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: 10481236
• 负责人: Kristen Addie McLaurin
• 金额: $ 13.3万
• 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/10481236
• 关键词: Address; Adolescence; Adolescent; Adolescent and Young Adult; Adult; Advisory Committees; Age-Years; Agonist; Attention; Biosensor; Brain; Cells; Chronic; Clinical; Communicable Diseases; Control Animal; Dependence; Dependovirus; Development; Developmental Process; Dopamine; Dose; Duct (organ) structure; 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; The Sun; Training; United States Substance Abuse and Mental Health Services Administration; Universities; Ventral Tegmental Area; Viral Proteins; Water; base; 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.

项目摘要/摘要 拟议的K99职业培训计划的目标包括：1）获得专业知识和研究经验 药物使用障碍（SUD），添加剂过程和阿片类药理学； 2）掌握立体定位 Geries，腺相关的病毒基因递送和体内纤维光度法； 3）掌握和应用ana- 评估第三个变量效应的抒情技能。拟议的研究为实现 培训计划的目标并应对处方oid流行的主要挑战。青少年和 年轻成年（即12-25岁）是与药物使用相关的关键发育期 启动和脑电路成熟，前者对后者具有关键的潜在影响。但是，迄今为止 青少年处方阿片类药物使用障碍（APOUD）在神经认知发展中的关键作用， 相关的神经机制尚未完全阐明。生物学和合并症的作用（即 HIV-1）将是实验设计不可或缺的。我们将在发生变化的指导假设中检验 在中皮层（DA）系统中，机械基础是神经认知的差异发展 实验性（羟考酮（氧）依赖性）与对照动物的发展；那独特的神经机甲 - Anism将由合并的Apoud和HIV-1参与。该假设将通过两个构建基础解决 AIMS（K99阶段），并在我的独立实验室（R00阶段）中进行了正式测试。人类apoud的关键方面 将使用临床前自愿口服氧自我给药实验范式进行建模。具体 AIM＃1（K99阶段），氧气自我管理的剂量依赖性神经认知发展（例如， 将使用纵向建立术语的过程，长期情节记忆，持续关注） 实验设计。在特定的目标＃2（K99阶段）中，中皮层DA系统中的多巴胺能改变 在评估高阶认知过程期间的氧气自我管理后，将确定 使用新型G蛋白偶联受体的生物传感器和体内纤维光度法。特定目标＃3（R00 阶段）提供了对由神经机制的因果检验 Apoud和/或合并症HIV-1；我独立实验室的基本目标。具体而言，中焦 - 使用设计器的接收器专门激活设计师药物在 评估高阶认知过程（例如，持续关注）。培训（K99阶段）将是 在国际上的指导下，在南卡罗来纳大学是一个杰出的环境 公认的心理团队，包括R.M.博士Booze（Mentor），E.M。Unterwald博士（Co-Contor）和A.J.博士 Fairchild（Co-Insor）。此外，专业发展咨询委员会，包括高度尊敬的 来自多个机构的教师（S. Letendre博士，T.D。Langford博士和S. Fitting博士）是职业不可或缺的 培训计划。成功完成拟议的培训，职业发展活动和研究将 为候选人向独立科学家的过渡提供了坚实的基础。