# Neurobiological mechanisms underlying resiliency and vulnerability to opioid use disorder

> **NIH NIH K99** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2024 · $190,663

## Abstract

PROJECT SUMMARY/ABSTRACT
There has been a significant rise in opioid use disorder (OUD) in the United States over the past decade, making
it imperative to gain a better understanding of the behavioral characteristics underlying OUD vulnerability.
Current rodent models focus on how one or few traits interact in a linear manner to predict substance use disorder
(SUD), however, OUD consists of several symptoms that interact with one another across the addiction process
and can vary between individuals to affect OUD vulnerability or resiliency. I contributed toward a rat model that
captures this behavioral complexity using male and female heterogeneous stock rats in an effort to better model
human OUD. Bayesian stochastic block model (SBM) network-based clustering analysis is used to separate rats
into resilient and vulnerable subpopulations. Using this model, we are able to assess the neurobiological
mechanisms contributing toward OUD vulnerability and resiliency, the latter of which is not well understood.
These opposing phenotypes are likely mediated by different cellular and circuitry adaptations, and will be the
focus of this proposal. The K99 aims assess how functional and morphological neuroplasticity differences in
nucleus accumbens core (NAcc) D1/D2 medium-spiny neuron (MSN) contribute to OUD resiliency and
vulnerability. I will first use whole-cell patch-clamp electrophysiology to characterize changes in AMPA/NMDA
ratios in vulnerable and resilient subpopulations following cued reinstatement (Aim 1). I will then inject an
intracellular label into the recorded cell and examine differences in D1/D2-MSN dendritic spine morphology (Aim
2). This approach will allow for the tracking of NAcc neuroplastic adaptations within the same cell across the two
phenotypes. The R00 portion of the proposal will assess how pathway specific regulation of dorsolateral ventral
pallidum (dlVP) projections contribute to OUD resiliency and vulnerability. Comparable to the NAcc, the dlVP,
the main functional output of the NAcc, shows cell-specific functional regulation of drug seeking and refraining
behavior, making it an ideal structure to evaluate circuit heterogeneity in individual variation in OUD propensity.
Using confocal microscopy and viral tracers, I will assess functional connectivity from the dlVP to the subthalamic
nucleus (STN), a region known to enhance seeking and likely vulnerability, and to the lateral habenula (LHb),
known to mediate aversion and hypothesized to promote resiliency (Aim 3a). I will then employ chemogenetic
technology to selectively isolate and manipulate these pathways in OUD resilient and vulnerable rats. (Aim 3b).
Lastly, using whole-cell patch-clamp electrophysiology, I will evaluate input adaptations in the STN and LHb
following dlVP stimulation within the two phenotypes following cued reinstatement (Aim 4). Experiments in this
proposal employ a novel rat model capturing individual variation in OUD propensity similar to what is o...

## Key facts

- **NIH application ID:** 10874699
- **Project number:** 5K99DA057390-02
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Brittany Nicole Kuhn
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $190,663
- **Award type:** 5
- **Project period:** 2023-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10874699

## Citation

> US National Institutes of Health, RePORTER application 10874699, Neurobiological mechanisms underlying resiliency and vulnerability to opioid use disorder (5K99DA057390-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10874699. Licensed CC0.

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