Ghrelin antogonism and excessive drinking

描述（由申请人提供）：最近的研究表明，作用于生长激素促分泌素受体（GHSR）的生长素释放肽拮抗剂可显著减弱过量酒精自我给药和相关的酒精奖励。由US产生的结果表明，生长激素释放肽拮抗剂D-Lys 3-GHRP-6（DLys）强烈和优先减少饮酒的小鼠“在黑暗中饮酒”（DID）模型的暴饮暴食样过度饮酒，这种减少是伴随着选择性抑制c-Fos表达的中央投射Edinger-Westphal核（EWcp）。EWcp是神经肽urocortin 1（Ucn 1，促肾上腺皮质激素释放因子受体的高效内源性配体）的主要脑来源，并且已被证明对乙醇高度敏感并参与调节酒精摄入。我们假设生长激素释放肽拮抗剂可用于减少不同动物模型的酒精摄入量，GHSR可作为开发过度饮酒药物治疗的重要靶点。该提案的目标是测试这一假设，并确定有助于这种减少的行为，解剖和分子机制。这一目标将在三个具体目标中加以阐述。在具体目标1中，我们将测试不同剂量的GHSR拮抗剂在不同阶段和不同的过量饮酒动物模型中减少酒精摄入的能力。在具体目标2中，我们将使用敲入GHSR无效突变小鼠和颅内注射到特定脑区来研究生长激素释放肽对过量饮酒的影响的解剖学底物。在具体目标3中，我们将通过分析小鼠、大鼠和非人灵长类动物过量酒精摄入后Ghsr mRNA的水平，并通过测试EWcp中乙醇诱导的信号转导机制是否被给予GHSR拮抗剂减弱，来研究ghrelin参与调节过量酒精摄入的分子机制 公共卫生相关性：过度饮酒和酗酒是主要的公共卫生问题，酒精造成全球约4%的死亡。我们的研究将提供一个全面的基础上使用的潜力ghrelin拮抗剂治疗酒精使用障碍和酒精中毒。

DESCRIPTION (provided by applicant): 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.