Behavioral and molecular characterization of oxytocin's effect on alcohol consumption

催产素对饮酒影响的行为和分子特征

• 批准号: 10380613
• 负责人: Sheena Potretzke
• 金额: $ 2.38万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2022-06-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10380613
• 关键词: Abstinence; Accounting; Acute; Address; Affect; Affinity; Alcohol consumption; Alcohols; Animals; Anxiety; Attention; Behavior; Behavioral; Behavioral Mechanisms; Binding; Birth; Blood - brain barrier anatomy; Brain; Brain region; CRISPR/Cas technology; California; Cells; Clinical; Complex; Consumption; Development; Disulfiram; Drug Design; Drug usage; FDA approved; Fluorescence; Fright; Health; Health Sciences; Hormones; Human; Hypothalamic structure; Immunohistochemistry; Implant; Individual; Institutes; Intake; Investigation; Knock-out; Laboratories; Lactation; Lead; Learning; Liquid substance; Literature; Measurement; Mediating; Mediator of activation protein; Memory; Microtus; Molecular; Mus; Naltrexone; Neurosciences; Oregon; Oxytocin; Oxytocin Receptor; Pair Bond; Patients; Pattern; Peripheral; Persons; Pharmaceutical Preparations; Pharmacotherapy; Placebos; Polymerase Chain Reaction; Prevalence; Primates; Process; Reporting; Research; Research Personnel; Reverse Transcription; Rewards; Rodent; Rodent Model; Role; San Francisco; Sex Differences; Social Behavior; Social Environment; Social Interaction; Social support; Spectrometry; Substance Use Disorder; Surveys; System; Testing; Time; Tissues; Translating; Treatment Efficacy; Treatment outcome; Universities; V1a vasopressin receptor; acamprosate; aged; alcohol abuse therapy; alcohol and other drug; alcohol behavior; alcohol craving; alcohol use disorder; antagonist; design; effective therapy; efficacious treatment; experimental study; knockout animal; novel; prairie vole; preclinical study; preference; radio frequency; receptor; receptor for advanced glycation endproducts; sex; social; social influence

PROJECT SUMMARY: Despite the prevalence and devastating impact of alcohol use disorder (AUD), only three FDA approved pharmacotherapies exist and even fewer have proved efficacious. Thus, development of new pharmacotherapies is necessary. Of crucial importance in designing such therapies are the complex interactions of alcohol-related behaviors with the social environment, demonstrating the need for incorporating social paradigms in alcohol consumption studies. Our laboratory utilizes the unique Herdsman cage system to allow for precise, individualized measurements of both consumption and behavior in a truly social setting. Oxytocin (oxt), a hormone with crucial roles in a variety of social behaviors has drawn attention as a promising pharmacotherapy for AUD with its implicated role in mediating the processes associated with drug use, as well as its social effects, which may serve to bolster abstinence. Oxt has been shown to be effective in decreasing alcohol consumption in rodents and alcohol craving in humans. Our laboratory recently demonstrated robust effects of repeated oxt treatment in decreasing alcohol consumption in the prairie vole (Microtus ochrogaster) - a socially monogamous rodent species with demonstrated translational validity to humans through common mechanisms regulating social behaviors. Given the pharmacotherapeutic potential of oxt, it is essential to characterize the behavioral and molecular mechanisms of oxt's demonstrated ability to decrease alcohol consumption. We aim to characterize the behavioral mechanisms of oxt's effect using our Herdsman system to examine whether oxt's effects on alcohol consumption are direct or mediated by increased social interaction. We also seek to demonstrate, for the first time in prairie voles, expression patterns of the receptor for advanced glycation end products (RAGE) in the brain and transport of oxt across the blood brain barrier (BBB) facilitated by RAGE using a selective antagonist. Finally, we aim to identify through which receptor oxt is exerting its effect using selective Oxtr knock out (KO) prairie voles generated using CRISPR/Cas9. We aim to examine possible sex differences throughout our investigation. These experiments will explicate oxt's role in mediating the reward processes associated with drug use and social behavior, particularly within the context of alcohol, and serve to clarify whether oxt is a promising target for pharmacotherapy for AUD.

项目摘要：尽管酒精使用障碍（AUD）产生了流行和破坏性的影响，但 存在三个FDA批准的药物治疗，甚至更少被证明是有效的。因此，发展 需要新的药物治疗。在设计这种疗法方面至关重要的是复杂的 与酒精相关的行为与社会环境的相互作用，表明需要合并 饮酒研究中的社会范例。我们的实验室利用独特的牧民笼子系统 在真正的社会环境中，允许对消费和行为进行精确的个性化测量。 催产素（OXT），一种在各种社会行为中具有关键作用的激素已引起人们的注意 AUD的药物疗法在介导与药物使用相关的过程中的作用 作为它的社会影响，可能会增强禁欲。已经证明oxt有效减少 啮齿动物和人类饮酒的饮酒。我们的实验室最近证明了强大的 反复的OXT治疗对降低草原Vole（Microtus ochrogaster）饮酒的影响 - 一种社会一夫一妻制的啮齿动物物种，通过共同证明了对人类的转化有效性 调节社会行为的机制。鉴于OXT的药物治疗潜力，必须 表征OXT的行为和分子机制，表现出降低酒精的能力 消耗。我们旨在使用我们的牧民制度来表征OXT效应的行为机制 检查OXT对饮酒的影响是直接或通过增加社交互动而导致的。 我们还试图在草原田鼠中首次证明受体的表达模式 大脑中的高级糖基化终产物（愤怒）和oxt跨血脑屏障（BBB）的运输 使用选择性拮抗剂来促进愤怒。最后，我们旨在确定哪个受体OXT是 使用CRISPR/CAS9产生的选择性Oxtr敲除（KO）草原田鼠发挥作用。我们的目标 在整个调查中检查可能的性别差异。这些实验将阐明OXT在 调解与吸毒和社会行为相关的奖励过程，尤其是在 酒精，并阐明OXT是否是AUD药物治疗的有希望的靶标。