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.