title: Ceftriaxone attenuates cocaine relapse after abstinence through modulation of nucleus accumbens AMPA subunit expression.
abstract: Using the extinction-reinstatement model of cocaine relapse, we and others have demonstrated that the antibiotic ceftriaxone attenuates cue- and cocaine-primed reinstatement of cocaine-seeking. Reinstatement is contingent on the release of glutamate in the nucleus accumbens core (NAc) and manipulations that reduce glutamate efflux or block post-synaptic glutamate receptors attenuate reinstatement. We have demonstrated that the mechanism of action by which ceftriaxone attenuates reinstatement involves increased NAc GLT-1 expression and a reduction in NAc glutamate efflux during reinstatement. Here we investigated the effects of ceftriaxone (100 and 200 mg/kg) on context-primed relapse following abstinence without extinction training and examined the effects of ceftriaxone on GluA1, GluA2 and GLT-1 expression. We conducted microdialysis during relapse to determine if an increase in NAc glutamate accompanies relapse after abstinence and whether ceftriaxone blunts glutamate efflux. We found that both doses of ceftriaxone attenuated relapse. While relapse was accompanied by an increase in NAc glutamate, ceftriaxone (200 mg/kg) was unable to significantly reduce NAc glutamate efflux during relapse despite its ability to upregulate GLT-1. GluA1 was reduced in the NAc by both doses of ceftriaxone while GluA2 expression was unchanged, indicating that ceftriaxone altered AMPA subunit composition following cocaine. Finally, GLT-1 was not altered in the PFC by ceftriaxone. These results indicate that it is possible to attenuate context-primed relapse to cocaine-seeking through modification of post-synaptic receptor properties without attenuating glutamate efflux during relapse. Furthermore, increasing NAc GLT-1 protein expression is not sufficient to attenuate glutamate efflux.
authors.affiliation: Psychology Department, University of Florida, Gainesville, FL, United States.
authors.forename: Amber L
authors.initials: AL
authors.lastname: LaCrosse
authors.affiliation: Psychology Department, University of Florida, Gainesville, FL, United States.
authors.forename: Kristine
authors.initials: K
authors.lastname: Hill
authors.affiliation: Psychology Department, University of Florida, Gainesville, FL, United States. Electronic address: knack@ufl.edu.
authors.forename: Lori A
authors.initials: LA
authors.lastname: Knackstedt
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use; D019540:Area Under Curve; D002443:Ceftriaxone / Q000494:pharmacology* / Q000627:therapeutic use*; D002851:Chromatography, High Pressure Liquid; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000188:drug therapy* / Q000209:etiology; D003216:Conditioning, Operant / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism*; D012646:Self Administration; D013997:Time Factors
chemical_list: D000900:Anti-Bacterial Agents; D027342:Excitatory Amino Acid Transporter 2; D018091:Receptors, AMPA; C493395:Slc1a2 protein, rat; D018698:Glutamic Acid; D002443:Ceftriaxone; D003042:Cocaine
keywords: Cocaine; GLT-1; GluA1; Glutamate; Nucleus accumbens; Relapse