title: Ceftriaxone upregulates the glutamate transporter in medial prefrontal cortex and blocks reinstatement of methamphetamine seeking in a condition place preference paradigm.
abstract: 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.
authors.affiliation: Department of Psychiatry and Behavioral Science, University of Southern California, Los Angeles, CA, USA. Abulseoud.osama@mayo.edu
authors.forename: Osama A
authors.initials: OA
authors.lastname: Abulseoud
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Miller
authors.forename: Jinhua
authors.initials: J
authors.lastname: Wu
authors.forename: Doo-Sup
authors.initials: DS
authors.lastname: Choi
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Holschneider
mesh_terms: D027322:Amino Acid Transport System X-AG / Q000096:biosynthesis; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002443:Ceftriaxone / Q000494:pharmacology*; D003216:Conditioning, Operant; D058999:Drug-Seeking Behavior / Q000187:drug effects* / Q000502:physiology; D027342:Excitatory Amino Acid Transporter 2 / Q000096:biosynthesis*; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology; D008297:Male; D008694:Methamphetamine / Q000009:adverse effects*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
chemical_list: D027322:Amino Acid Transport System X-AG; D000900:Anti-Bacterial Agents; D027342:Excitatory Amino Acid Transporter 2; D012333:RNA, Messenger; C493395:Slc1a2 protein, rat; D008694:Methamphetamine; D002443:Ceftriaxone