# Neuroimmune mechanisms of alcohol reward

> **NIH NIH R01** · BRIGHAM YOUNG UNIVERSITY · 2024 · $326,967

## Abstract

PROJECT SUMMARY/ABSTRACT
The prevailing dogma in the alcohol field is that the rewarding properties of ethanol (EtOH) result from
enhancement of ventral tegmental area (VTA) dopamine (DA) neural activity and accompanying DA release in
the mesolimbic reward system. In preliminary studies, we will demonstrate that some of EtOH’s effects on
midbrain neurons and NAc DA release are mediated by peripheral substrates including DA D2-subtype 2
receptor (D2R) expressing monocyte-derived macrophages (MDMs). These findings suggest a neuroimmune
interaction for acute EtOH use and challenge the dogma that EtOH has exclusively central effects on DA
neuronal activity, release, and reward. Our proposed studies constitute a focused investigation into the role of
neuroimmune interactions in EtOH effects on VTA neurons, DA transmission, and EtOH reward and consumption.
The core thesis is that acute EtOH enhancement of mesolimbic DA transmission and EtOH reward is
mediated by EtOH enhancement of blood DA, subsequent activation of D2R-expressing MDMs, and
subsequent cytokine modulation of VTA neurons, that are responsible for chronic adaptations in VTA
GABA neurons and DA release. Prior and preliminary evidence supporting our hypothesis include: 1)
Peripheral DA increases the activity of DA neurons and NAc DA release, reduces locomotor activity, and
promotes reward via peripheral D2Rs; 2) EtOH enhances blood DA, inhibits VTA GABA neurons, enhances
brain DA, and reduces intoxication via peripheral D2Rs; 3) EtOH induces microglia activation and enhances D2
receptor expression on monocytes, neurons, and microglia; 4) Depletion of MDMs reduces EtOH effects on VTA
GABA neurons and DA release; 5) Select cytokines enhance VTA neuron excitability and DA release; 6) Last,
we show preliminary evidence of DA and ATP co-release from DA terminals, and motility effects of EtOH on
microglia, which indicate further study for potential NAc EtOH immune interactions in vivo.
 These data will provide new, fundamental knowledge on the neurobiology of EtOH reward and
dependence and the role of peripheral substrates that may help improve drug development efforts. To test the
hypotheses, we propose two Specific Aims: 1) Define the role of peripheral neuroimmune interactions in EtOH
effects on VTA GABA neurons and NAc DA release, and related behaviors; 2) Describe effects of EtOH on NAc
DA terminals and microglia, co-release of DA and ATP. We will use wild-type and transgenic mouse models
(GAD67-GFP knock-in; VGAT-Chr2, VGAT-Cre/GAD67-GFP; and MaFIA mice) and MDM depletion to study
neurochemical and electrochemical recordings of DA release. Cytometry techniques will be used to determine
cytokine factors involved in mesolimbic alterations. Multiphoton microscopy approaches to study microglia
chemotaxis in the context of DA and ATP as measured by fast scan cyclic voltammetry. Multiphoton microscopy
will be used in vivo through endoscopic relay gradient index lenses to study GFP labeled satelli...

## Key facts

- **NIH application ID:** 10877791
- **Project number:** 5R01AA030577-02
- **Recipient organization:** BRIGHAM YOUNG UNIVERSITY
- **Principal Investigator:** Jordan Thomas Yorgason
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $326,967
- **Award type:** 5
- **Project period:** 2023-07-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10877791

## Citation

> US National Institutes of Health, RePORTER application 10877791, Neuroimmune mechanisms of alcohol reward (5R01AA030577-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10877791. Licensed CC0.

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