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.

项目概要 美国全国阿片类药物危机继续蔓延。阿片类药物的有效治疗方法很少 使用障碍（OUD）是存在的，并且需要新的药物来治疗 OUD。 OUD 的治疗方法是 酒精的共同使用使情况变得复杂。众所周知，长期使用阿片类药物和饮酒会破坏多巴胺 和伏隔核中的谷氨酸稳态；调节成瘾寻求的大脑区域 药物。在考虑使用阿片类酒精多物质的治疗时，一种能够作用于阿片类物质的治疗剂 这些共同的机制，通过恢复伏隔核多巴胺和谷氨酸，可能是 有利。催产素可有效减少临床前模型中的酒精和阿片类药物摄入量以及复发 仅使用一种药物（单一物质使用），已知作用于多巴胺和谷氨酸 系统。临床试验表明鼻内催产素可有效治疗酒精使用障碍 (AUD)。基于 根据临床和临床前证据，我们认为催产素可能是治疗以下疾病的可行疗法： 阿片类酒精多物质的使用。本提案中概述的实验将研究催产素的作用 阿片类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 对羟考酮的需求，2) 催产素减少了单一物质模型中对羟考酮的需求，此处 我们将测试催产素对男性和女性仅使用羟考酮的羟考酮需求的剂量依赖性影响 以及使用我们建立的羟考酮+醇多物质使用模型的羟考酮+醇多物质大鼠。 根据我们之前的研究表明，催产素会增加伏隔核多巴胺和谷氨酸的流出 经历过可卡因的老鼠的伏核，在这里我们将研究催产素的影响 给予羟考酮和羟考酮+酒精经历过的大鼠的多巴胺和谷氨酸流出。这 拟议的工作将提供有关催产素减少羟考酮治疗潜力的重要数据 单一物质的使用和羟考酮+酒精多物质的使用，阐明了这些物质中潜在的性别差异 作用，并阐明伏隔核多巴胺和谷氨酸流出在催产素作用中的作用。