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

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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.