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: 10231974
• 负责人: Sheena Potretzke
• 金额: $ 4.6万
• 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 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10231974
• 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; 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; 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

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.

尽管酒精使用障碍（AUD）的流行和破坏性影响，只有 存在三种FDA批准的药物疗法，并且甚至更少的药物疗法被证明是有效的。因此，发展 需要新的药物治疗。在设计这种疗法中至关重要的是 酒精相关行为与社会环境的相互作用，表明需要将 酒精消费研究的社会范式。我们的实验室利用独特的Herdsman笼系统， 允许在真正的社会环境中对消费和行为进行精确的、个性化的测量。 催产素（oxt），一种在各种社会行为中起关键作用的激素，作为一种有前途的 AUD的药物治疗及其在介导药物使用相关过程中的作用，以及 因为它的社会影响，这可能有助于支持禁欲。Oxt已被证明是有效的减少 啮齿动物的酒精消耗和人类的酒精渴望。我们的实验室最近证明了 重复oxt治疗对减少草原田鼠（Microtus ochrogaster）酒精消耗量的影响- 一种社会性一夫一妻制的啮齿动物物种，通过共同的遗传转化证明了对人类的有效性。 规范社会行为的机制。鉴于oxt的药理学潜力， 描述oxt减少酒精的能力的行为和分子机制 消费我们的目标是使用我们的Herdsman系统来描述oxt效应的行为机制， 检查oxt对酒精消耗的影响是直接的还是通过增加社交互动来介导的。 我们还试图首次在草原田鼠中证明， 晚期糖基化终末产物（Advanced Glycation End Products，OXT）在脑中的作用及OXT跨血脑屏障（Blood Brain Barrier，BBB）的转运 通过使用选择性拮抗剂来促进。最后，我们的目标是确定通过哪种受体oxt是 使用CRISPR/Cas9产生的选择性Oxtr敲除（KO）草原田鼠发挥其作用。我们的目标是 在整个调查过程中检查可能的性别差异。这些实验将阐明oxt在 调解与药物使用和社会行为相关的奖励过程，特别是在 酒精，并有助于澄清oxt是否是一个有前途的目标，为AUD的药物治疗。