# Locus coeruleus-norepinephrine regulation of stress-induced anxiety and opioid reinstatement

> **NIH NIH F32** · UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA · 2024 · $76,756

## Abstract

PROJECT SUMMARY
 Exposure to psychosocial stress has widespread deleterious effects on the body and brain that lead to
the development of many physiological and neuropsychiatric disorders. Importantly, conditions such as anxiety
and opioid use disorder (OUD) are two of the most common stress comorbidities that not only cause drastic
effects on the patient but also represent an extreme public health crisis. Notably, females often suffer from these
conditions at twice the rate of men, but research into the potential sex differences that allow for this susceptibility
has traditionally been under studied. Further, the underlying neural mechanisms by which stress confers
susceptibility to future psychiatric illness has not been fully explored. The overall goal of this project is to
determine the neural alterations induced by psychosocial stress in discrete stress-sensitive brain regions in
animal models utilizing both male and female rats. Specifically, these experiments aim to investigate
neuroimmune signaling within the locus coeruleus (LC) to determine how stress-induced alteration of microglial
activation influences noradrenergic output and subsequent anxiety-like and drug seeking behaviors. Increased
neuroimmune signaling in this brain region has been associated with increased norepinephrine (NE) output, but
the downstream impact of stress-induced microglial alterations of LC-NE activity on projection regions involved
in the control of anxiety and drug seeking behaviors has not been assessed. Therefore, these experiments have
been designed to test the hypothesis that stress exposure augments microglial signaling within the LC which, in
turn, affects noradrenergic tone in downstream regions including the basolateral amygdala (BLA), a region
known for its control of anxiety- and drug-related behaviors. This hypothesis will be tested using a variety of
techniques including behavioral pharmacology, chemogenetics, and microdialysis to modulate and measure the
impact of stress-induced LC microglial activation on anxiety-like and opioid seeking behaviors. Male and female
rats will be exposed to our model of vicarious social stress, witness stress, where a rat experiences the sensory
and psychological aspects of a social defeat encounter. Aim 1 is designed to determine the effects of LC
microglia modulation, through intra-LC DREADD mediated inactivation of microglia, on anxiety-like and opioid
reinstatement behaviors using marble burying and opioid conditioned place preference testing. These animals
will also be implanted with microdialysis probes within the BLA for Aim 2 which is designed to determine the
downstream effects of LC microglial modulation on NE activity in the BLA. These studies have the potential to
identify novel mediators of maladaptive stress responses that escalate to opioid use disorder with the ultimate
goal of determining preventative treatments for stress-induced comorbidities. These data support the mission of
the NIH in the searc...

## Key facts

- **NIH application ID:** 10874435
- **Project number:** 5F32DA058380-02
- **Recipient organization:** UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
- **Principal Investigator:** Cora Smiley
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $76,756
- **Award type:** 5
- **Project period:** 2023-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10874435

## Citation

> US National Institutes of Health, RePORTER application 10874435, Locus coeruleus-norepinephrine regulation of stress-induced anxiety and opioid reinstatement (5F32DA058380-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10874435. Licensed CC0.

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