Ghrelin antogonism and excessive drinking

描述（由申请人提供）：最近的研究表明，生长素拮抗剂作用于生长激素促分泌受体（GHSR），可有效减轻过度饮酒和相关的酒精奖励。US的研究结果表明，生长素拮抗剂D-Lys3-GHRP-6 （dlyys）在小鼠“黑暗中饮酒”（DID）模型中强烈且优先地减少酒精摄入，并且这种减少伴随着中央突出的Edinger-Westphal核（EWcp）中c-Fos表达的选择性抑制。EWcp是神经肽尿皮质素1 （Ucn1，一种强效的促肾上腺皮质激素释放因子受体内源性配体）的主要脑源，已被证明对乙醇高度敏感，并参与酒精摄入的调节。我们假设生长素拮抗剂可以用于减少不同动物模型的酒精摄入量，并且GHSR可以作为开发过度饮酒药物治疗的重要靶点。本提案的目的是测试这一假设，并确定行为，解剖和分子机制有助于这种减少。这一目标将在三个具体目标中得到解决。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过量饮酒的动物模型中减少酒精摄入量的能力。在特定目标2中，我们将通过敲入GHSR零突变小鼠和颅内注射特定脑区来研究ghrelin对过量饮酒影响的解剖学基础。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饮酒后Ghsr mRNA的水平，并通过测试Ghsr拮抗剂是否减弱乙醇在EWcp中诱导的信号转导机制，来研究ghrelin参与过量饮酒调节的分子机制

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