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) 普遍存在并具有破坏性影响，但只有 FDA 批准了三种药物疗法，但被证明有效的药物疗法就更少了。因此，发展 新的药物疗法是必要的。设计此类疗法至关重要的是复杂的 酒精相关行为与社会环境的相互作用，表明需要将 酒精消费研究中的社会范式。我们的实验室利用独特的牧人笼系统 允许在真正的社交环境中对消费和行为进行精确、个性化的测量。 催产素 (oxt) 是一种在多种社会行为中发挥关键作用的激素，作为一种有前景的激素而引起人们的关注。 AUD 的药物治疗及其在介导与药物使用相关的过程中的隐含作用，以及 作为其社会影响，这可能有助于加强禁欲。 Oxt 已被证明可以有效减少 啮齿动物的饮酒量和人类的酒精渴望。我们的实验室最近证明了强大的 重复 oxt 治疗对减少草原田鼠 (Microtus ochrogaster) 酒精消耗的影响 - 一种社会上实行一夫一妻制的啮齿类动物，通过共同的行为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，有必要 描述 oxt 降低酒精含量的行为和分子机制 消耗。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 对饮酒的影响是直接的还是通过增加的社交互动来介导的。 我们还试图首次在草原田鼠中证明受体的表达模式 大脑中的晚期糖基化终末产物 (RAGE) 和 oxt 穿过血脑屏障 (BBB) 的运输 RAGE 使用选择性拮抗剂促进。最后，我们的目标是确定 oxt 通过哪个受体 利用 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存在的性别差异。这些实验将阐明 oxt 在 调节与吸毒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 AUD 药物治疗的一个有前景的靶点。