# Opioid-induced dysregulation of lateral mesolimbic dopamine circuits and motivated behavior

> **NIH NIH R21** · MARQUETTE UNIVERSITY · 2022 · $181,688

## Abstract

Project Summary
Opioid abuse remains a costly epidemic in the US, prompting research into new and effective interventions to
curb addiction-like behavior. Amongst the therapeutic characteristics of opioids, their associated withdrawal
effects are substantial and recognized to contribute to relapse and prolonged intake. While the acute somatic
symptoms of opioid withdrawal are relatively well characterized, their prolonged affective counterparts are less
understood. This proposal will investigate opioid-induced motivational changes following prolonged abstinence
from morphine by focusing on mesolimbic dopamine (DA), or the `reward system'. Regulating a broad array of
affective behaviors, the mesolimbic dopamine system has been demonstrated as both necessary and sufficient
for reward-related behavior towards opioids. Despite this, limitations of previous studies concerning
heterogeneity of mesolimbic circuitry and a shortage of assessments of opioid-induced changes to motivated
behavior have stifled clear demonstrations of motivational dysfunction following opioid dependence. Here, we
aim to expand upon our lab's novel pilot data demonstrating both increased inhibitory tone and decreased
excitability selective to a lateral-specific mesolimbic sub-circuit of DA neurons following 14 days of abstinence
from a dependence-inducing regimen of morphine injections. Our pilot data also show that this plasticity aligns
temporally with a reduction in motivation for natural rewards but an increase in motivation for morphine and an
overall escalation in drug intake compared previously non-dependent animals.
Aim1 will build this data and test
 morphine dependence induces a persistent shift in motivation that drives escalation of intake,
in part by establishing a novel choice model with both rewards simultaneously present. Aim2 will investigate the
necessity and sufficiency of the lateral mesolimbic subcircuit in this bidirectional shift in motivated behavior using
excitatory and inhibitory chemogenetic approaches in DAT-IRES-Cre transgenic mice. Finally, Aim 3 will seek to
identify the locus of increased inhibition to latVTA-latShell DA sub-circuit under identical conditions using ex vivo
electrophysiology to assess both pre- and postsynaptic changes in GABAergic signaling arising from the opioid
sensitive, rostral tegmental nucleus, and if this increased inhibition aligns with reductions in basal DA
transmission using the DA sensor, dLight. The outcomes of these studies will further our understanding of neural
circuits that regulate motivational states and inform us of adaptations in these circuits produced by opioid
dependence that may confer enduring susceptibility.
the hypothesis that

## Key facts

- **NIH application ID:** 10492420
- **Project number:** 5R21DA052706-02
- **Recipient organization:** MARQUETTE UNIVERSITY
- **Principal Investigator:** Matthew Carl Hearing
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $181,688
- **Award type:** 5
- **Project period:** 2021-09-30 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10492420

## Citation

> US National Institutes of Health, RePORTER application 10492420, Opioid-induced dysregulation of lateral mesolimbic dopamine circuits and motivated behavior (5R21DA052706-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10492420. Licensed CC0.

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