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