Adolescent Oxycodone Exposure on Oxycodone Reinforcement and Reward Neurocircuitry in Adulthood

青少年羟考酮暴露对成年期羟考酮强化和奖励神经回路的影响

• 批准号: 10285458
• 负责人: Sheketha Renay Hauser
• 金额: $ 7.93万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10285458
• 关键词: 17 year old; Acute; Adolescence; Adolescent; Adult; Affect; Age; Animal Model; Applications Grants; Behavior; Corpus striatum structure; Data; Development; Dopamine; Drug Addiction; Drug Exposure; Elderly; Exposure to; Future; Gender; Goals; Grant; Hormonal Change; Intervention; Intravenous; Knowledge; Long-Term Effects; Measures; Molecular; Neurobiology; Nucleus Accumbens; Oral; Oxycodone; Pathway interactions; Pharmaceutical Preparations; Preventive; Procedures; Property; Psychological reinforcement; Rewards; Self Administration; Testing; Time; United States Substance Abuse and Mental Health Services Administration; data modeling; drug of abuse; drug reinforcement; emerging adulthood; mesolimbic system; neural circuit; neuroadaptation; opioid use disorder; pre-clinical; prescription opioid; prescription opioid misuse; response; reward circuitry

ABSTRACT: Adolescence is one of the most vulnerable stages for the long-term effects of drugs of abuse and an estimated 3.4 million from adolescence have misused prescription opioids in the past year, with 3.5% of them being in early/mid stage of adolescents (12 -17 years old) and 7.1% of them being in the late adolescence to emerging adulthood stage (ages 18-25) (Substance Abuse and Mental Health Services Administration, 2017). Early adolescent initiation of prescriptions opioids is more likely to result in subsequent prescription opioid misuse in adulthood than late adolescent initiation (McCabe et al., 2007). Therefore, there is a need to better understand the long-term neurobiological consequences that misuse of prescription opioids in early/mid and late adolescence may have in adulthood in order to develop unique interventions. Oxycodone is one of the most commonly misused prescription opioids among adolescents. However, there is a substantial gap in knowledge about the long-term neurobiological consequences of adolescence exposure to oxycodone on reward-related behaviors in adulthood. The use of pre-clinical animal models can help to understand the effects of adolescent exposure to oxycodone on adult mesolimbic reward pathway. The major goal of this small grant project (R03) is to obtain proof of concept data to show that adolescent oxycodone exposure leads to a persistent increase in reinforcing properties/dopamine release in adulthood. Therefore, the overall objectives are to determine the effects of early and late adolescence exposure to oxycodone on drug reinforcement and dopamine release in nucleus accumbens in adulthood and assess if there are differential effects between early and late adolescence exposure. Since the early and late adolescence drug exposure will have differential effects on the neurobiology of reward circuits due to hormonal changes (Spears, 2000; 2015), we will utilize two time-points of adolescence exposure. This proposal will utilize state-of-the-art procedures to elucidate how adolescence exposure alters reinforcing properties of oxycodone within the mesolimbic dopamine system. This is a highly significant project that will provide first data on how adolescent exposure to oxycodone will have long-lasting effects on VTA rewarding properties in adulthood. Once we establish this phenomenon in this model, the data will be used to further understand the persistent changes in reward circuitry and molecular mechanisms in future R01 application.

摘要： 青少年是最容易受到滥用药物长期影响的阶段之一， 3.4在过去的一年里，有100万青少年滥用处方阿片类药物，其中3.5%在 青少年（12 - 17岁）的早期/中期和7.1%的人处于青春期后期至出现 成年阶段（18-25岁）（药物滥用和精神卫生服务管理局，2017年）。早期 青少年开始处方阿片类药物更可能导致随后的处方阿片类药物滥用， 成年期比青少年后期开始（McCabe等人，2007年）。因此，有必要更好地了解 早期/中期和晚期滥用处方阿片类药物的长期神经生物学后果 青少年在成年期可能会采取的措施，以便制定独特的干预措施。羟考酮是目前 青少年中经常滥用处方阿片类药物。然而，在知识方面存在着巨大的差距， 青少年暴露于羟考酮对奖励相关的长期神经生物学后果 成年后的行为。使用临床前动物模型可以帮助了解青少年的影响， 暴露于羟考酮对成年中脑边缘奖赏通路的影响。本小额赠款项目的主要目标（R 03） 是获得概念验证数据，以表明青少年羟考酮暴露导致持续增加 在成年期加强多巴胺的释放。因此，总体目标是确定 青少年早期和晚期暴露于羟考酮对药物强化和多巴胺释放的影响 在成年期的脑桥核，并评估是否有早期和晚期之间的差异效应 青春期暴露。由于青春期早期和晚期的药物暴露将有不同的影响， 由于荷尔蒙变化（Spears，2000; 2015），我们将利用两个时间点 青春期暴露。这项提案将利用最先进的程序来阐明青春期是如何 暴露改变了羟考酮在中脑边缘多巴胺系统内的强化性质。这是一个高度 重要的项目，将提供关于青少年接触羟考酮将如何产生长期影响的第一批数据。 对成年后VTA奖励特性的影响。一旦我们在这个模型中建立了这种现象， 将被用于进一步了解奖励电路和分子机制的持续变化， 未来的R 01应用。