# Neurobiological mechanisms underlying chronic tolerance to the aversive properties of ethanol

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2022 · $359,775

## Abstract

PROJECT SUMMARY
Chronic alcohol exposure is associated with the development of tolerance to alcohol’s aversive properties, which
serve to limit drinking. In contrast, the response to alcohol’s rewarding properties, which promote drinking, remain
unchanged. The brain undergoes a host of neuroadaptive changes as a result of chronic alcohol exposure but
the neural mechanisms underlying this tolerance are unknown. Impaired signaling in circuits encoding aversion
is a likely candidate mechanism. The rostromedial tegmental nucleus (RMTg) is characterized for its involvement
in aversion including signaling the aversive properties of ethanol. The prelimbic (PL) medial prefrontal cortex
(mPFC) shares important functional similarities with the RMTg including facilitation of aversion learning and
regulating the behavioral response to aversive stimuli. The neighboring infralimbic (IL) subregion of the mPFC
exerts opposing effects to PL mPFC by facilitating extinction of aversive responding. Our work has uncovered a
dense projection from the mPFC to the RMTg that spans both PL and IL subregions. Our findings from
experiments investigating the function mPFC inputs to the RMTg support a role for these circuits in regulating
aversive responding. These data lead us to hypothesize that subregion- and circuit-specific dependence-induced
plasticity in RMTg-projecting mPFC neurons facilitates chronic tolerance to ethanol’s aversive properties. The
aims described in the current proposal will use innovative, circuit-specific strategies to test this hypothesis. Aim
1 will use in vivo fiber photometry to measure changes in calcium signal in RMTg-projecting PL and IL mPFC
inputs during the development of tolerance. Aim 2 will use closed-loop in vivo optogenetics to dissect the effects
of bidirectional manipulation of PL and IL mPFC inputs to the RMTg on measures of chronic tolerance to
ethanol’s aversive properties. Aim 3 will use whole-cell patch-clamp slice electrophysiology and a virally-
mediated intersectional approach to identify dependence-induced changes in synaptic and structural plasticity
underlying tolerance to ethanol’s aversive properties. The results of these studies will provide crucial insight into
the circuit-specific neural mechanisms that contribute to uncontrolled alcohol drinking. In doing so, our findings
have the potential to uncover new therapeutic targets for the treatment of alcohol use disorder.

## Key facts

- **NIH application ID:** 10428482
- **Project number:** 5R01AA029130-02
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Elizabeth J Glover
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $359,775
- **Award type:** 5
- **Project period:** 2021-06-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10428482

## Citation

> US National Institutes of Health, RePORTER application 10428482, Neurobiological mechanisms underlying chronic tolerance to the aversive properties of ethanol (5R01AA029130-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10428482. Licensed CC0.

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