Effects of Ghrelin on Alcohol Cue Reactivity and Craving

描述(申请人提供)：美国食品和药物管理局(FDA)只批准了三种治疗酒精依赖的药物，即双硫仑、纳曲酮和氨基己酸酯。然而，双硫仑的疗效研究结果微乎其微，纳曲酮和氨基己酸酯的治疗效果也不是很好。人们迫切需要找到提供更有效治疗方法的方法。因此，确定治疗酒精依赖的新的潜在神经药理靶点是国家酒精滥用和酒精中毒研究所(NIAAA)的高度优先事项。Ghrelin是一种由28个氨基酸组成的多肽，作为生长激素促分泌素受体(GHS-R)的内源性配体。Ghrelin最初是从胃中分离出来的，但也证明了中央下丘脑产生Ghrelin。Ghrelin在食欲调节中起着关键作用。与控制食物和酒精消耗的常见神经生物学底物一致，临床前研究表明Ghrelin在酒精依赖的神经生物学中发挥作用，因此代表着一个新的潜在神经药理学靶点。与临床前研究一致，我们和其他小组的人体研究表明，酒精消费如何影响血液胃促生长素水平，血液胃促生长素水平与酒精依赖个人的渴望测量显著正相关。静脉注射外源性Ghrelin的效果。然而，从未对酒精依赖者进行过研究。目前的项目提出了一项随机、双盲、安慰剂对照的3组受试者间实验室研究，旨在调查外源性Ghrelin静脉注射的效果。关于寻求酒精依赖的非治疗对象的饮酒冲动、对线索的注意和相关的心理生理措施。这个试探性/开发性项目的目标是：i)进行酒精实验室研究，测试ghrelin静脉注射的作用，从而证明这种研究的可行性和ghrelin静脉注射的安全性。当给予酒精依赖者时；以及ii)探索ghrelin静脉注射的效果。在受控条件下对酒精渴求进行评估，例如线索反应实验。这项研究将解决当ghrelin水平通过ghrelin静脉注射而急剧改变时，酒精渴求是否会受到影响。注射。鉴于迫切需要扩大我们对酒精中毒潜在神经生物学的理解，这项研究可能会为药物治疗的发展确定新的靶点，从而改善对酒精依赖者的干预。 公共卫生相关性：酒精使用障碍每年造成10万人额外死亡，并造成相当大的死亡率和发病率。人们迫切需要发现新的、更有效的酒精使用障碍治疗方法。研究发现，Ghrelin系统是酒精渴求的媒介。更好地表征Ghrelin在酒精生物行为效应中的作用可能会导致对酒精使用障碍进行更有效的药物治疗。

DESCRIPTION (provided by applicant): Only three medications are approved by the Food and Drug Administration (FDA) for the treatment of alcohol dependence, namely disulfiram, naltrexone and acamprosate. However, the findings for efficacy of disulfiram are minimal and treatment effects for naltrexone and acamprosate are modest. There exists a substantial need for discovering ways to provide more effective treatments. Accordingly, identifying new potential neuropharmacological targets in the treatment of alcohol dependence represents a high priority of National Institute on Alcohol Abuse and Alcoholism (NIAAA). Ghrelin is a 28-amino acid peptide acting as the endogenous ligand for the growth hormone secretagogue receptor (GHS-R). Ghrelin was first isolated from the stomach, but a central hypothalamic production of ghrelin has also been demonstrated. Ghrelin plays a key role in the regulation of appetite. Consistent with the common neurobiological substrates for control of food and alcohol consumption, preclinical investigations suggest that ghrelin plays a role in the neurobiology of alcohol dependence, thus representing a new potential neuropharmacology target. In keeping with the preclinical studies, our and other groups' human investigations showed how alcohol consumption affects blood ghrelin levels and that blood ghrelin levels significantly and positively correlate with craving measurements in alcohol-dependent individuals. The effects of exogenous ghrelin injected i.v. in alcohol-dependent individuals, however, have never been investigated. The current project proposes a randomized double-blind placebo-controlled 3-group between- subject laboratory study aimed at investigating the effects of exogenous ghrelin i.v. on non-treatment seeking alcohol-dependent subjects in terms of urges to drink, attention to cues and related psychophysiological measures. This Exploratory/Developmental project has the goals to: i) conduct an alcohol laboratory study testing the role of ghrelin i.v., therefore demonstrating the feasibility of such a study and the safety of ghrelin i.v. when administered to alcohol-dependent individuals; and ii) explore the effects of ghrelin i.v. on alcohol craving assessed under controlled conditions, such as a cue-reactivity experiment. This study will address whether alcohol craving is affected when ghrelin levels are modified acutely via a ghrelin i.v. injection. Given the crucial need to expand our understanding of the underlying neurobiology of alcoholism, this study potentially will lead to identify new targets for the development of pharmacological treatments that may improve interventions for alcohol dependent individuals. PUBLIC HEALTH RELEVANCE: Public Health Relevance Alcohol use disorders account for 100,000 excess deaths per year and considerable mortality and morbidity. There exists a substantial need for discovering new, more effective treatments for alcohol use disorders. Research has identified the ghrelin system as a mediator of alcohol craving. Better characterizing the role of ghrelin in the biobehavioral effects of alcohol may lead to more effective pharmacological treatments for alcohol use disorders.