# Project 3: Adolescent vulnerability to chronic ethanol: neurophysiological, molecular, and behavioral mechanisms of adult AUD

> **NIH NIH P50** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2024 · $317,685

## Abstract

Project 3: Adolescent vulnerability to chronic ethanol: neurophysiological, molecular, and behavioral
 mechanisms of adult AUD
Brian McCool, Kimberly Raab-Graham
The neurobiological mechanisms controlling the transition from alcohol use to abuse are poorly understood.
Our overall approach is to examine vulnerable populations to highlight specific cellular/molecular pathways
involved in this transition. For example, human adolescents exposed to heavy alcohol use are at much greater
risk for the development of alcoholism as adults. Recent studies suggest similar liabilities for adolescent
animals including rodents. Our published work indicates chronic ethanol exposure differentially modulates both
glutamatergic and GABAergic neurotransmission in the lateral/basolateral amygdala (BLA), a ‘node’ within
circuits critical for the integration cognitive and sensory information during emotional responses, in an input-
specific fashion. We provide preliminary evidence within this application that chronic ethanol differentially
facilitates glutamatergic and GABAergic neurotransmission onto young adult BLA neurons projecting to the
nucleus accumbens core (BLANAc cells) and those projecting to the bed nucleus of the stria terminalis (BLABNST
cells). These effects are both input- and sex-specific. Together our findings strongly suggest that chronic
ethanol differentially influences BLA neurons that control both reward- and aversion-like responses. The overall
goal of the current project is to therefore to understand the neurobiological, molecular, and behavioral
vulnerabilities of adolescent rats compared to mature adults. We will specifically test the central hypothesis that
periadolescent vulnerability to chronic ethanol is conferred by unique neurobiological and molecular responses
within distinct reward/aversion circuits. The proposed work includes three specific aims: Aim 1 will characterize
age-dependent vulnerability of BLA neurophysiology within BLANAc and BLABNST neurons; Aim 2 will help us
understand the molecular basis for adolescent circuit- and sex-specific vulnerability to chronic ethanol; and,
Aim 3 will define the behavioral consequences of circuit- and sex-specific functional/molecular adaptations
within the BLA. Together these aims are significant because they leverage a vulnerable population
(adolescents), innovative technical and conceptual approaches, and the substantial expertise of our research
team to help identify specific cellular signaling processes governing the impact of ethanol exposure across
multiple levels of analysis. We will also directly test if these processes represent potential therapeutic targets
for treatments designed to interrupt the transition from ethanol use to abuse.

## Key facts

- **NIH application ID:** 10758548
- **Project number:** 5P50AA026117-07
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** BRIAN A MCCOOL
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $317,685
- **Award type:** 5
- **Project period:** 2017-12-10 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10758548

## Citation

> US National Institutes of Health, RePORTER application 10758548, Project 3: Adolescent vulnerability to chronic ethanol: neurophysiological, molecular, and behavioral mechanisms of adult AUD (5P50AA026117-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10758548. Licensed CC0.

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