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

项目总结 美国的全国阿片类药物危机继续发展。阿片类药物的有效治疗方法寥寥无几 使用障碍(OUD)的存在，需要新的药物来治疗OUD。对OUD的治疗是 因同时饮酒而变得更复杂。众所周知，长期使用阿片类药物和饮酒分别会扰乱多巴胺。 伏隔核中的谷氨酸稳态；这是一个调节成瘾性寻求的大脑区域 毒品。在考虑阿片酒精多物质使用的治疗时，有能力对其采取行动的治疗者 这些共同的机制，通过伏隔核多巴胺和谷氨酸的恢复，可能是 有利的。催产素有效减少临床前模型中酒精和阿片类药物的摄入和复发 仅使用一种药物(单次使用)，已知对多巴胺和谷氨酸起作用 系统。临床试验表明，鼻内催产素治疗酒精使用障碍(AUD)有效。基座 根据临床和临床前证据，我们认为催产素可能是一种可行的治疗方法。 阿片-酒精复合物质的使用。这项提案中概述的实验将研究催产素 阿片-酒精多物质使用的治疗潜力。根据我们之前的发现，酒精会改变 对羟考酮的需求和2)催产素在单一实体模型中减少了对羟考酮的需求。 我们将测试催产素对仅服用羟考酮的男性和女性羟考酮需求的剂量依赖性影响 羟考酮+酒精多物质大鼠，采用我们建立的羟考酮+酒精多物质使用模型。 根据我们以前的工作，催产素增加了伏隔核多巴胺和谷氨酸的外流。 可卡因诱导的大鼠伏隔核，我们将观察催产素的作用 羟考酮和羟考酮+酒精对大鼠多巴胺和谷氨酸外排的影响。这个 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 单一物质使用和羟考酮+酒精多物质使用，阐明了这些潜在的性别差异 并阐明伏隔核多巴胺和谷氨酸外流在催产素作用中的作用。

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.