title: Role of the major glutamate transporter GLT1 in nucleus accumbens core versus shell in cue-induced cocaine-seeking behavior.
abstract: Relapse to cocaine-seeking behavior requires an increase in nucleus accumbens (NAc) core glutamate transmission. Decreased expression of glutamate type I transporter (GLT1), which is responsible for >90% of glutamate clearance, occurs in the core of rats withdrawn from cocaine self-administration, while treatment with ceftriaxone, a β-lactam antibiotic previously shown to increase GLT1 expression and function in rodents, upregulates GLT1 and attenuates cue-induced cocaine reinstatement. Here, we tested the effects of increasing GLT1 expression on cue-induced cocaine seeking in rats exposed to either limited (2 h/d) or extended (6 h/d) cocaine access followed by short (2 d) or long (45 d) withdrawal periods. Treatment with ceftriaxone (200 mg/kg, i.p.) upregulated core GLT1 expression and attenuated cue-induced cocaine-seeking behavior only in rats exposed to long withdrawal periods, with a greater effect in the extended-access condition. Pearson's correlation revealed GLT1 expression in core to be inversely correlated with cue-induced cocaine-seeking behavior. To localize the effects of GLT1 upregulation within NAc, we tested the hypothesis that blockade of GLT1 in NAc core, but not shell, would reverse the ceftriaxone-mediated effect. Rats withdrawn from cocaine self-administration were treated with the same dose of ceftriaxone followed by intracore or intrashell infusions of one of two GLT1 blockers, dihydrokainic acid (500 μM) or DL-threo-β-benzyloxyaspartate (250 μM), or saline. Our results reveal that the ceftriaxone-mediated attenuation of cue-induced cocaine reinstatement is reversed by GLT1 blockade in core, but not shell, and further implicate core GLT1 as a potential therapeutic target for cocaine relapse.
authors.affiliation: Program in Neuroscience, Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana 47405, USA.
authors.forename: Kathryn D
authors.initials: KD
authors.lastname: Fischer
authors.forename: Alexander C W
authors.initials: AC
authors.lastname: Houston
authors.forename: George V
authors.initials: GV
authors.lastname: Rebec
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001224:Aspartic Acid / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D002443:Ceftriaxone / Q000494:pharmacology; D019970:Cocaine-Related Disorders / Q000503:physiopathology / Q000523:psychology*; D003216:Conditioning, Operant / Q000187:drug effects; D003463:Cues; D027342:Excitatory Amino Acid Transporter 2 / Q000037:antagonists & inhibitors* / Q000502:physiology*; D005247:Feeding Behavior / Q000502:physiology; D007608:Kainic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012008:Recurrence; D013375:Substance Withdrawal Syndrome / Q000523:psychology
chemical_list: D027342:Excitatory Amino Acid Transporter 2; C493395:Slc1a2 protein, rat; C120673:benzyloxyaspartate; D001224:Aspartic Acid; C020889:dihydrokainic acid; D002443:Ceftriaxone; D007608:Kainic Acid