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.
