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

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.

Effects of orally administered Augmentin on glutamate transporter 1, cystine-glutamate exchanger expression and ethanol intake in alcohol-preferring rats

“…In fact, it was shown that downregulation of GLT-1 following chronic ethanol exposure was associated with an elevation in extracellular glutamate concentration in NAc (5). Interestingly, several reports have demonstrated the upregulatory effect of β-lactams parenteral administration on GLT-1 and xCT expression in the central reward brain regions (5, 24, 25, 39, 43). …”

“…We found that in association with the reduction of ethanol consumption, oral gavage of Augmentin revealed a significant upregulation of GLT-1 expression in the NAc and PFC. Moreover, several studies have reported that administration of β-Lactams upregulated GLT-1 expression in mesocorticolimbic brain regions (16, 25, 43, 48). This effect was, at least in part, associated with a reduction of ethanol consumption (16, 48) and normalization of extracellular glutamate concentration in NAc (5).…”

“…Both compounds have a central β-lactam core which is proposed to be the reason for the upregulatory effect on GLT-1 (21). Importantly, clavulanic acid also has been reported to upregulate GLT-1 expression, which was associated with reduction in reinforcing effects of cocaine in mice (43). Studies are warranted to investigate the role of clavulanic acid in ethanol dependence.…”

The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis

“…Clavulanic acid has greater oral availability and brain penetrability compared with ceftriaxone and enhances expression of GLT-1. Studies show that clavulanic acid treatment inhibits cocaine intake (Kim et al, 2016) as well as morphine CPP (Schroeder et al, 2014). Additional experimentation is required to determine whether clavulanic acid will surpass ceftriaxone as the most effective b-lactam-based treatment of relapse vulnerability.…”

β-Lactamase inhibitor, clavulanic acid, attenuates ethanol intake and increases glial glutamate transporters expression in alcohol preferring rats

“…Importantly, the drug does not have any antibiotic activity as compared to ceftriaxone. CA has been reported to upregulate GLT-1 expression in mice (47). In this study, CA significantly attenuated ethanol consumption and upregulated GLT-1 expression in the NAc at 20-fold lower dose than ceftriaxone.…”