# The role of brainstem norepinephrine in binge alcohol drinking and taste aversion

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $349,875

## Abstract

Abstract
Frequent binge drinking, and common pattern of alcohol (ethanol) consumption across the lifespan, has been
linked to numerous adverse consequences. Particularly concerning is the fact that regular binge drinking
significantly increases an individual’s risk of developing ethanol dependence. Thus, it is a highly significant goal
to identify neuronal mechanisms that modulate binge drinking as such knowledge will provide insight into novel
pharmaceutical treatments to help curb binge drinking and which in turn may reduce the risk of progressing to
more serious forms of alcohol use disorders (AUDs). Research aimed at the neurobiology of AUDs has focused
considerable attention to the reinforcing effects of ethanol and how these effects motivate binge-like ethanol
intake. Interestingly there is accumulating evidence that ethanol also entails aversive effects and that these
effects, because they are clearly dose related, can act as a deterrent to overconsumption. Because the
neurocircuitry underlying the aversive effects of ethanol is still poorly understood, in the last funding period we
began to characterize the neuronal mechanisms that modulate the aversive reactions to ethanol and their role
in modulating binge-like ethanol consumption. We found that binge-like ethanol drinking increases the activity of
neurons in the A2 (caudal nucleus of the solitary tract; NTS) and A6 (locus coeruleus; LC) brainstem regions,
two of the primary sources of norepinephrine (NE) that send afferent projections to numerous brain structures
that modulate motivated behaviors. Interestingly, we discovered that chemogenetic activation of NE+ circuits
from the LC to the rostromedial tegmental nucleus (RMTg) or the A2 to the lateral parabrachial nucleus (PBN),
target regions that have been implicated in modulating the aversive properties of ethanol, significantly blunted
binge-like ethanol intake in mice. Further, activating the NE+ LC  RMTg circuit induced unconditioned aversive
behaviors in mice, and silencing this pathway attenuated ethanol-induced conditioned taste aversion (CTA). Our
guiding hypothesis is that activation of these NE+ circuits trigger a protective mechanism to “break” ethanol
intake by promoting aversive responses to ethanol. More recently, we observed NE circuits arising from the LC
and A2 that directly innervate the ventral tegmental area (VTA), a brain region critical for modulating both reward
and aversion. Surprisingly, there has been almost no investigation into the role of NE signaling in the VTA in the
modulation of ethanol intake or the aversive properties of ethanol. Proposed experiments logically flow from the
original grant but will significantly advance our understanding of the novel mechanisms under investigation by 1)
revealing novel NE+ circuits that modulate binge-like ethanol intake and the aversive properties of ethanol, 2)
identifying the adrenergic receptors (AR) that are involved, and 3) identifying neuroplastic changes in A...

## Key facts

- **NIH application ID:** 10828859
- **Project number:** 5R01AA025809-07
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** TODD Eric THIELE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $349,875
- **Award type:** 5
- **Project period:** 2018-04-15 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10828859

## Citation

> US National Institutes of Health, RePORTER application 10828859, The role of brainstem norepinephrine in binge alcohol drinking and taste aversion (5R01AA025809-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10828859. Licensed CC0.

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