Ceftriaxone upregulates the glutamate transporter in medial prefrontal cortex and blocks reinstatement of methamphetamine seeking in a condition place preference paradigm

Brain Res. 2012 May 25:1456:14-21. doi: 10.1016/j.brainres.2012.03.045. Epub 2012 Mar 27.


Glutamate signaling plays an essential role in drug-seeking behavior. Using reinstatement of conditioned place preference (CPP), we determined whether ceftriaxone, a β-lactam antibiotic known to increase the expression and activity of the glutamate transporter (EAAT₂) on glial cells, blocks methamphetamine-triggered reinstatement of CPP. Rats acquired methamphetamine CPP following 7 consecutive days of conditioning, during which each animal received pairings of alternating morning methamphetamine (2.5 mg/kg, IP) and afternoon saline (IP). Animals showing CPP were successfully extinguished with repeated twice daily saline administration over a 7-day period. Ceftriaxone (200 mg/kg, IP) was administered (vs. saline) once a day for 7 days during the extinction period. Upon successful extinction, animals received a single dose of methamphetamine (2.5 mg/kg, IP) for reinstatement and were tested for CPP one day later. Using real time PCR, EAAT₂ mRNA levels in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) were quantified in response to ceftriaxone. Ceftriaxone blocked methamphetamine-triggered reinstatement of CPP and significantly increased EAAT₂ mRNA levels in the mPFC, with a trend towards significance in the NAc. In conclusion, Ceftriaxone modulated the expression of the glutamate transporter in a critical region of the cortico-striatal addiction circuitry and attenuated drug-seeking behavior in rats. Further research is needed to test the efficacy of compounds targeting the EAAT₂ in human methamphetamine-dependent users.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Transport System X-AG / biosynthesis
  • Animals
  • Anti-Bacterial Agents / pharmacology*
  • Ceftriaxone / pharmacology*
  • Conditioning, Operant
  • Drug-Seeking Behavior / drug effects*
  • Drug-Seeking Behavior / physiology
  • Excitatory Amino Acid Transporter 2 / biosynthesis*
  • Extinction, Psychological / drug effects
  • Extinction, Psychological / physiology
  • Male
  • Methamphetamine / adverse effects*
  • Prefrontal Cortex / drug effects*
  • Prefrontal Cortex / metabolism
  • RNA, Messenger / analysis
  • Rats
  • Rats, Sprague-Dawley
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Up-Regulation


  • Amino Acid Transport System X-AG
  • Anti-Bacterial Agents
  • Excitatory Amino Acid Transporter 2
  • RNA, Messenger
  • Slc1a2 protein, rat
  • Methamphetamine
  • Ceftriaxone