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

前额纹状体垂体腺苷酸环化酶激活多肽在过量和强迫性乙醇饮酒中的作用

• 批准号: 10261394
• 负责人: Margaret Minnig
• 金额: $ 5.1万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-11 至 2024-08-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10261394
• 关键词: Adult; Affect; Alcohol consumption; Alcohol dependence; Alcohols; Animals; Behavior; Brain; Calcium; Cells; Chemosensitization; Chronic; Communication; Corpus striatum structure; Data; Disease; Female; Future; Glutamates; Goals; Heavy Drinking; Human; Hyperactivity; Image; Infusion procedures; Investigation; Laboratories; Lead; Lifestyle-related condition; Link; Mediating; Mental disorders; Messenger RNA; Microscope; Modeling; Mus; N-Methyl-D-Aspartate Receptors; Neurons; Neuropeptides; Nucleus Accumbens; Pathway interactions; Pharmacology; Photons; Population; Quinine; Rattus; Regulation; Reporting; Rodent; Role; Self Administration; Sex Differences; Site; Sucrose; System; Techniques; Testing; addiction; adverse outcome; alcohol abuse therapy; alcohol availability; alcohol exposure; alcohol research; alcohol use disorder; design; designer receptors exclusively activated by designer drugs; drinking; drinking behavior; drug action; drug of abuse; glutamatergic signaling; in vivo; insight; interest; male; miniaturize; mouse model; neural circuit; neuroadaptation; neurobiological mechanism; new therapeutic target; novel; pituitary adenylate cyclase activating polypeptide; receptor; receptor function; reinforcer; transmission process

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.

抽象的 在美国，大约有12人滥用或依赖酒精。饮酒障碍（AUD） 由持续过多的酒精摄入量定义，即使面对不良的饮酒 结果。严重酒精摄入量的神经生物学机制以及强迫性 喝酒，不完全理解。前额叶投影的谷氨酸能信号增加 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皮层（PRL）到伏隔核（NACC）的这些投影神经元 在新型神经肽，垂体腺苷酸环化酶激活肽（PACAP）及其受体的背景下 PAC1R。啮齿动物和人类的报告已开始将PACAP/PAC1R系统与毒品的作用联系起来 滥用以及谷氨酸能信号的增强。我们的初步数据将该系统定位为PRL NACC投影神经元，并建议PACAP/PAC1R系统参与过度饮用 行为。该领域中存在一个主要差距，以理解PACAP在AUD相关行为中的作用。所以， 我的长期目标是了解该系统和其他神经肽系统与饮酒过多的关系如何 酒精依赖和与听众相关的行为。该提议的总体假设是 PRLPACAP对NACC神经元的多动症增加了NACC内的谷氨酸能信号传导，并导致 尽管后果负面影响，但过度饮酒过多。该假设将通过数组进行检验 尖端技术，包括化学发生刺激和抑制作用，位点特异性药理学 1），以及在自由表现的动物中进行钙成像（AIM 2）。该提案的结果将大大增加 酒精研究领域以及我们对过度和强迫性饮酒的理解。