A Novel Compound for Alcoholism Treatment: a Translational Strategy

酒精依赖（AD）困扰着约10%的美国人口，并导致严重的发病率， mortality. Ghrelin是一种由28个氨基酸组成的肽，可以刺激食欲和食物摄入。这是一 生长激素促分泌素受体（GHSR 1a）的内源性配体。临床前研究 这表明胃饥饿素也调节酒精奖励过程。中央胃饥饿素管理局 小鼠的酒精摄入量显著增加，当生长激素释放肽 双侧给予特定的大脑奖励节点，例如腹侧被盖区。 类似地，在酗酒者中，较高的血浆ghrelin浓度与较高的 酒精消耗和消费。总的来说，这些研究提供的证据表明， 影响酒精的渴望和消费。因此，口服生物可利用的， 生长激素释放肽受体拮抗剂，可以通过血脑屏障具有特别的希望 作为AD治疗。该提案将使我们能够生成有关安全性的初步证据， 通过三个项目评估此类药物的疗效，即：(P1)一组实验 在充分验证的酒精寻求行为的动物模型中测试该药物的效果;（P2）a 确定人体安全性的药物/酒精相互作用研究（1b期）;和（P3）人体 实验室研究，通过一组良好的， 经验证的程序（酒精提示反应性、酒精自我给药、静脉注射酒精 渐进比例输注）以及药物对奖励处理的影响的表征 使用功能磁共振成像（2a期）酒精背景下的神经回路。这些项目将在 NIAAA校内计划（PI：Leggio）。此外，这三个项目将包括 药代动力学（PK）和药效学（PD）研究在University of 罗得岛（URI; PI：Akhlaghi）。PK/PD部分将包括（i）测量总的、未结合的 或使用液相色谱串联质谱法（LC-MS）测定药物的组织浓度。 MS/MS）和效果生物标志物的评估，以及（ii）PK和PD参数的估计。 通过使用常规和半机械建模的动物和人体研究 有助于确定AD中药物的最佳给药方案的方法。总之，这 研究将调查这种新的药理学的耐受性，有效性和机制。 因此，这可能导致识别出一种新的AD治疗方法。

Alcohol dependence (AD) afflicts ~10% of the US population and causes serious morbidity and mortality. Ghrelin is a 28-aminoacid peptide that stimulates appetite and food intake. It is an endogenous ligand for the growth hormone secretagogue receptor (GHSR1a). Preclinical studies suggest that ghrelin also modulates alcohol reward processing. Central ghrelin administration to mice significantly increased alcohol intake, and this increase was even more robust when ghrelin was administered bilaterally into specific brain reward nodes, e.g. the ventral tegmental area. Similarly, in alcoholic individuals, higher plasma ghrelin concentrations are associated with higher alcohol craving and consumption. Collectively, these studies provide evidence that manipulations of the ghrelin system affect alcohol craving and consumption. Therefore, an orally bioavailable, ghrelin receptor antagonist, that can pass through the blood brain barrier holds particular promise as an AD treatment. This proposal will allow us to generate preliminary evidence on the safety and efficacy of such pharmacological agent via three projects, i.e.: (P1) a set of experiments testing the effect of this drug in well-validated animal models of alcohol-seeking behavior; (P2) a drug/alcohol interaction study to establish safety in humans (Phase 1b); and (P3) a human laboratory study to assess the efficacy of this drug on alcohol-seeking behavior via a set of well- validated procedures (alcohol cue-reactivity, alcohol self-administration, intravenous alcohol progressive ratio infusion) as well as characterization of the drug effect on reward processing neurocircuitry in the context of alcohol using fMRI (Phase 2a). These projects will be conducted in the NIAAA Intramural Program (PI: Leggio). Furthermore, all three projects will include pharmacokinetics (PK) and pharmacodynamic (PD) investigations conducted at University of Rhode Island (URI; PI: Akhlaghi). The PK/PD component will include (i) measuring total, unbound or tissue concentrations of the drug using liquid chromatography tandem mass spectrometry (LC- MS/MS) and evaluation of biomarkers of effect and (ii) estimation of PK and PD parameters in both animal and human studies by the use of conventional and semimechanistic modeling approaches to assist in identifying an optimal dosing regimen of the drug in AD. In summary, this research will investigate the tolerability, efficacy and mechanism of this novel pharmacological approach for AD thus leading to the potential identification of a new treatment for AD.