# CRF neurons of the extended amygdala and alcohol drinking

> **NIH NIH R01** · UNIVERSITY OF TEXAS AT AUSTIN · 2021 · $346,459

## Abstract

PROJECT SUMMARY
Alcohol use disorder is a major public health problem. To date, available treatment options are limited to
psychosocial intervention, three FDA approved medications (disulfuram, acamprosate, and naltrexone) and a
few drugs approved for other indications, all with relatively small effect sizes. There is a clear need for
additional treatments based on a deeper understanding of neurobiological mechanisms. Corticotrophin
releasing factor (CRF) is a 41-amino acid neuropeptide produced mainly by neurons of the paraventricular
hypothalamus, central amygdala (CeA), and bed nucleus of the stria terminalis (BNST) where it plays an
important role in behavioral and physiological responses to stress. CRF has been long implicated in driving
excessive ethanol consumption through prior studies that used CRF receptor antagonists in rodents. However,
recent attempts to test CRF receptor antagonists as treatments for alcohol craving in humans have been
disappointing. Part of this lack of success may be due to inadequate drug-like properties of some compounds
and by a need for different human laboratory models that test drug effects on withdrawal and negative
reinforcement in dependent subjects. Another reason may be due to the fact that CRF is released from
neurons with other peptides and neurotransmitters that may act in synergy to drive excessive drinking.
Understanding which of these co-released factors is important necessitates a different strategy that focuses on
the CRF neurons themselves rather than on CRF receptors.
The lack of genetic access to subpopulations of CRF neurons has made it difficult to study the biology of CRF
neurons, the sources of CRF in different brain regions, and the circuitry underlying CRF-regulated behaviors.
To fill this gap, we generated a BAC transgenic Wistar rat line in which Cre recombinase is expressed from the
Crh gene promoter to enable genetic access to CRF neurons. In this project, we will use these rats to pursue
the hypothesis that as animals develop ethanol dependence, CRF neurons in the CeA and BNST promote
ethanol consumption through the coordinated release of GABA, CRF, and other neuropeptides. We will
examine this hypothesis by selectively activating or inhibiting these neuronal populations and their projections
using chemogenetic tools, and we will address the relative importance of the different transmitters and
modulators released from these neurons using Cre-dependent RNA interference. Finally, we will investigate
the role of repeated ethanol consumption on the transcriptome of these CRF neuronal populations to
understand how ethanol changes their phenotype, which should provide us with important new clues as to how
they drive excessive drinking.
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## Key facts

- **NIH application ID:** 10189451
- **Project number:** 5R01AA026075-05
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** ROBERT O. MESSING
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $346,459
- **Award type:** 5
- **Project period:** 2017-07-20 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10189451

## Citation

> US National Institutes of Health, RePORTER application 10189451, CRF neurons of the extended amygdala and alcohol drinking (5R01AA026075-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10189451. Licensed CC0.

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