Scientific Report 2008
Committee on the Neurobiology of Addictive Disorders
Neurobiology of Feeding, Motivation, and Stress
E.P. Zorrilla, L. Steardo,* A. Tabarin,**
S. Iwasaki,*** É. Fekete, Y. Zhao, V. Sabino, P. Cottone, M. Brennan,
* University of Palermo, Palermo, Italy
** Université Victor Ségalen Bordeaux 2,
Hopital du Haut-Lévêque, Pessac, France
*** Osaka City University
Medical School, Osaka, Japan
We continue to
study motivated behavior, with an emphasis on brain reward and stress neurocircuits
that control food intake and appetitive behavior. In an ongoing collaboration with
B. Conti and M. Sanchez-Alavez, Molecular and Integrative Neurosciences Department,
we identified a regulatory role for the cytokine IL-18 in energy homeostasis. Male
and female mice that lacked IL-18 overate and became obese in adulthood. Conversely,
central or peripheral administration of IL-18 suppressed food intake in fasted wild-type
mice without producing malaise. We also showed a metabolic function for IL-18. Female
mice that lacked this cytokine had reduced energy expenditure, whereas administration
of IL-18 reduced feed efficiency in fasted mice.
We also studied the hedonic control of
food intake by using diet-cycling models. Intermittent access to palatable (i.e.,
highly preferred) food decreased the reinforcing efficacy and intake of a less preferred,
but otherwise acceptable, food. Rats withdrawn from access to palatable food also
had increased anxiety-like behavior and activation of stress-regulatory corticotropin-releasing
factor (CRF) systems in the central nucleus of the amygdala, changes not detected
when palatable food was available. Restoration of access to palatable food led to
overeating. Administration of a CRF1 receptor antagonist blocked the
increase in anxiety-like behavior and normalized the reinforcing efficacy of less
preferred food while also blunting the observed changes in food intake. Despite
eating no more overall than rats that were fed chow, diet-cycled rats ultimately
became heavier and fatter, with elevated levels of adipokines associated with metabolic
syndrome. Thus, intermittent access to palatable food had several effects that resembled
those of addictive substances and which were reduced by CRF1 receptor
We also combined pharmacologic and transgenic
approaches to study the functional importance of urocortin-CRF2 receptor
systems in the control of food intake. Local injection of urocortin 3 into the hypothalamus
suppressed food intake via a CRF2 mechanism more potently than did administration
into the hindbrain. Urocortin 3 prolonged satiety after a meal and slowed the rate
and regularity of feeding within meals. Intracranial administration of urocortin
3 did not elicit anxiety-like or malaise-like behavior, whereas selective CRF1
receptor agonists did. Mutant mice lacking CRF2 had increased nocturnal
food intake and abbreviated stress-induced anorexia, supporting a physiologic role
for the CRF2 receptor in the control of food intake. Most recently, we
showed that urocortin 2 is less potent, but has normal efficacy, in rats genetically
vulnerable to diet-induced obesity compared with rats resistant to obesity. The
ability of urocortin 2 to suppress high-fat food intake in obesity models is being
Previously, in a collaborative study
with K.D. Janda, Department of Chemistry, we showed that active immunization against
the N-terminal residues of ghrelin, an acylated 28-residue stomach hormone that
stimulates appetite and reduces lipid oxidation, slowed fat gain in rats proportional
to the degree to which the rats generated antibodies that bind ghrelin. This research
on active immunization against ghrelin continues, with a focus on the development
of haptens, conjugated to feasible carrier proteins and designed not to elicit undesired
cytotoxic T-cell responses, that can be commercialized. This work also involves
further study of mechanism, efficacy, and safety. In addition, we recently found
that acute administration of a catalytic antibody that facilitates degradation of
ghrelin to its inactive des-acyl form increases energy expenditure in fasting mice
and blunts refeeding after fasting. This finding suggests the practicality of passive
administration approaches, which we are investigating by using several high-affinity,
N terminally directed monoclonal antibodies.
