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

> **NIH NIH P50** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2022 · $326,340

## Abstract

SUMMARY
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 adolescent 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. Our data also suggest a critical role for mammalian target of rapamycin (mTOR)-
dependent signaling cascades in synaptic strengthening. Further, we provide preliminary data suggesting that
many of these synaptic effects are absent or greatly diminished in adult animals. This suggests that mTOR-
dependent signaling directly regulates synaptic modulation during adolescent ethanol exposure. The overall
goal of the current project is to therefore use a well-established ethanol vapor exposure in adolescent rats to
understand the long-term impact of this exposure in adult animals by integrating cellular, molecular, and
behavioral methodologies. The proposed work includes three specific aims: Aim 1 will characterize the effects
of adolescent ethanol exposure on adult BLA glutamatergic and GABAergic neurotransmission using whole-
cell patch clamp electrophysiology; Aim 2 will describe the effect of adolescent ethanol exposure on mTOR
signaling in both postsynaptic and presynaptic compartments in the BLA; and, Aim 3 will examine
pharmacological intervention along the mTOR-signaling pathway and its impact on the long-term behavioral
consequences of adolescent ethanol exposure. 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 directly test if these signaling processes represent
potential therapeutic targets for treatments designed to interrupt the transition from ethanol use to abuse.

## Key facts

- **NIH application ID:** 10310702
- **Project number:** 5P50AA026117-05
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** BRIAN A MCCOOL
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $326,340
- **Award type:** 5
- **Project period:** 2017-12-10 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10310702

## Citation

> US National Institutes of Health, RePORTER application 10310702, Project 3:  Adolescent vulnerability to chronic ethanol: neurophysiological, biochemical, and behavioral mechanisms of adult AUD (5P50AA026117-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10310702. Licensed CC0.

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