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 阿片类药物危机在美国继续发展。阿片类药物的有效治疗方法 存在使用障碍（OUD），并且需要新的药物来治疗OUD。OUD的治疗方法是 因为同时使用酒精而变得复杂长期使用阿片类药物和酒精，分别被认为会破坏多巴胺 和谷氨酸体内平衡;一个大脑区域，介导成瘾的寻求 毒品在考虑治疗阿片-酒精多物质使用时， 这些共同的机制，通过恢复脑桥核多巴胺和谷氨酸，可能是 优势的催产素在临床前模型中有效地减少酒精和阿片类药物的摄入和复发 仅使用一种药物（单物质使用），已知作用于多巴胺和谷氨酸 系统.临床试验显示鼻内催产素作为酒精使用障碍（AUD）的治疗的功效。基于 根据临床和临床前的证据，我们认为催产素可能是治疗 使用阿片-酒精多种物质。本提案中概述的实验将研究催产素的 阿片-酒精多物质使用的治疗潜力。根据我们之前的发现，1）酒精会改变 2）催产素在单物质模型中减少了对羟考酮的需求， 我们将测试催产素对仅使用羟考酮的男性和女性的羟考酮需求的剂量依赖性作用 和羟考酮+酒精多药组大鼠。 基于我们先前的工作，催产素增加了多巴胺和谷氨酸的流出， 可卡因经验的大鼠脑桥核，在这里，我们将研究催产素的影响 给药对羟考酮和羟考酮+酒精经历的大鼠中多巴胺和谷氨酸流出的影响。的 拟议的工作将提供有关催产素的治疗潜力，以减少羟考酮的重要数据 单物质使用和羟考酮+酒精多物质使用，阐明了这些潜在的性别差异 的影响，并阐明在催产素的影响，丘脑核多巴胺和谷氨酸外流的作用。