Involvement of neuropeptide systems in excessive alcohol drinking

摘要 在美国，大约有1800万人（每12个成年人中就有1人）滥用或依赖酒精。 酒精使用障碍的病因是复杂的;遗传易感性因素与环境因素相互作用。 是产生和维持疾病状态的因素。因此，当前神经科学研究的一个目标是， 确定神经适应介导的倾向，消费大量的酒精，无论是先天或 环境起源。特别是，前额叶-纹状体投射功能障碍被认为是 在酒精成瘾中的重要作用。 本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PAC 1 R。对苍蝇、啮齿动物和人类的研究已经开始， 揭示了PACAP/PAC 1 R系统在动机行为和药物滥用行为中的关键作用。 缺乏探索其在酒精成瘾中作用的研究构成了该领域发展的障碍。 我们的初步数据强烈地表明，在核的PACAP/PAC 1 R系统的神经适应， NAcc Core（NAcc Core）是一种调节过度饮酒的敏感性的核心。 我们的长期目标是解开遗传饮酒倾向的分子机制 过度和过渡到酒精依赖。这一提议的首要假设是， 内侧前额叶皮层中PACAP/PAC 1系统的过度激活-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可塑性变化。我们将测试我们的 使用多学科方法的假设，包括使用化学遗传学，药理学， 神经化学和分子技术。 实验结果将为神经适应性变化提供关键的见解 负责过度饮酒。

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.