TY - JOUR
T1 - Ceftriaxone upregulates the glutamate transporter in medial prefrontal cortex and blocks reinstatement of methamphetamine seeking in a condition place preference paradigm
AU - Abulseoud, Osama A.
AU - Miller, Joseph D.
AU - Wu, Jinhua
AU - Choi, Doo Sup
AU - Holschneider, Daniel P.
N1 - Funding Information:
This work was supported by internal funding from the Department of Psychiatry at the University of Southern California and by grants from the NIH/NCRR CTSA KL2 to Dr. Abulseoud ( RR024151 ), National Institutes of Health to D.-S.C. ( AA018779 , AA017830-Project 1 ), and R21 DA026970 to D.P.H. We would like to thank David Xiong, Marco Ocampo, Yumei Guo, Jesse Costales, Kalisa G Myers, and Moonnoh R. Lee for their assistance with the experiments.
PY - 2012/5/25
Y1 - 2012/5/25
N2 - 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 (EAAT 2) 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, EAAT 2 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 EAAT 2 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 EAAT 2 in human methamphetamine-dependent users.
AB - 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 (EAAT 2) 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, EAAT 2 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 EAAT 2 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 EAAT 2 in human methamphetamine-dependent users.
KW - Addiction
KW - Ceftriaxone
KW - Conditioned place preference
KW - Excitatory amino acid transporter
KW - Glutamate
KW - Glutamate transporter
KW - Methamphetamine
KW - Relapse
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U2 - 10.1016/j.brainres.2012.03.045
DO - 10.1016/j.brainres.2012.03.045
M3 - Article
C2 - 22521042
AN - SCOPUS:84860638271
SN - 0006-8993
VL - 1456
SP - 14
EP - 21
JO - Brain Research
JF - Brain Research
ER -