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 x(c)(-,) 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 x(c)(-). First, we examined whether the cysteine prodrug N-acetylcysteine attenuates cocaine-primed reinstatement by targeting system x(c)(-). Rats were trained to self-administer cocaine (1 mg/kg/200 mu l, 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 x(c)(-) inhibitor (S)-4-carboxyphenylglycine (CPG; 0.5 mu M; 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 x(c)(-) 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 mu l, i.v.; 6 h/day) since this procedure has previously been shown to prevent reduced activity of system x(c)(-). On the reinstatement test day, we then acutely impaired system x(c)(-) in some of the rats by infusing CPG (0.5 mu M) 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 x(c)(-) in the nucleus accumbens as a key mechanism contributing to cocaine-primed reinstatement. (C) 2008 IBRO. Published by Elsevier Ltd. All rights reserved.