Blunted cystine-glutamate antiporter function in the nucleus accumbens promotes cocaine-induced drug seeking.
Repeated cocaine alters glutamate neurotransmission, in part, by reducing cystine-glutamate exchange via system xc-, which maintains glutamate levels and receptor stimulation in the extrasynaptic compartment. In the present study, we undertook two approaches to determine the significance of plasticity involving system xc-. First, we examined whether the cysteine prodrug N-acetylcysteine attenuates cocaine-primed reinstatement by targeting system xc-. Rats were trained to self-administer cocaine (1 mg/kg/200 microl, i.v.) under extended access conditions (6 h/day). After extinction training, cocaine (10 mg/kg, i.p.) primed reinstatement was assessed in rats pretreated with N-acetylcysteine (0-60 mg/kg, i.p.) in the presence or absence of the system xc- inhibitor (S)-4-carboxyphenylglycine (CPG; 0.5 microM; infused into the nucleus accumbens). N-acetylcysteine attenuated cocaine-primed reinstatement, and this effect was reversed by co-administration of CPG. Secondly, we examined whether reduced system xc- activity is necessary for cocaine-primed reinstatement. To do this, we administered N-acetylcysteine (0 or 90 mg/kg, i.p.) prior to 12 daily self-administration sessions (1 mg/kg/200 microl, i.v.; 6 h/day) since this procedure has previously been shown to prevent reduced activity of system xc-. On the reinstatement test day, we then acutely impaired system xc- in some of the rats by infusing CPG (0.5 microM) into the nucleus accumbens. Rats that had received N-acetylcysteine prior to daily self-administration sessions exhibited diminished cocaine-primed reinstatement; this effect was reversed by infusing the cystine-glutamate exchange inhibitor CPG into the nucleus accumbens. Collectively these data establish system xc- in the nucleus accumbens as a key mechanism contributing to cocaine-primed reinstatement.
Kau
K S
KS
Department of Biomedical Sciences, Marquette University, Suite 426, 561 North 15th Street, Milwaukee, WI 53233, USA.
Madayag
A
A
Mantsch
J R
JR
Grier
M D
MD
Abdulhameed
O
O
Baker
D A
DA
D000818:Animals; D017920:Antiporters / Q000378:metabolism*; D001522:Behavior, Animal / Q000187:drug effects; D003042:Cocaine / Q000494:pharmacology; D019970:Cocaine-Related Disorders / Q000378:metabolism* / Q000503:physiopathology; D003553:Cystine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D005108:Extinction, Psychological / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012646:Self Administration; D013569:Synapses / Q000378:metabolism
D017920:Antiporters; D018765:Dopamine Uptake Inhibitors; D018698:Glutamic Acid; D003553:Cystine; D003042:Cocaine; C030905:N-monoacetylcystine