Scientific Report 2007
Committee on the Neurobiology of Addictive Disorders
Neurobiology of Feeding, Motivation, and Stress
E.P. Zorrilla, L. Steardo,* K. Inoue,** A. Tabarin,*** S. Iwasaki,** A. Chen,****
D.V. Coscina,***** É. Fekete, Y. Zhao, V. Sabino, P. Cottone, M. Brennan,
* University of Palermo, Palermo, Italy
** Osaka City University Medical School, Osaka, Japan
*** Université Victor Ségalen Bordeaux 2, Hopital du Haut-Lévêque, Pessac, France
**** Weizmann Institute of Science, Rehovot, Israel
***** Wayne State University, Detroit, Michigan
study motivated behavior, with emphasis on brain reward and stress neurocircuits
that control food intake. In the past year, in our research on ghrelin, a 28-residue
stomach hormone that signals "energy insufficiency" to the brain, we made
progress toward a vaccine to control body weight. Ghrelin hinders consolidation
of weight loss. In collaborative studies with K.D. Janda, Department of Chemistry,
we found that n-octanoylation and the N-terminal third residue of ghrelin are critical
for the hormone's biological activity. Therefore, we used active immunization
to generate antibodies against the N terminus of ghrelin. The vaccine slowed the
accrual of body weight and fat in rats in proportion to the amount of ghrelin-binding
antibodies produced. We now are using passive immunization with transfer of antibodies
(whole immunoglobulin G or single-chain variable fragments) targeting the acylated
ghrelin N terminus. We also studied the roles of urocortin 2, urocortin 3, the benzodiazepine
receptor, and, with T. Bartfai and X. Liu, Molecular and Integrative Neurosciences
Department, galanin in the control of food intake and stress-related behavior.
we developed models of the hedonic (rather than homeostatic) control of food intake.
Rats with intermittent, limited access to highly preferred food ate increasing quantities
of these foods even when fed to satiation before given access to the preferred foods.
Conversely, with increasing experience with preferred foods, rats ate less than
normal amounts of their otherwise acceptable chow, despite weight loss. Thus, food
intake became controlled less by nutritional need and more by taste in both positive
("binge") and negative ("finickiness") directions. Rats had
increased anxiety-like behavior when access to preferred food was withdrawn and,
despite consuming fewer calories overall than rats maintained on chow, ultimately
became heavier and fatter, with elevated levels of adipokines associated with metabolic
opioid receptor antagonists, which reduce pleasurable aspects of addictive substances
such as ethanol, heroin, and morphine, reduced both bingelike eating and finickiness.
Thus, intermittent access to preferred food had effects that resemble those of addictive
substances, and opioid receptor antagonists reduced the influence of food preference
on food intake.
on addiction to classic substances of abuse, we found that opioid receptor antagonists
reduced bingelike alcohol drinking in rats genetically selected to prefer alcohol
and that antagonists of corticotropin-releasing factor type 1 receptors reduced
the heightened intake associated with ethanol withdrawal. In collaboration with
G.F. Koob, Committee on the Neurobiology of Addictive Disorders, we developed models
of heroin and nicotine dependence. We found that the pattern of drug intake and
consumption of alternative, natural rewards (e.g., food or water) similarly changed
during the development of dependence to either drug, suggesting a commonality in
the nature and neurobiology of addiction.
S.A., O'Dell, L.E., Hoefer, M.E., Greenwell, T.N., Zorrilla, E.P., Koob, G.F.
Unlimited access to
heroin self-administration: independent motivational markers of opiate dependence
[published correction appears in Neuropsychopharmacology 31:2802, 2006]. Neuropsychopharmacology
K., Koob, G., Cole, M., Zorrilla, E.P., Roberts, A.
Dependence-induced increases in ethanol self-administration in mice are blocked
by the CRF1 receptor antagonist antalarmin and by CRF1 receptor
knockout. Pharmacol. Biochem. Behav. 86:813, 2007.
B., Sanchez-Alavez, M., Winsky-Sommerer, R., Morale, M.C., Lucero, J., Brownell,
S., Fabre, V., Huitron-Resendiz, S., Henriksen, S., Zorrilla, E.P., de Lecea, L.,
Bartfai, T. Transgenic
mice with a reduced core body temperature have an increased life span. Science 314:825,
P., Sabino, V., Steardo, L., Zorrilla, E.P. FG
7142 specifically reduces meal size and the rate and regularity of sustained feeding
in female rats: evidence that benzodiazepine inverse agonists reduce food palatability.
Neuropsychopharmacology 32:1069, 2007.
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, in press.
É.M., Inoue, K., Zhao, Y., Rivier, J.E., Vale, W.W., Szucs, A, Koob, G.F.,
Zorrilla, E.P. Delayed
satiety-like actions and altered feeding microstructure by a selective type 2 corticotropin-releasing
factor agonist in rats: intra-hypothalamic urocortin 3 administration reduces food
intake by prolonging the post-meal interval. Neuropsychopharmacology 32:1052, 2007.
É.M., Zorrilla, E.P. Physiology,
pharmacology, and therapeutic relevance of urocortins in mammals: ancient CRF paralogs.
Front. Neuroendocrinol. 28:1, 2007.
C.K., Zorrilla, E.P., Lee, M.J., Rice, K.C., Koob, G.F. Corticotropin-releasing
factor 1 antagonists selectively reduce ethanol self-administration in ethanol-dependent
rats. Biol. Psychiatry 61:78, 2007.
L.E., Chen, S.A., Smith, R.T., Specio, S.E., Balster, R.L., Paterson, N.E., Markou,
A., Zorrilla, E.P., Koob, G.F.
Extended access to nicotine self-administration leads to dependence: circadian measures,
withdrawal measures, and extinction behavior in rats. J. Pharmacol. Exp. Ther. 320:180,
V., Cottone, P., Koob, G.F., Steardo, L., Lee, M.J., Rice, K.C., Zorrilla, E.P.
opioid and CRF1 antagonist sensitive drinking in Sardinian alcohol-preferring
rats. Psychopharmacology (Berl.) 189:175, 2006.
V., Cottone, P., Steardo, L., Schmidhammer, H., Zorrilla, E.P. 14-Methoxymetopon,
a highly potent μ opioid
agonist, biphasically affects ethanol intake in Sardinian alcohol-preferring rats.
Psychopharmacology (Berl.) 192:537, 2007.
E.P., Brennan, M., Sabino, V., Lu, X., Bartfai, T. Galanin
type 1 receptor knockout mice show altered responses to high-fat diet and glucose
challenge. Physiol. Behav. 91:479, 2007.
E.P., Iwasaki, S., Moss, J.A., Chang, J., Otsuji, J., Inoue, K., Meijler, M.M.,
Janda, K.D. Vaccination
against weight gain. Proc. Natl. Acad. Sci. U. S. A. 103:13226, 2006.