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, J. Helfers

* 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

We 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.

In addition, 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 Rats had increased anxiety-like behavior when access to preferred food was withdrawn and, despite consuming fewer calories overall than rats maintained on chow, ultimately became heavier and fatter, with elevated levels of adipokines associated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 syndrome.

Treatment with 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.

In studies 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.

Publications

Chen, 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 31:2692, 2006.

Chu, 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.

Conti, 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, 2006.

Cottone, 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.

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, in press.

Fekete, 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.

Fekete, É.M., Zorrilla, E.P. Physiology, pharmacology, and therapeutic relevance of urocortins in mammals: ancient CRF paralogs. Front. Neuroendocrinol. 28:1, 2007.

Funk, 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.

O'Dell, 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, 2007.

Sabino, V., Cottone, P., Koob, G.F., Steardo, L., Lee, M.J., Rice, K.C., Zorrilla, E.P. Dissociation between opioid and CRF₁ antagonist sensitive drinking in Sardinian alcohol-preferring rats. Psychopharmacology (Berl.) 189:175, 2006.

Sabino, 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.

Zorrilla, 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.

Zorrilla, 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.