The role of prefrontostriatal Pituitary Adenylate Cyclase Activating Polypeptide in excessive and compulsive ethanol drinking

摘要 在美国，每12个人中就有1人滥用或依赖酒精。酒精使用障碍（AUD） 是指持续过量的酒精摄入，强迫性饮酒，即使面对不利的 后果严重酒精摄入以及强迫性行为的神经生物学机制 喝酒，并不完全了解。来自额前-纹状体投射的突触能信号增加 神经元与饮酒和强迫性饮酒行为的升级有关。这个项目 将研究这些投射神经元从前边缘皮层（PrL）到核丘脑核心（NAcc） 在一种新的神经肽--腺苷酸环化酶激活肽（PACAP）及其受体的背景下， PAC 1 R。啮齿动物和人类的研究报告已经开始将PACAP/PAC 1 R系统与药物的作用联系起来 滥用的影响，以及增强神经递质信号的作用。我们的初步数据将该系统定位于PrL NAcc投射神经元，并建议参与PACAP/PAC 1 R系统过量饮酒 行为在理解PACAP在审计相关行为中的作用方面，该领域存在一个主要的差距。因此，我们认为， 我的长期目标是了解这个和其他神经肽能系统与过量饮酒的关系， 酒精依赖和AUD相关行为。这一提议的首要假设是， PrLPACAP对NAcc神经元的过度活性增加了NAcc内的多巴胺能信号传导，并导致 过度和强迫性饮酒，尽管有负面影响。这个假设将用一个数组来检验 包括化学发生刺激和抑制、位点特异性药理学（Aim 1），钙成像在自由行为的动物（目的2）。这项建议的结果将大大增加 酒精研究领域和我们对过度和强迫性饮酒的理解。

ABSTRACT Approximately 1 in 12 people in the USA abuse or are dependent on alcohol. Alcohol use disorder (AUD) is defined by persistent excessive alcohol intake, and compulsive drinking even in the face of adverse consequences. The neurobiological mechanisms underlying severe alcohol intake, as well as compulsive drinking, are not entirely understood. Increased glutamatergic signaling from prefrontal-striatal projection neurons has been implicated in the escalation of alcohol drinking and compulsive drinking behavior. This project will investigate these projection neurons from the prelimbic cortex (PrL) to the nucleus accumbens core (NAcc) in the context of a novel neuropeptide, Pituitary Adenylate Cyclase Activating Peptide (PACAP), and its receptor PAC1R. Reports in rodents and humans have begun to link the PACAP/PAC1R system to the actions of drugs of abuse, as well as the potentiation of glutamatergic signaling. Our preliminary data localizes this system to PrL to NAcc projection neurons, and suggests the involvement of the PACAP/PAC1R system in excessive drinking behavior. A major gap exists in the field in understanding the role of PACAP in AUD-related behaviors. Therefore, my long-term goal is to understand how this and other neuropeptidergic systems relate to excessive drinking, alcohol dependence, and AUD-related behaviors. The overarching hypothesis of this proposal is that hyperactivity of the PrLPACAP to NAcc neurons increases glutamatergic signaling within the NAcc and leads to excessive and compulsive drinking despite negative consequences. This hypothesis will be tested with an array of cutting-edge techniques including chemogenetic stimulation and inhibition, site-specific pharmacology (Aim 1), and calcium imaging in freely behaving animals (Aim 2). The results of this proposal will greatly add to the field of alcohol research and our understanding of excessive and compulsive drinking.