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

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/10599270
• 关键词: Address; Adolescence; Adolescent; Adolescent and Young Adult; Adult; Advisory Committees; Age Years; Agonist; Biosensor; Brain; Cells; Chronic; Clinical; Communicable Diseases; Control Animal; Dependence; Dependovirus; Development; Developmental Process; Dopamine; Dose; Environment; Episodic memory; Evaluation; Experimental Designs; Exposure to; Faculty; Female; Fiber; Foundations; Functional disorder; G-Protein-Coupled Receptors; Gene Delivery; Goals; HIV; HIV-1; Hour; Human; Infection; Institution; Intake; International; Laboratories; Mentors; Modeling; Muscarinics; National Institute of Drug Abuse; Neurocognitive; Neurocognitive Deficit; Operative Surgical Procedures; Opioid; Oral; Overdose; Oxycodone; Pharmacology; Phase; Photometry; Prefrontal Cortex; Process; Public Health; Rattus; Research; Role; Saline; Scientist; Self Administration; South Carolina; Strategic Planning; Substance Use Disorder; Synapses; System; Testing; Training; United States Substance Abuse and Mental Health Services Administration; Universities; Ventral Tegmental Area; Viral Proteins; Water; biological sex; biological systems; career; career development; cognitive process; comorbidity; critical developmental period; designer receptors exclusively activated by designer drugs; dopamine system; experience; experimental study; exposure route; high risk population; in vivo; male; neuromechanism; new therapeutic target; novel; opioid abuse; opioid epidemic; opioid use disorder; postnatal; pre-clinical; prescription opioid; skills; substance use; sustained attention; therapeutic target; young adult

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 基因、腺相关病毒基因传递和体内光纤光度测定； 3）掌握并应用分析 用于评估第三变量效应的分解技能。拟议的研究提供了实现这一目标的场所 培训计划的目标并解决处方阿片类药物流行的主要挑战。青春期和 成年早期（即 12-25 岁）是与物质使用相关的关键发育时期 启动和大脑回路成熟，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。我们将因果检验指导假设，即改变 中皮质多巴胺（DA）系统中的神经认知差异发展机制是 实验动物（羟考酮 (OXY) 依赖性）与对照动物的发育情况；以及那种独特的神经机制 共病 APOUD 和 HIV-1 会参与各种动物行为。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进行正式测试（R00阶段）。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。具体来说 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 实验设计。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 使用基于新型 G 蛋白偶联受体的生物传感器和体内光纤光度测定。具体目标 #3 (R00 阶段）提供了对神经认知损伤背后的神经机制的因果测试 APOUD 和/或合并 HIV-1；我的独立实验室的根本目标。具体来说，介观 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。 高阶认知过程的评估（例如持续注意力）。培训（K99阶段）将持续进行 南卡罗来纳大学环境优越，师从国际知名学者 公认的指导团队，包括 Dr. R.M. Booze（导师）、E.M. Unterwald 博士（共同导师）和 A.J. 费尔柴尔德（联合导师）。此外，还设有专业发展咨询委员会，其中包括备受推崇的 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将 为候选人过渡为独立科学家提供坚实的基础。