# Molecular Mechanisms of Ethanol Reinforcement

> **NIH NIH R37** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $304,000

## Abstract

Drugs of abuse gain control over behavior by usurping the activity of brain reward circuits. Thus, identifying
behaviorally significant adaptations in these circuits is crucial for understanding the etiology and progression
of alcohol addiction. Our preclinical research identified CaMKIIα-AMPAR signaling as a novel target of
moderate alcohol intake that also regulates the positive reinforcing effects of the drug in mice. This indicates
that alcohol misappropriates molecular mechanisms of neuroplasticity within brain reward circuits. We
propose that this maladaptive activity represents a molecular gateway from use to abuse, suggesting that the
initial hit to this pathway is exacerbated during the development of dependence. We also showed that
CaMKII signaling in the amygdala vs. mPFC differentially regulates alcohol self-administration. Since CaMKII
is prominent in glutamate projection neurons, this suggests that excitatory efferents from these brain regions
differentially regulate alcohol reinforcement. In this MERIT extension, we propose to move the field forward
by testing the overall hypothesis that excitatory CaMKIIα-positive corticolimbic circuits serve as functional
units in the regulation of alcohol self-administration in a manner that is exacerbated by dependence.
First, we will take a multidisciplinary approach to characterize the effects of initial alcohol use on activity of
CaMKIIα-dependent glutamate circuits (amygdala-to-accumbens and cortex-to-accumbens) and determine if
alcohol-induced changes are exacerbated by dependence. These innovative discovery-based studies will
inform subsequent goals of the project and move the field forward in our understanding of how alcohol
dependence altered brain reward pathway function. Second, we will conduct mechanistic studies using
optogenetic and pharmacological strategies to test the hypothesis that these neural circuits differentially
regulate alcohol self-administraion during initial use and dependence. Overall, these innovative mechanistic
studies will identify specific nuclei and circuits in which increased glutamate signaling contributes to
escalated alcohol use in dependence; thus, identifying and validating novel mechanisms of a critical
behavioral pathology that pervades the development and progression of alcohol addiction.

## Key facts

- **NIH application ID:** 9967904
- **Project number:** 5R37AA014983-15
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Clyde W Hodge
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $304,000
- **Award type:** 5
- **Project period:** 2005-08-05 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9967904

## Citation

> US National Institutes of Health, RePORTER application 9967904, Molecular Mechanisms of Ethanol Reinforcement (5R37AA014983-15). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9967904. Licensed CC0.

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