A Novel Compound for Alcoholism Treatment: a Translational Strategy

酒精依赖(AD)困扰着大约10%的美国人口，并导致严重的发病率和 死亡率。Ghrelin是一种由28个氨基酸组成的多肽，可以刺激食欲和食物摄入量。这是一个 生长激素促分泌素受体(GHSR1a)的内源性配体。临床前研究 提示Ghrelin也调节酒精奖赏过程。中央Ghrelin管理 小鼠显著增加酒精摄入量，这种增加在Ghrelin时更加强劲 双侧注射到特定的大脑奖赏节点，例如腹侧被盖区。 同样，在酗酒的人中，较高的血浆Ghrelin浓度与较高的Ghrelin浓度相关 对酒精的渴望和消费。总而言之，这些研究提供了证据表明操纵 Ghrelin系统的变化会影响饮酒欲望和饮酒。因此，一种口服生物利用度， Ghrelin受体拮抗剂，可以通过血脑屏障，具有特殊的前景 作为治疗阿尔茨海默病的方法。这项提案将使我们能够产生关于安全性的初步证据 通过三个项目，即：(P1)一组实验，对这种药理药剂的有效性进行评估 在经过充分验证的酒精寻觅行为的动物模型中测试这种药物的效果； 药物/酒精相互作用研究，以确定对人类的安全性(1b阶段)；和(P3)人类 一项实验室研究，通过一系列良好的实验来评估这种药物对酗酒行为的疗效。 有效程序(酒精提示反应性、酒精自我给药、静脉注射酒精 累进比率输注)以及药物对奖赏加工的影响的特征 使用功能磁共振成像研究酒精环境下的神经回路(2a期)。这些项目将在 NIAAA内部计划(PI：Leggio)。此外，所有三个项目都将包括 药代动力学(PK)和药效学(PD)研究在加州大学进行 罗德岛(URI；PI：Akhlaghi)。PK/PD组件将包括：(I)测量合计，未绑定 或组织浓度使用液相色谱串联质谱(LC-MS) MS/MS)和生物标志物的评价以及(Ii)PK和Pd参数的估计 通过使用常规和半机械模型进行的动物和人体研究 帮助确定AD中药物的最佳剂量方案的方法。总而言之，这是 研究将调查这种新型药物的耐受性、有效性和作用机制。 治疗阿尔茨海默病的方法因此可能导致确定一种治疗阿尔茨海默病的新方法。

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.