Recent studies show that ghrelin antagonists acting on growth hormone secretagogue receptor (GHSR) robustly attenuate excessive alcohol self-administration and associated alcohol reward. Findings generated by US indicate that the ghrelin antagonist D-Lys3-GHRP-6 (DLys) strongly and preferentially decreases alcohol drinking in the mouse "drinking-in-the-dark" (DID) model of binge-like excessive alcohol consumption, and that this decrease is accompanied by selective suppression of c-Fos expression in the centrally-projecting Edinger-Westphal nucleus (EWcp). The EWcp is the main brain source of the neuropeptide urocortin 1 (Ucn1, a highly potent endogenous ligand of corticotropin releasing factor receptors) and has been shown to be highly sensitive to ethanol and be involved in regulation of alcohol intake. We hypothesize that ghrelin antagonists can be used to decrease alcohol intake across different animal models and that GHSR can serve as an important target for development of pharmacotherapy of excessive alcohol consumption. The goal of this proposal is to test this hypothesis and identify behavioral, anatomical and molecular mechanisms contributing to this decrease. This goal will be addressed in the three specific aims.
In specific aim 1 we will test the ability of different doses of GHSR antagonists to decrease alcohol intake across different phases and different animal models of excessive alcohol consumption.
In specific aim 2 we will investigate the anatomical substrates of ghrelin's effects on excessive alcohol drinking using knock-in GHSR null mutant mice and intracranial injections into specific brain regions.
In specific aim 3 we will investigate the molecular mechanisms of ghrelin's involvement in regulation of excessive alcohol intake by analyzing levels of Ghsr mRNA after excessive alcohol intake in mice, rats and non-human primates and by testing whether signal transduction mechanisms induced by ethanol in EWcp are attenuated by administration of GHSR antagonists

Public Health Relevance

Excessive alcohol use and alcoholism are major public health concerns, with alcohol causing approximately 4% of deaths globally. Our studies will provide a comprehensive basis for the potential of the use of ghrelin antagonism in the treatment of alcohol-use disorders and alcoholism.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AA016647-07
Application #
8327797
Study Section
Special Emphasis Panel (ZAA1-DD (50))
Program Officer
Regunathan, Soundar
Project Start
2006-09-30
Project End
2016-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
7
Fiscal Year
2012
Total Cost
$256,806
Indirect Cost
$90,049
Name
Oregon Health and Science University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Gomez, Juan L; Ryabinin, Andrey E (2014) The effects of ghrelin antagonists [D-Lys(3) ]-GHRP-6 or JMV2959 on ethanol, water, and food intake in C57BL/6J mice. Alcohol Clin Exp Res 38:2436-44
Ryabinin, Andrey E; Cocking, Davelle L; Kaur, Simranjit (2013) Inhibition of VTA neurons activates the centrally projecting Edinger-Westphal nucleus: evidence of a stress-reward link? J Chem Neuroanat 54:57-61
Giardino, William J; Ryabinin, Andrey E (2013) CRF1 receptor signaling regulates food and fluid intake in the drinking-in-the-dark model of binge alcohol consumption. Alcohol Clin Exp Res 37:1161-70
Cruz, Maureen T; Herman, Melissa A; Cote, Dawn M et al. (2013) Ghrelin increases GABAergic transmission and interacts with ethanol actions in the rat central nucleus of the amygdala. Neuropsychopharmacology 38:364-75
Ryabinin, Andrey E; Tsoory, Michael M; Kozicz, Tamas et al. (2012) Urocortins: CRF's siblings and their potential role in anxiety, depression and alcohol drinking behavior. Alcohol 46:349-57
Kaur, Simranjit; Li, Ju; Stenzel-Poore, Mary P et al. (2012) Corticotropin-releasing factor acting on corticotropin-releasing factor receptor type 1 is critical for binge alcohol drinking in mice. Alcohol Clin Exp Res 36:369-76
Giardino, William J; Ryabinin, Andrey E (2012) Corticotropin-releasing factor: innocent until proven guilty. Nat Rev Neurosci 13:70; author reply 70
Giardino, William J; Cocking, Davelle L; Kaur, Simranjit et al. (2011) Urocortin-1 within the centrally-projecting Edinger-Westphal nucleus is critical for ethanol preference. PLoS One 6:e26997
Anacker, Allison M J; Loftis, Jennifer M; Kaur, Simranjit et al. (2011) Prairie voles as a novel model of socially facilitated excessive drinking. Addict Biol 16:92-107
Kozicz, Tamas; Bittencourt, Jackson C; May, Paul J et al. (2011) The Edinger-Westphal nucleus: a historical, structural, and functional perspective on a dichotomous terminology. J Comp Neurol 519:1413-34

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