Oxytocin regulation of intravenous oxycodone demand: a role for nucleus accumbens

催产素对静脉注射羟考酮需求的调节：伏隔核的作用

• 批准号: 10605449
• 负责人: Courtney Wilkinson
• 金额: $ 4.77万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-16 至 2026-05-15
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605449
• 关键词: Alcohol consumption; Alcohols; Americas; Attenuated; Behavioral; Blood alcohol level measurement; Brain region; Chronic; Clinical; Clinical Trials; Cocaine; Data; Dopamine; Dose; Drug Use Disorder; Drug abuse; Economics; Female; Glutamates; Goals; High Pressure Liquid Chromatography; Homeostasis; Hour; Human; Infusion procedures; Intake; Intravenous; Investigation; Mediating; Microdialysis; Modeling; Neurobiology; Neuropeptides; Nucleus Accumbens; Opioid; Oral; Outcome; Oxycodone; Oxytocin; Pharmaceutical Preparations; Population; Positioning Attribute; Pre-Clinical Model; Publishing; Rattus; Regulation; Relapse; Rewards; Rodent; Role; Self Administration; Sex Differences; System; Techniques; Testing; Therapeutic; Time; Training; Treatment outcome; United States; Water; Work; alcohol abuse therapy; alcohol availability; alcohol use disorder; allostasis; effective therapy; efficacy evaluation; experience; experimental study; illicit drug use; in vivo; insight; intravenous administration; logarithm; male; novel; opioid epidemic; opioid use; opioid use disorder; overdose death; pharmacologic; polysubstance use; pre-clinical; pre-clinical research; preclinical study; prescription opioid; prevent; restoration; sex; theories; therapeutically effective

PROJECT SUMMARY The national opioid crisis continues to progress in the United States. Few effective treatments for opioid use disorder (OUD) exist and there is a need for new medications to treat OUD. Treatment for OUD is complicated by the co-use of alcohol. Chronic opioid and alcohol use, separately, are known to disrupt dopamine and glutamate homeostasis in the nucleus accumbens; a brain region that mediates the seeking of addictive drugs. In considering treatments for opioid-alcohol polysubstance use, a therapeutic with the ability to act upon these common mechanisms, through restoration of nucleus accumbens dopamine and glutamate, may be advantageous. Oxytocin effectively reduces alcohol and opioid intake and relapse in pre-clinical models employing the use of only one drug (monosubstance use) and is known to act on dopamine and glutamate systems. Clinical trials show efficacy for intranasal oxytocin as a treatment for alcohol use disorder (AUD). Based on the clinical and pre-clinical evidence, we posit that oxytocin may be a viable therapeutic in the treatment of opioid-alcohol polysubstance use. The experiments outlined in this proposal will investigate oxytocin’s therapeutic potential in opioid-alcohol polysubstance use. Based on our previous findings that 1) alcohol alters demand for oxycodone and 2) that oxytocin reduces demand for oxycodone in a monosubstance model, here we will test the dose-dependent effects of oxytocin on oxycodone demand in male and female oxycodone-only and oxycodone+alcoholpolysubstance rats using our established oxycodone+alcoholpolysubstance use model. Based on our prior work showing that oxytocin increases nucleus accumbens dopamine and glutamate efflux in the nucleus accumbens of cocaine-experienced rats, here we will investigate the effects of oxytocin administration on dopamine and glutamate efflux in oxycodone and oxycodone+alcohol-experienced rats. The proposed work will provide important data regarding oxytocin’s therapeutic potential to reduce oxycodone monosubstance use and oxycodone+alcohol polysubstance use, illuminate potential sex differences in these effects, and elucidate the role of nucleus accumbens dopamine and glutamate efflux in the effects of oxytocin.

项目摘要 全国阿片类药物危机在美国继续进展。阿片类药物的有效治疗很少 存在使用障碍（OUD），需要新的药物来治疗OUD。 Oud的治疗是 与酒精的共同使用变得复杂。已知慢性阿片类药物和饮酒会破坏多巴胺 伏隔核中的谷氨酸稳态；介导寻求添加剂的大脑区域 毒品。在考虑使用阿片类药物多醇的治疗方法时，具有作用的治疗方法 通过恢复伏隔核多巴胺和谷氨酸核的这些常见机制，可能是 有利。催产素有效地减少了临床前模型中的酒精和阿片类药物摄入和缓解 仅使用一种药物（单固体使用），并且已知可以对多巴胺和谷氨酸作用 系统。临床试验表明，鼻内氧作为对酒精使用障碍的治疗（AUD）的效率。基于 关于临床和临床前证据，我们认为氧气可能是一种可行的治疗方法 Opioid-Alcohol polysubstance使用。该提案中概述的实验将研究氧气细胞素 阿片类酒精多醇的治疗潜力。根据我们以前的发现，1）酒精会改变 对羟考酮的需求和2）催产素减少了单材模型中对羟考酮的需求，此处 我们将测试催产素对雄性和雌性羟考酮的需求的剂量依赖性作用 使用我们已建立的羟考酮+酗酒的使用模型的羟考酮+酒精含量的大鼠。 基于我们先前的工作，表明氧增加了伏隔核的多巴胺和谷氨酸外排 可卡因经验丰富的大鼠的伏隔核，在这里我们将研究催产素的作用 在羟考酮和羟考酮+酒精经验的大鼠中给予多巴胺和谷氨酸外排。这 拟议的工作将提供有关催产素减少羟考酮的治疗潜力的重要数据 单体固定使用和羟考酮+酒精多核固定，阐明了这些潜在的性别差异 影响，并阐明伏隔核多巴胺和谷氨酸外排在催产素的作用中的作用。