# Novel GLT-1 activators for the treatment of alcohol dependence: preclinical studies

> **NIH NIH R01** · UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS · 2024 · $419,512

## Abstract

Abstract:
Emerging evidence indicates that many aspects of ethanol (EtOH) and drug dependence involve
changes in glutamate transmission in central reward brain regions, including the nucleus
accumbens and medial prefrontal cortex. Upregulation of glutamate transporter 1 (GLT-1) in these
brain regions with i.p. injections of several β-lactams, including ceftriaxone, attenuated EtOH intake
and EtOH relapse behaviors in alcohol-preferring rats (P rats). GLT-1 is responsible for the uptake
of the majority of extracellular glutamate. In addition, cystine/glutamate exchanger (xCT) is another
astroglial protein involved in regulating glutamate homeostasis. The premise of this work is to
pursue a very extensive preclinical study that will investigate the neuropharmacology of novel GLT-
1 upregulators, MC-100093, and derivatives as well as a non-antibiotic FDA-approved β-lactam,
clavulanic acid (CLAV), which is a β-lactamase inhibitor in both continuous EtOH intake and EtOH
relapse behavior. In this study, we will investigate novel -lactams (MC-100093 and derivatives),
which do not have antibiotic action, on the expression of GLT-1 and xCT, and anti-inflammatory
effects. The experimental goals are: (Aim 1) Investigate the pharmacokinetics.pharmacodynamics
and target engagement of MC-100093 and, its derivatives and CLAV to determine dosing, and
nominate efficacy biomarkers for subsequent use in P rats; (Aim 2) Investigate the
pharmacological mechanisms of action of MC-100093 and its derivatives, and CLAV involving the
upregulation of GLT-1 and xCT, and attenuation of neuroinflammation in P rats. Data generated
from this project will show that novel drugs can upregulate GLT-1 expression and could have
significant clinical implications for alcohol dependence and other neuropsychiatric disorders
characterized by the hyperglutamatergic state as well as modulating neuroinflammation associated
with an increase in extracellular glutamate in central brain regions that regulate drug dependence;
and (Aim 3) to identify optimized, more lipophilic analogs of MC-100093 with drug-like properties
and pharmacokinetic profiles that support once-dosing.

## Key facts

- **NIH application ID:** 10852913
- **Project number:** 5R01AA029674-03
- **Recipient organization:** UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
- **Principal Investigator:** Magid Abou-Gharbia
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $419,512
- **Award type:** 5
- **Project period:** 2022-09-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10852913

## Citation

> US National Institutes of Health, RePORTER application 10852913, Novel GLT-1 activators for the treatment of alcohol dependence: preclinical studies (5R01AA029674-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10852913. Licensed CC0.

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