title: Ceftriaxone normalizes nucleus accumbens synaptic transmission, glutamate transport, and export following cocaine self-administration and extinction training.
abstract: Decreased basal glutamate levels are observed in the rat nucleus accumbens (NA) core following cocaine self-administration. This disruption of glutamate homeostasis arises from a reduction in the export of glutamate via system x(C)(-) and is accompanied by a decrease in expression of xCT, the catalytic subunit of system x(C)(-). A second hallmark of disrupted homeostasis is a decrease in expression and function of the major glutamate transporter, GLT-1. We have previously shown that chronic treatment with the antibiotic ceftriaxone restores xCT and GLT-1 expression following cocaine self-administration and attenuates both cue- and cocaine-primed reinstatement. Here we used a (3)H-glutamate uptake assay and microdialysis to test the hypothesis that ceftriaxone restores the function of both GLT-1 and xCT (glutamate reuptake and export, respectively) in the NA core following cocaine self-administration. We also used electrophysiology to investigate the ability of ceftriaxone to normalize measures of synaptic plasticity following cocaine. We found that 5 d of ceftriaxone treatment following cocaine self-administration restores basal glutamate levels in the accumbens core, likely through an upregulation of system x(C)(-) function. We also found that ceftriaxone restores glutamate reuptake and attenuates the increase in synaptically released glutamate that accompanies cocaine-primed reinstatement. Ceftriaxone also reversed the cocaine-induced synaptic potentiation in the accumbens core, evidenced by normalized spontaneous EPSC amplitude and frequency and evoked EPSC amplitude. These data indicate that ceftriaxone normalizes multiple aspects of glutamate homeostasis following cocaine self-administration and thus holds the potential to reduce relapse in human cocaine addicts.
authors.affiliation: Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Trantham-Davidson
authors.forename: Ryan T
authors.initials: RT
authors.lastname: LaLumiere
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Reissner
authors.forename: Peter W
authors.initials: PW
authors.lastname: Kalivas
authors.forename: Lori A
authors.initials: LA
authors.lastname: Knackstedt
mesh_terms: D000818:Animals; D002443:Ceftriaxone / Q000494:pharmacology*; D003042:Cocaine / Q000008:administration & dosage*; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology*; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D012646:Self Administration; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
chemical_list: D018698:Glutamic Acid; D002443:Ceftriaxone; D003042:Cocaine