Neuroadaptations in cystine-glutamate exchange underlie cocaine relapse.
Repeated cocaine treatment and withdrawal produces changes in brain function thought to be involved in relapse to drug use. Withdrawal from repeated cocaine reduced in vivo extracellular glutamate in the nucleus accumbens of rats by decreasing the exchange of extracellular cystine for intracellular glutamate. In vivo restoration of cystine/glutamate exchange by intracranial perfusion of cystine or systemically administered N-acetylcysteine normalized the levels of glutamate in cocaine-treated subjects. To determine if the reduction in nonvesicular glutamate release is a mediator of relapse, we examined cocaine-primed reinstatement of drug seeking after cocaine self-administration was stopped. Reinstatement was prevented by stimulating cystine/glutamate exchange with N-acetylcysteine and restoring extracellular glutamate. Thus, withdrawal from repeated cocaine increases susceptibility to relapse in part by reducing cystine/glutamate exchange, and restoring exchanger activity prevents cocaine-primed drug seeking.
Baker
David A
DA
Department of Physiology and Neuroscience, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
McFarland
Krista
K
Lake
Russell W
RW
Shen
Hui
H
Tang
Xing-Chun
XC
Toda
Shigenobu
S
Kalivas
Peter W
PW
D000111:Acetylcysteine / Q000494:pharmacology; D000222:Adaptation, Physiological / Q000502:physiology*; D000704:Analysis of Variance; D000818:Animals; D003042:Cocaine / Q000008:administration & dosage; D019970:Cocaine-Related Disorders / Q000378:metabolism / Q000503:physiopathology*; D003216:Conditioning, Operant / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D003553:Cystine / Q000008:administration & dosage / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005100:Expectorants / Q000494:pharmacology; D005108:Extinction, Psychological / Q000187:drug effects; D005110:Extracellular Space / Q000737:chemistry / Q000378:metabolism; D018698:Glutamic Acid / Q000008:administration & dosage / Q000378:metabolism*; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012008:Recurrence; D012054:Reinforcement, Psychology; D012646:Self Administration; D013375:Substance Withdrawal Syndrome; D013997:Time Factors
D005100:Expectorants; D018698:Glutamic Acid; D003553:Cystine; D003042:Cocaine; D000111:Acetylcysteine