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Amino Acids. 2016 Mar;48(3):689-696. doi: 10.1007/s00726-015-2117-8. Epub 2015 Nov 5.

Clavulanic acid enhances glutamate transporter subtype I (GLT-1) expression and decreases reinforcing efficacy of cocaine in mice.

Author information

1
Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA, USA.
2
Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA, USA.
3
Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA, USA.
4
Department of Neurosciences, Temple University School of Medicine, Philadelphia, PA, USA.
5
Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA, USA. scott.rawls@temple.edu.
6
Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA, USA. scott.rawls@temple.edu.

Abstract

The β-lactam antibiotic ceftriaxone (CTX) reduces cocaine reinforcement and relapse in preclinical assays through a mechanism involving activation of glutamate transporter subtype 1 (GLT-1). However, its poor brain penetrability and intravenous administration route may limit its therapeutic utility for indications related to CNS diseases. An alternative is clavulanic acid (CA), a structural analog of CTX that retains the β-lactam core required for GLT-1 activity but displays enhanced brain penetrability and oral activity relative to CTX. Here, we tested the hypothesis that CA (1, 10 mg/kg ip) would enhance GLT-1 expression and decrease cocaine self-administration (SA) in mice, but at lower doses than CTX. Experiments revealed that GLT-1 transporter expression in the nucleus accumbens of mice treated with repeated CA (1, 10 mg/kg) was enhanced relative to saline-treated mice. Repeated CA treatment (1 mg/kg) reduced the reinforcing efficacy of cocaine (0.56 mg/kg/inf) in mice maintained on a progressive-ratio (PR) schedule of reinforcement but did not affect acquisition of cocaine SA under fixed-ratio responding or acquisition or retention of learning. These findings suggest that the β-lactamase inhibitor CA can activate the cellular glutamate reuptake system in the brain reward circuit and reduce cocaine's reinforcing efficacy at 100-fold lower doses than CTX.

KEYWORDS:

Ceftriaxone; Clavulanic acid; Cocaine; GLT-1; Glutamate; Reinforcing; Self-administration; β-Lactamase inhibitor

PMID:
26543027
PMCID:
PMC4754134
[Available on 2017-03-01]
DOI:
10.1007/s00726-015-2117-8
[Indexed for MEDLINE]
Free PMC Article

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