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

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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Clavulanic Acid / administration & dosage*
  • Cocaine / administration & dosage
  • Cocaine / adverse effects
  • Cocaine-Related Disorders / drug therapy*
  • Cocaine-Related Disorders / genetics
  • Cocaine-Related Disorders / metabolism
  • Excitatory Amino Acid Transporter 2 / genetics*
  • Excitatory Amino Acid Transporter 2 / metabolism
  • Glutamates / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / metabolism
  • Self Administration

Substances

  • Excitatory Amino Acid Transporter 2
  • Glutamates
  • Clavulanic Acid
  • Cocaine