Adolescent Oxycodone Exposure on Oxycodone Reinforcement and Reward Neurocircuitry in Adulthood

摘要： 青春期是滥用药物长期影响最脆弱的阶段之一，据估计 在过去的一年里，340万青少年滥用处方阿片类药物，其中3.5%的人在 青春期早、中期(12~17岁)，7.1%处于青春期后期至初露期 成人期(18-25岁)(药物滥用和精神卫生服务管理局，2017年)。早些时候 青少年开始处方阿片类药物更有可能导致随后的处方阿片类药物滥用 成年期比青春期后期开始(McCabe等人，2007年)。因此，有必要更好地理解 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 青春期可能会在成年期形成独特的干预措施。羟考酮是最多的 青少年中普遍滥用的处方阿片类药物。然而，在知识方面存在着巨大的差距。 青春期接触羟考酮对奖赏相关的长期神经生物学影响 成年后的行为。临床前动物模型的使用可以帮助理解青少年的影响 羟考酮对成人中脑边缘奖赏通路的影响。这一小额赠款项目的主要目标(R03) 是获得概念证据数据，以表明青少年接触羟考酮会导致持续增加 在成年期增强性能/释放多巴胺。因此，总体目标是确定 青春期早期和晚期羟考酮暴露对大鼠药物强化和多巴胺释放的影响 成年期的伏隔核并评估早期和晚期是否有不同的影响 青春期暴露。由于青春期早期和晚期的药物暴露会对 荷尔蒙变化引起的奖赏回路的神经生物学(Spears，2000；2015)，我们将利用两个时间点 青春期暴露的风险。这项提案将利用最先进的程序来阐明青春期 暴露改变了羟考酮在中脑边缘多巴胺系统中的强化特性。这是一个高度的 一个重大项目，将提供有关青少年接触羟考酮将如何长期持续的首个数据 成年后对VTA奖赏特性的影响。一旦我们在这个模型中建立了这种现象，数据 将被用来进一步理解奖赏回路和分子机制的持续变化 未来的R01应用。

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.