# Drug-induced plasticity in mesolimbic dopamine circuits in opioid dependence

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2022 · $38,911

## Abstract

Project Summary
Opioid addiction is a devastating illness with far-reaching personal and public health consequences. The
physiological tolerance and dependence that develop with repeated opioid treatment are a common precursor
to addictive behaviors. This proposal is aimed at determining which midbrain circuits are altered by prolonged
opioid use and, more specifically, which neurons contribute to opioid dependence. When given acutely, opioids
disinhibit the release of dopamine from midbrain neurons as inhibitory opioid receptors on GABAergic neurons
are activated. This leads to increases of dopamine tone downstream. With repeated exposure, a receptor-
independent, homeostatic mechanism increases the activity of these GABAergic neurons to an opioid tolerant
state. Tolerant GABAergic neurons are hyper active and strongly inhibit dopaminergic neurons in the absence
of opioids. This is a likely cause of the decrease in dopamine tone that is associated with opioid withdrawal.
These GABAergic and dopaminergic changes occur primarily in the ventral tegmental area (VTA), a midbrain
region involved in both reward and aversion. Since the discovery of these opioid mechanisms, multiple distinct
VTA dopamine circuits have been described and found to have different functions with respect to reward and
aversion which calls into question the circuit-specificity of known opioid effects. Overall, a comprehensive
characterization of acute and long-term opioid effects in midbrain sub-circuits is very much lacking. The
proposed studies use patch clamp electrophysiology with retrograde tracers to determine the effects of opioids
on different VTA output pathways and identify which neurons demonstrate the previously described cellular
withdrawal characteristics. They also explore the relevance of different mesolimbic sub-regions to opioid
dependence by recording dopamine release changes in vivo using fiber photometry with a genetically encoded
dopamine sensor. Our previous research suggests that the rewarding aspects of opioid exposure and the
aversive responses to opioid dependence (withdrawal) may be mechanistically separable. By separating the
acute and chronic components of opioid use at the circuit level, this research will fill a gap in our understanding
of how dependence develops in the brain. This work has implications both for improved treatment of opioid
addiction and for development of safer analgesics with reduced risk for dependence. As a fellowship project, it
will also provide a framework for training in several essential neuroscience techniques with the help of a
diverse collection of experts in a highly collaborative research environment.

## Key facts

- **NIH application ID:** 10470911
- **Project number:** 5F31DA051116-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Sarah Warren Gooding
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $38,911
- **Award type:** 5
- **Project period:** 2020-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10470911

## Citation

> US National Institutes of Health, RePORTER application 10470911, Drug-induced plasticity in mesolimbic dopamine circuits in opioid dependence (5F31DA051116-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10470911. Licensed CC0.

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