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 #
5U01AA016647-08
Application #
8526287
Study Section
Special Emphasis Panel (ZAA1-DD (50))
Program Officer
Regunathan, Soundar
Project Start
2006-09-30
Project End
2016-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
8
Fiscal Year
2013
Total Cost
$238,829
Indirect Cost
$83,745
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
Smith, M L; Li, J; Cote, D M et al. (2016) Effects of isoflurane and ethanol administration on c-Fos immunoreactivity in mice. Neuroscience 316:337-43
Smith, Monique L; Hostetler, Caroline M; Heinricher, Mary M et al. (2016) Social transfer of pain in mice. Sci Adv 2:e1600855
Barkley-Levenson, Amanda M; Ryabinin, Andrey E; Crabbe, John C (2016) Neuropeptide Y response to alcohol is altered in nucleus accumbens of mice selectively bred for drinking to intoxication. Behav Brain Res 302:160-70
Pina, Melanie M; Young, Emily A; Ryabinin, Andrey E et al. (2015) The bed nucleus of the stria terminalis regulates ethanol-seeking behavior in mice. Neuropharmacology 99:627-38
Park, Hyo-Jin; Ran, Yong; Jung, Joo In et al. (2015) The stress response neuropeptide CRF increases amyloid-β production by regulating γ-secretase activity. EMBO J 34:1674-86
Gomez, Juan L; Cunningham, Christopher L; Finn, Deborah A et al. (2015) Differential effects of ghrelin antagonists on alcohol drinking and reinforcement in mouse and rat models of alcohol dependence. Neuropharmacology 97:182-93
Smith, Monique L; Li, Ju; Ryabinin, Andrey E (2015) Increased alcohol consumption in urocortin 3 knockout mice is unaffected by chronic inflammatory pain. Alcohol Alcohol 50:132-9
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
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
Hostetler, Caroline M; Ryabinin, Andrey E (2013) The CRF system and social behavior: a review. Front Neurosci 7:92

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