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

摘要 在美国，大约每12人中就有1人酗酒或依赖酒精。酒精使用障碍(AUD) 被定义为持续过量饮酒，即使面对不利的情况也要强制饮酒 后果。严重饮酒以及强迫症背后的神经生物学机制 饮酒，还没有完全被理解。前额叶-纹状体投射增加谷氨酸能信号 神经元与饮酒和强迫性饮酒行为的升级有关。这个项目 将研究这些从初级皮质(PRL)到伏核核心(NAcc)的投射神经元 在一种新的神经肽--垂体腺苷环化酶激活肽(PACAP)及其受体的背景下 PAC1R。在啮齿动物和人类中的报告已经开始将PACAP/PAC1R系统与药物的作用联系起来 滥用，以及谷氨酸能信号的增强。我们的初步数据将这个系统定位到PRL NAcc投射神经元，提示PACAP/PAC1R系统参与过量饮酒 行为。在理解PACAP在AUD相关行为中的作用方面，该领域存在着重大差距。因此， 我的长期目标是了解这个和其他神经肽能系统是如何与过量饮酒有关的， 酒精依赖和AUD相关行为。这项提议的首要假设是 PrLPACAP对NAcc神经元的过度激活增加了NAcc内的谷氨酸能信号，并导致 酗酒和强迫饮酒，尽管有负面后果。这一假设将通过一个数组进行检验 尖端技术，包括化学生成刺激和抑制、特定部位药理学(AIM 1)，以及自由行为动物的钙成像(目标2)。这项提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.