anxiolytic-like effects of urocortin 3, a highly selective type 2 corticotropin-releasing factor agonist. Brain Res. 980:206, 2003.

Valdez, G.R., Zorrilla, E.P., Roberts, A.J., Koob, G.F. Antagonism of corticotropin-releasing factor attenuates the enhanced responsiveness to stress observed during protracted ethanol abstinence. Alcohol 29:55, 2003.

Zorrilla, E.P., Koob, G.F. The therapeutic potential of CRF1 antagonists for anxiety. Expert Opin. Investig. Drugs, in press.

Zorrilla, E.P., Reinhardt, L.E., Valdez, G.R., Inoue, K., Rivier, J., Vale, W.W., Koob, G.F. Human urocortin 2, a CRF2 agonist, and ovine CRF, a CRF1 agonist, differentially alter feeding and motor activity. J. Pharmacol. Exp. Ther., in press.

Zorrilla, E.P., Taché, Y., Koob, G.F. Nibbling at CRF receptor control of feeding and gastrocolonic motility. Trends Pharmacol. Sci. 24:421, 2003.

 


Eric P. Zorrilla, Ph.D.
Assistant Professor