title: 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.
authors.affiliation: Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA, USA.|Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Jae
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: John
authors.affiliation: Department of Neurosciences, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Dianne
authors.initials: D
authors.lastname: Langford
authors.affiliation: Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA, USA.|Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA, USA.
authors.forename: Ellen
authors.initials: E
authors.lastname: Walker
authors.affiliation: Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA, USA.|Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Ward
authors.affiliation: Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA, USA. scott.rawls@temple.edu.|Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA, USA. scott.rawls@temple.edu.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Rawls
mesh_terms: D000818:Animals; D019818:Clavulanic Acid / Q000008:administration & dosage*; D003042:Cocaine / Q000008:administration & dosage / Q000009:adverse effects; D019970:Cocaine-Related Disorders / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D027342:Excitatory Amino Acid Transporter 2 / Q000235:genetics* / Q000378:metabolism; D005971:Glutamates / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D012646:Self Administration
chemical_list: D027342:Excitatory Amino Acid Transporter 2; D005971:Glutamates; D019818:Clavulanic Acid; D003042:Cocaine
keywords: Ceftriaxone; Clavulanic acid; Cocaine; GLT-1; Glutamate; Reinforcing; Self-administration; β-Lactamase inhibitor