# Limbic glutamatergic circuits in ethanol dependence and escalated operant self-administration

> **NIH NIH P60** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $256,810

## Abstract

Project Summary/Abstract
Research Component 1. Alcohol use disorder (AUD) is a multiphasic neural and behavioral pathology that is
characterized, in part, by dependence-induced escalated alcohol use. Robust prior work shows that synaptic
activity of calcium permeable AMPA receptors (CP-AMPARs) is a target of alcohol that mediates the positive
reinforcing effects of the drug via activity within the brain reward pathway. Despite this progress in understanding
the molecular mechanisms of AUD, the role of CP-AMPAR activity in dependence-induced escalated alcohol
self-administration remains to be fully elucidated. Strong preliminary data show that alcohol dependence both
escalates the reinforcing effects of alcohol, as measured by operant self-administration, and upregulates AMPAR
expression in the basolateral amygdala (BLA) and other brain regions that send glutamatergic projections to the
nucleus accumbens (Acb), a central component of the reward pathway. This convergence of molecular,
physiological, and behavioral data supports the overall hypothesis that: CP-AMPAR expression and activity in
the BLAAcb pathway is a target of alcohol dependence that, in turn, drives escalated alcohol self-
administration. We propose to test this hypothesis in three separate but integrated aims using male and female
C57Bl/6J mice. First, an integrated set of molecular and electrophysiology studies will evaluate the impact of
alcohol dependence, induced by the well-characterized chronic intermittent ethanol vapor (CIE-v) method, on
AMPAR subunit expression and CP-AMPAR synaptic activity within the BLAAcb pathway. Second, loss of
function behavioral studies will evaluate mechanistic regulation of dependence-induced escalated operant
alcohol self-administration by CP-AMPARs in the BLA, and by GluA1-containing AMPARs in BLA neurons that
project to the Acb using an innovative CRISPR/Cas9 method for specifically deleting the GluA1 subunit in this
pathway. Third, based on strong preliminary data, we will conduct multi-channel fiber photometry to assess the
impact of alcohol dependence on calcium signaling in genetically tagged excitatory and inhibitory cells during
escalated operant alcohol self-administration. The mechanistic role of upregulated calcium signaling in escalated
operant alcohol self-administration will be evaluated by inhibiting calcium/calmodulin-dependent protein kinase
II (CaMKII) in the BLA, which is required for CP-AMPAR activity. These groundbreaking studies will move the
field forward in understanding how calcium-dependent glutamatergic mechanisms in the BLAAcb circuit
regulate the escalated reinforcing effects of alcohol associated with AUD.

## Key facts

- **NIH application ID:** 10758588
- **Project number:** 5P60AA011605-27
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Clyde W Hodge
- **Activity code:** P60 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $256,810
- **Award type:** 5
- **Project period:** 1997-12-01 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10758588

## Citation

> US National Institutes of Health, RePORTER application 10758588, Limbic glutamatergic circuits in ethanol dependence and escalated operant self-administration (5P60AA011605-27). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10758588. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*