Neurocognitive Impairments Resulting from Adolescent Prescription Opioid Use Disorder: Longitudinal Impact, Neural Mechanisms, and Comorbidities

项目概要/摘要 拟议的K99职业培训计划的目标包括：1）获得以下方面的专业知识和研究经验 物质使用障碍（SUD），成瘾过程和阿片类药物药理学; 2）掌握立体定位术， 腺相关病毒基因传递和体内纤维光度测定; 3）掌握和应用分析， 第三变量效应的分析技巧。拟议的研究提供了一个场所，以实现 这将有助于实现培训计划的目标，并应对处方类阿片流行病中的关键挑战。青春期和 青年期（即，12 - 25岁）是与物质使用相关的关键发育期 启动和脑回路成熟，前者对后者具有关键的潜在影响。然而，迄今为止， 青少年处方阿片类药物使用障碍（APOUD）对神经认知发育的关键作用，以及 相关的神经机制尚未完全阐明。生物性别和合并症的作用（即， HIV-1）将是实验设计的组成部分。我们将因果检验的指导假设，改变 中皮层多巴胺（DA）系统的机制是神经认知的差异进展的基础 实验动物（羟考酮（OXY）依赖性）与对照动物的发育;以及独特的神经机制， APOUD和HIV-1共病时，该假设将通过两个构建块来解决 目标（K99阶段），并在我的独立实验室（R00阶段）正式测试。人类APOUD的关键方面 将使用临床前自愿口服OXY自我给药实验范例进行建模。在特定 目的#1（K99阶段），OXY自我给药对神经认知发育的剂量依赖性（例如， 前注意过程，长期情景记忆，持续注意力）将使用纵向 实验设计在特定目标#2（K99期）中，中皮层DA系统中的多巴胺能改变 在高阶认知过程评估期间，将确定OXY自我给药后 使用新的G蛋白偶联受体为基础的生物传感器和在体内纤维光度法。具体目标#3（R00 阶段）提供了一个因果测试的神经机制的神经认知障碍造成的 APOUD和/或共病HIV-1;我的独立实验室的基本目标。具体来说，中观- 将使用由设计药物专门激活的设计受体来刺激设计DA系统， 高阶认知过程的评估（例如，持续关注）。培训（K99阶段）将继续- 在南卡罗来纳州，一个杰出的环境，在国际导师的监护下， 包括R.M.博士在内的知名导师团队。酒（导师），E.M.博士。Unterwald（共同导师）和A.J.博士 费尔柴尔德（共同导师）。此外，专业发展咨询委员会，包括备受推崇的 来自多个机构的教师（博士S。让我来T.D.医生Langford和S.适合），是不可或缺的职业生涯 培训计划。成功完成拟议的培训、职业发展活动和研究， 为候选人向独立科学家的过渡奠定了坚实的基础。

PROJECT SUMMARY/ABSTRACT The goals of the proposed K99 career training plan include: 1) gaining expertise and research experience in substance use disorders (SUD), addictive processes, and opioid pharmacology; 2) mastering stereotaxic sur- geries, adeno-associated virus gene delivery, and in vivo fiber photometry; and 3) mastering and applying ana- lytical skills for the evaluation of third variable effects. The proposed research affords a venue to achieve the goals of the training plan and address key challenges in the prescription opioid epidemic. Adolescence and young adulthood (i.e., 12-25 years of age) are critical developmental periods associated with substance use initiation and brain circuit maturation, with the former having key potential impacts on the latter. To date, however, the critical role of adolescent prescription opioid use disorder (APOUD) on neurocognitive development, and associated neural mechanisms, has yet to be fully elucidated. The role of biological sex and comorbidities (i.e., HIV-1) will be integral to the experimental design. We will causally test the guiding hypothesis that alterations in the mesocortical dopamine (DA) system mechanistically underlie the differential progression of neurocognitive development in experimental (oxycodone (OXY) dependent) vs. control animals; and that unique neural mech- anisms will be engaged by comorbid APOUD and HIV-1. The hypothesis will be addressed via two building block aims (K99 phase) and formally tested in my independent laboratory (R00 phase). Key aspects of human APOUD will be modeled using a preclinical voluntary oral OXY self-administration experimental paradigm. In Specific Aim #1 (K99 phase), the dose-dependency of OXY self-administration for neurocognitive development (e.g., preattentive processes, long-term episodic memory, sustained attention) will be established using a longitudinal experimental design. In Specific Aim #2 (K99 phase), dopaminergic alterations in the mesocortical DA system following OXY self-administration during assessments of higher-order cognitive processes will be determined using novel G protein-coupled receptor based biosensors and in vivo fiber photometry. Specific Aim #3 (R00 phase) affords a causal test of the neural mechanism underlying neurocognitive impairments resulting from APOUD and/or comorbid HIV-1; the fundamental goal of my independent laboratory. Specifically, the mesocor- tical DA system will be stimulated using designer receptors exclusively activated by designer drugs during assessments of higher-order cognitive processes (e.g., sustained attention). Training (K99 phase) will be con- ducted at the University of South Carolina, an outstanding environment, under the tutelage of an internationally recognized mentoring team, including Dr. R.M. Booze (mentor), Dr. E.M. Unterwald (co-mentor) and Dr. A.J. Fairchild (co-mentor). Additionally, a Professional Development Advisory Committee, including highly-regarded faculty from multiple institutions (Dr. S. Letendre, Dr. T.D. Langford, and Dr. S. Fitting), is integral to the career training plan. Successful completion of the proposed training, career development activities, and research will provide a strong foundation for the candidate’s transition to an independent scientist.