Finally, we also found, partly in collaboration
with G.F. Koob, Committee on the Neurobiology of Addictive Disorders, and A. Roberts,
Molecular and Integrative Neurosciences Department, that previously known and novel
small-molecule selective CRF1 receptor antagonists reduce anxiety-like
behavior and blunt the excess drug self-administration that occurs in rodent models
of alcohol, nicotine, and cocaine dependence.
Cottone, P., Sabino, V., Nagy, T.R.,
Coscina, D.V., Zorrilla, E.P.
Feeding microstructure in diet-induced obesity susceptible versus resistant rats:
central effects of urocortin 2. J. Physiol. 583:487, 2007.
Cottone, P., Sabino, V., Steardo,
L., Zorrilla, E.P. Opioid-dependent
anticipatory negative contrast and binge-like eating in rats with limited access
to highly preferred food. Neuropsychopharmacology 33:524, 2008.
George, O., Ghozland,
S., Azar, M.R., Cottone, P., Zorrilla, E.P., Parsons, L.H., O'Dell, L.E., Richardson,
H.N., Koob, G.F. CRF-CRF1
system activation mediates withdrawal-induced increases in nicotine self-administration
in nicotine-dependent rats. Proc. Natl. Acad. Sci. U. S. A. 104:17198, 2007.
Lu, X., Ross, B., Sanchez-Alavez,
M., Zorrilla, E.P., Bartfai, T.
Phenotypic analysis of GalR2 knockout mice in anxiety and depression-related behavioral
tests. Neuropeptides 42:387, 2008.
Richardson, H.N., Zhao, Y., Fekete,
É.M., Funk, C.K., Wirsching, P., Janda, K.D., Zorrilla, E.P., Koob, G.F.
MPZP: a novel small molecule corticotropin-releasing factor type 1 receptor (CRF1)
antagonist. Pharmacol. Biochem. Behav. 88:497, 2008.
Specio, S.E., Wee, S., O'Dell,
L.E., Boutrel, B., Zorrilla, E.P., Koob, G.F.
CRF1 receptor antagonists attenuate escalated cocaine self-administration
in rats. Psychopharmacology (Berl). 196:473, 2008.
Tabarin, A., Diz-Chaves, Y., Consoli,
D., Monsaingeon, M., Bale, T.L., Culler, M.D., Datta, R., Drago, F., Vale, W.W.,
Koob, G.F., Zorrilla, E.P., Contarino, A.
Role of the corticotropin-releasing factor receptor type 2 in the control of food
intake in mice: a meal pattern analysis. Eur. J. Neurosci. 26:2303, 2007.
Zhao, Y., Valdez, G.R., Fekete, É.M.,
Rivier, J.E., Vale, W.W., Rice, K.C., Weiss, F., Zorrilla, E.P.
Subtype-selective corticotropin-releasing factor receptor agonists exert contrasting,
but not opposite, effects on anxiety-related behavior in rats. J. Pharmacol. Exp.
Ther. 323:846, 2007.
Zhao, Y., Weiss, F., Zorrilla, E.P.
Remission and resurgence of
anxiety-like behavior across protracted withdrawal stages in ethanol-dependent rats.
Alcohol. Clin. Exp. Res. 31:1505, 2007.
Zorrilla, E.P., Koob, G.F. Peptides.
In: Encyclopedia of Stress, 2nd ed. Fink, H. (Ed.). Academic Press, Burlington,
MA, 2007, Vol. 3, p. 91.
Zorrilla, E.P., Sanchez-Alavez, M.,
Sugama, S., Brennan, M., Fernandez, R., Bartfai, T., Conti, B.
Interleukin-18 controls energy homeostasis by suppressing appetite and feed efficiency.
Proc. Natl. Acad. Sci. U. S. A. 104:11097, 2007.
Zorrilla, E.P., Zhao, Y., Koob, G.F.
Anti-CRF. In: Encyclopedia of Stress, 2nd ed. Fink, H. (Ed.). Academic Press,
Burlington, MA, 2007, Vol. 1, p. 206.