# Role of GluN2A and MMPs in the CeA in Dependence-Induced Escalation of Etoh Drinking

> **NIH NIH R21** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2022 · $217,063

## Abstract

Project Summary
The legal status and widespread use of alcohol among the US population is associated with adverse health
outcomes in both adolescents and adults. Nearly 88% of the US population have used alcohol at least once
during their lifetime and rates of binge drinking and heavy alcohol use continue to be of concern. Pharmacological
treatments for alcohol abuse show limited effectiveness and only three medications are FDA approved for
treating alcohol dependence. One factor that underlies this problem is a lack of understanding of the mechanisms
that contribute to excessive drinking. Recent results from our previous studies show that knock-in mice
expressing ethanol resistant GluN2A N-methyl-D-aspartate receptors (NMDARs) drink the same as wild-type
mice under baseline conditions but, unlike their wild-type counterparts, fail to escalate their drinking following
repeated cycles of chronic intermittent ethanol exposure. These findings suggest that GluN2A NMDARs play a
key role for in the loss of control over drinking observed in alcohol dependent subjects. Importantly, a similar lack
of escalated drinking is observed following administration of inhibitors of zinc-dependent matrix
metalloproteinases (MMPs) either i.c.v. or directly into the central nucleus of the amygdala (CeA). MMPs are key
mediators of NMDA-mediated forms of synaptic plasticity where they remodel the extracellular matrix to support
new growth and enlargement of glutamatergic dendritic spines. In this proposal we test the overarching
hypothesis that MMPs and ethanol-sensitive GluN2A NMDARs in the CeA are critically involved in the transition
to heavy drinking that is a hallmark of alcohol dependence. In Aim 1, we use slice electrophysiology, in vivo
zymography and western blot analysis to test the hypothesis that CIE-induced changes in CeA neural signaling
and MMP activity are absent in the GluN2A knock-in mice. In Aim 2, we use Crispr expressing AAVs and guide
RNAs targeting the GluN2A gene to test the hypothesis that the CIE-induced increases in drinking and MMP
activity requires functional GluN2A NMDARs in the CeA. The findings from these novel studies will provide critical
data to support a future R01 grant application focused on determining which CeA cell types drive the altered
drinking phenotype of the GluN2A knock-in mice and whether their expression in other key addiction-related
brain areas contribute to this effect.

## Key facts

- **NIH application ID:** 10525274
- **Project number:** 1R21AA030159-01A1
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** John J. Woodward
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $217,063
- **Award type:** 1
- **Project period:** 2022-08-02 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10525274

## Citation

> US National Institutes of Health, RePORTER application 10525274, Role of GluN2A and MMPs in the CeA in Dependence-Induced Escalation of Etoh Drinking (1R21AA030159-01A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10525274. Licensed CC0.

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