title: Ceftriaxone attenuates acute cocaine-evoked dopaminergic neurotransmission in the nucleus accumbens of the rat.
abstract: OBJECTIVE
  Ceftriaxone is a β-lactam antibiotic and glutamate transporter activator that reduces the reinforcing effects of psychostimulants. Ceftriaxone also reduces locomotor activation following acute psychostimulant exposure, suggesting that alterations in dopamine transmission in the nucleus accumbens contribute to its mechanism of action. In the present studies we tested the hypothesis that pretreatment with ceftriaxone disrupts acute cocaine-evoked dopaminergic neurotransmission in the nucleus accumbens.
  
  
  METHODS
  Adult male Sprague-Dawley rats were pretreated with saline or ceftriaxone (200 mg kg(-1) , i.p. × 10 days) and then challenged with cocaine (15 mg kg(-1) , i.p.). Motor activity, dopamine efflux (via in vivo microdialysis) and protein levels of tyrosine hydroxylase (TH), the dopamine transporter and organic cation transporter as well as α-synuclein, Akt and GSK3β were analysed in the nucleus accumbens.
  
  
  RESULTS
  Ceftriaxone-pretreated rats challenged with cocaine displayed reduced locomotor activity and accumbal dopamine efflux compared with saline-pretreated controls challenged with cocaine. The reduction in cocaine-evoked dopamine levels was not counteracted by excitatory amino acid transporter 2 blockade in the nucleus accumbens. Pretreatment with ceftriaxone increased Akt/GSK3β signalling in the nucleus accumbens and reduced levels of dopamine transporter, TH and phosphorylated α-synuclein, indicating that ceftriaxone affects numerous proteins involved in dopaminergic transmission.
  
  
  CONCLUSIONS
  These results are the first evidence that ceftriaxone affects cocaine-evoked dopaminergic transmission, in addition to its well-described effects on glutamate, and suggest that its ability to attenuate cocaine-induced behaviours, such as psychomotor activity, is due in part to reduced dopaminergic neurotransmission in the nucleus accumbens.
authors.affiliation: Department of Pharmacology and Centre for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Barr
authors.affiliation: Department of Pharmacology and Centre for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: Rasmussen
authors.affiliation: Department of Pharmacology and Centre for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: C S
authors.initials: CS
authors.lastname: Tallarida
authors.affiliation: Centre for Brain and Behaviour Research, Division of Basic Biomedical Sciences, Sanford School of Medicine at the University of South Dakota, Vermillion, SD, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Scholl
authors.affiliation: Centre for Brain and Behaviour Research, Division of Basic Biomedical Sciences, Sanford School of Medicine at the University of South Dakota, Vermillion, SD, USA.
authors.forename: G L
authors.initials: GL
authors.lastname: Forster
authors.affiliation: Department of Pharmacology and Centre for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Unterwald
authors.affiliation: Department of Pharmacology and Centre for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Rawls
mesh_terms: D000818:Animals; D002443:Ceftriaxone / Q000494:pharmacology*; D003042:Cocaine; D004298:Dopamine / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission / Q000187:drug effects*
chemical_list: D002443:Ceftriaxone; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D003042:Cocaine; D004298:Dopamine