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

青少年处方阿片类药物使用障碍导致的神经认知障碍：纵向影响、神经机制和合并症

基本信息

批准号：
10599270
负责人：
Kristen Addie McLaurin
金额：
$ 12.93万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2024-03-31
项目状态：
已结题

项目摘要

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.

项目概要/摘要拟议的 K99 职业培训计划的目标包括：1）获得以下领域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）掌握立体定向治疗；基因、腺相关病毒基因传递和体内光纤光度测定；3) 掌握和应用分析所提出的研究为评估第三变量效应提供了一个场所。培训计划的目标并解决青少年和青少年处方阿片类药物流行的主要挑战。成年早期（即 12-25 岁）是与物质使用相关的关键发育时期然而，迄今为止，前者对后者具有重要的潜在影响。青少年处方阿片类药物使用障碍 (APOUD) 对神经认知发展的关键作用，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）将成为实验设计的一部分，我们将因果性地测试指导假设：改变。中皮质多巴胺（DA）系统是神经认知差异发展的机械基础实验动物（羟考酮 (OXY) 依赖性）与对照动物的发育情况；以及独特的神经机制；共病 APOUD 和 HIV-1 会参与该假设，该假设将通过两个构建模块得到解决。目标（K99 阶段）并在我的独立实验室（R00 阶段）进行了正式测试。将使用临床前自愿口服 OXY 自我给药实验范例进行建模。目标#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）将通过纵向建立在特定目标#2（K99 阶段）中，中皮质 DA 系统中的多巴胺能改变。在高阶认知过程评估期间进行 OXY 自我管理后，将确定使用新型 G 蛋白偶联受体生物传感器和体内光纤光度测定法 (R00)。阶段）提供了对神经认知障碍引起的神经机制的因果测试 APOUD 和/或合并症 HIV-1；我的独立实验室的基本目标是中性病。在治疗过程中，将使用专门由设计药物激活的设计受体来刺激 tical DA 系统。将进行高阶认知过程（例如持续注意力）的评估（K99 阶段）。南卡罗来纳大学环境优越，师从国际知名学者公认的导师团队，包括 R.M. Booze 博士（导师）、E.M. Unterwald 博士（共同导师）和 A.J. 费尔柴尔德（联合导师）。来自多个机构的教师（S. Letendre 博士、T.D. Langford 博士和 S. Fitting 博士）是职业生涯不可或缺的一部分培训计划。成功完成拟议的培训、职业发展活动和研究。为候选人过渡为独立科学家提供坚实的基础。