# Role of beta2 nicotinic acetylcholine receptors in the insula-BNST pathway in ethanol consumption and abstinence-induced negative affect.

> **NIH NIH F31** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2024 · $51,974

## Abstract

Project Summary
In 2021, there was an estimated 29.5 million people that were diagnosed with alcohol use disorder (AUD),
resulting in an estimated annual cost of $249 billion to the US economy. AUD is an ongoing, severe health
crisis that requires further research to identify therapeutic targets. Stress can drive initial and sustained drug
use, as well as trigger relapse during abstinence, however the mechanisms that drive this effect are under
active research. The insula is a highly interconnected brain region that has been implicated in multiple
disorders, including AUD. Interestingly, fMRI studies have shown that alcohol-dependent individuals have
reduced insular cortex volumes, which was correlated with self-reports of impulsivity. PTSD patients have
increased connectivity between the insula and the bed nucleus of the stria terminalis (BNST), suggesting this
pathway is recruited by salient negative affective states. We have shown that the insula-BNST pathway drives
negative affect-like behavior during abstinence, however the molecular mechanisms involved in this pathway
are not understood. Nicotinic acetylcholine receptors (nAChRs) have been repeatedly shown to play an
important role in reward and stress involved with drug misuse, however further research is needed to
understand circuit specific nAChRs in these behaviors. Ethanol (EtOH) acts on nAChRs in a subunit specific
manner. Multiple nAChR subunits have been implicated in AUD, one of the most prominent being α4β2, which
are highly expressed throughout the brain. Moreover, multiple compounds acting on α4β2 nAChRs reduced
binge-like EtOH consumption. Chronic alcohol exposure in rhesus monkeys resulted in decreased α4β2
nAChRs in the insular cortex, suggesting a role for these receptors in driving AUD associated behaviors. The
overarching goal of this proposal is to characterize the role of α4β2 nAChRs expressed in mid-insulaBNST
neurons in modulating compulsive-like EtOH consumption and abstinence-induced negative affect-like
behavior. We will use whole-cell electrophysiology and calcium imaging in Aim 1 to determine the changes in
sensitivity to α4β2 nAChRs expressed in insula-BNST neurons following binge-like EtOH drinking, aversion-
resistant drinking and abstinence from alcohol. In aim 2, we will use bidirectional genetic manipulation of β2
nAChRs in this specific cell population to determine whether these receptors are sufficient and necessary for
binge-like drinking and abstinence-induced negative affect. These studies will highlight the potential for
nAChRs expressed in the insula-BNST pathway as a potential therapeutic target for AUD.

## Key facts

- **NIH application ID:** 10998254
- **Project number:** 1F31AA031625-01A1
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Benjamin M Williams
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $51,974
- **Award type:** 1
- **Project period:** 2024-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10998254

## Citation

> US National Institutes of Health, RePORTER application 10998254, Role of beta2 nicotinic acetylcholine receptors in the insula-BNST pathway in ethanol consumption and abstinence-induced negative affect. (1F31AA031625-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10998254. Licensed CC0.

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