Involvement of neuropeptide systems in excessive alcohol drinking

神经肽系统参与过量饮酒

• 批准号: 9757590
• 负责人: VALENTINA SABINO
• 金额: $ 37.13万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-20 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9757590
• 关键词: Acute; Adult; Affect; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Amino Acids; Cells; Chronic; Complex; Consultations; Consumption; Corpus striatum structure; Data; Disease; Drug effect disorder; Environmental Risk Factor; Ethanol; Ethanol dependence; Etiology; Exposure to; Functional disorder; G-Protein-Coupled Receptors; Genetic; Glutamates; Goals; Heavy Drinking; Heritability; Human; Hyperactive behavior; Immunohistochemistry; Intake; Medial; Mediating; Molecular; Motivation; Neurobiology; Neuronal Plasticity; Neurons; Neuropeptides; Neurosciences Research; Neurotransmitters; Nucleus Accumbens; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Play; Population; Predisposition; Prefrontal Cortex; Property; Rattus; Relapse; Resistance; Rewards; Rodent; Role; Saccharin; Sucrose; System; Techniques; Testing; Virus; Water; Withdrawal; alcohol abuse therapy; alcohol preferring rats; alcohol use disorder; base; brain dysfunction; disorder risk; drinking; drug of abuse; experimental study; fly; insight; interdisciplinary approach; knock-down; motivated behavior; neuroadaptation; neurobiological mechanism; neurochemistry; novel; pituitary adenylate cyclase activating polypeptide; preference; receptor; small hairpin RNA; vapor

ABSTRACT Approximately 18 million people (1 in every 12 adults) in the USA abuse or are dependent on alcohol. The etiology of alcohol use disorders is complex; heritable susceptibility factors interact with environmental factors to produce and maintain the disease state. One goal of current neuroscience research is, therefore, to identify the neuroadaptations mediating the propensity to consume high amounts of alcohol, of either innate or environmental origin. In particular, dysfunctions of prefronto-striatal projections have been proposed to play a critical role in alcohol addiction. This project concerns pituitary adenylate cyclase-activating polypeptide (PACAP), a highly conserved 38 amino acid neuropeptide, and its receptor PAC1R. Studies in flies, rodents and humans have started to reveal a crucial role for the PACAP/PAC1R system in motivated behaviors and in the actions of drugs of abuse. The lack of studies exploring its role in alcohol addiction constitutes a barrier to the advancement of the field. Our preliminary data strongly suggest that neuroadaptions in the PACAP/PAC1R system of the nucleus accumbens core (NAcc Core) mediate the susceptibility to drink excessively. Our long-term goal is to unravel the molecular mechanisms underlying the genetic propensity to drink excessively and the transition to alcohol dependence. The overarching hypothesis of this proposal is that hyperactivation of the PACAP/PAC1 system in the medial prefrontal cortex -NAcc Core pathway mediates excessive drinking and the long-lasting neuroplastic changes observed in alcohol dependence. We will test our hypotheses using a multidisciplinary approach which includes the use of chemogenetic, pharmacological, neurochemical, and molecular techniques. The results of the proposed experiments will provide key insights into the neuroadaptive changes responsible for excessive drinking.

抽象的 美国约有 1800 万人（每 12 名成年人中就有 1 人）滥用酒精或依赖酒精。 酒精使用障碍的病因很复杂。遗传易感因素与环境相互作用 产生和维持疾病状态的因素。因此，当前神经科学研究的目标之一是 识别调节大量饮酒倾向的神经适应，无论是先天性的还是 环境起源。特别是，前额纹状体投射功能障碍被认为可以发挥 在酒精成瘾中起关键作用。 该项目涉及垂体腺苷酸环化酶激活多肽（PACAP），一种高度保守的 38个氨基酸的神经肽及其受体PAC1R。对苍蝇、啮齿动物和人类的研究已经开始 揭示 PACAP/PAC1R 系统在动机行为和滥用药物行为中的关键作用。 缺乏探索其在酒精成瘾中的作用的研究构成了该领域进步的障碍。 我们的初步数据强烈表明，细胞核 PACAP/PAC1R 系统中的神经适应 伏隔核（NAcc Core）调节过度饮酒的易感性。 我们的长期目标是揭示饮酒遗传倾向背后的分子机制 过度并过渡到酒精依赖。该提案的总体假设是 内侧前额皮质 PACAP/PAC1 系统过度激活 -NAcc 核心通路介导 过度饮酒和酒精依赖中观察到的长期神经塑性变化。我们将测试我们的 使用多学科方法提出假设，包括使用化学遗传学、药理学、 神经化学和分子技术。 拟议实验的结果将为神经适应性变化提供重要见解 过度饮酒负有责任。