Upregulation of GLT1 attenuates cue-induced reinstatement of cocaine-seeking behavior in rats.
Relapse to cocaine-seeking behavior depends on increased glutamate transmission in key regions of the mesocorticolimbic motive circuit, including prefrontal cortex (PFC) and nucleus accumbens (NAcc). Because GLT1 is responsible for the uptake of >or=90% of extracellular glutamate, we tested the hypothesis that increased GLT1 expression attenuates cocaine relapse. Rats were trained to self-administer cocaine (0.125 mg per intravenous infusion) in a lever-pressing task in a daily 2 h session for 10-14 d followed by 5 d of extinction training. Immediately after each extinction session, rats received ceftriaxone (intraperitoneally), a beta-lactam antibiotic believed to increase GLT1 expression, or vehicle. On the following day, presentation of the cue (light and tone) previously associated with cocaine self-administration reinstated lever pressing in rats treated with vehicle, whereas 100 or 200, but not 50 mg/kg ceftriaxone blocked this response. Immunoblotting confirmed that the ceftriaxone-induced blockade of cocaine relapse was associated with an increase in GLT1 expression in both PFC and NAcc. In separate groups of rats, 200 mg/kg ceftriaxone failed to block cue-induced food seeking, arguing against a ceftriaxone-induced effect unique to extinction training or lever pressing. Our results suggest that glutamate plays a key role in cue-induced relapse to cocaine-seeking behavior, implicating GLT1 as a potential therapeutic target for cocaine addiction.
Sari
Youssef
Y
Program in Neuroscience and Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana 47405, USA.
Smith
Kathryn D
KD
Ali
Pir K
PK
Rebec
George V
GV
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage; D016739:Behavior, Addictive / Q000503:physiopathology*; D002443:Ceftriaxone / Q000008:administration & dosage; D003042:Cocaine / Q000008:administration & dosage; D019970:Cocaine-Related Disorders / Q000503:physiopathology*; D003463:Cues; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism*; D005108:Extinction, Psychological; D005247:Feeding Behavior / Q000187:drug effects; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects / Q000503:physiopathology*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012008:Recurrence; D012646:Self Administration; D015854:Up-Regulation / Q000187:drug effects
D000900:Anti-Bacterial Agents; D018765:Dopamine Uptake Inhibitors; D027342:Excitatory Amino Acid Transporter 2; D002443:Ceftriaxone; D003042:Cocaine