Blunted cystine–glutamate antiporter function in the nucleus accumbens promotes cocaine-induced drug seeking

Abstract

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 Nacetylcysteine attenuates cocaine-primed reinstatement by targeting system x c -. Rats were trained to self-administer cocaine (1 mg/kg/200 µl, IV) under extended access conditions (6 hr/day). After extinction training, cocaine (10 mg/kg, IP) primed reinstatement was assessed in rats pretreated with N-acetylcysteine (0-60 mg/kg, IP) in the presence or absence of the system x c -inhibitor (S)-4-carboxyphenylglycine (CPG; 0.5 µM; 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, IP) prior to twelve daily self-administration sessions (1 mg/kg/200 µl, IV; 6 hr/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 µM) 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. Keywords extrasynaptic; nonvesicular; glutamate; microdialysis; cystine-glutamate antiporter; reinstatement Long-term plasticity resulting in altered excitatory neurotransmission within corticostriatal pathways has been implicated in addiction. Human cocaine abusers exposed to cravinginducing stimuli exhibit increased activation of excitatory circuits originating in cortical regions, including orbital or prefrontal cortex, and projecting to the ventral striatum (Breiter et al., 1997;Dackis and O'Brien, 2005;Volkow et al., 2005). Preclinical data indicate that an injection of cocaine increases Fos protein expression throughout the corticostriatal pathway in

Reversing cocaine-induced synaptic potentiation provides enduring protection from relapse

“…The reduction in basal extracellular concentrations of glutamate in the NAcore by chronic cocaine use is a marker of disrupted glutamate homeostasis, arising from an enduring reduction in cystine-glutamate exchange (20,21,25). Basal extracellular glutamate concentrations assayed in the NAcore by in vivo microdialysis arise largely from cystine-glutamate exchange rather than from synaptic activity (19).…”

“…Second, although regulating cystine-glutamate exchange in the NAcore modulates reinstated cocaine-seeking (20), it is important to consider that systemically administered N-acetylcysteine will have broader actions that could indirectly influence glutamate homeostasis and synaptic plasticity in the NAcore. For example, basal activity in the prefrontal cortex is blunted in human addicts and in animal models (12,15), and by restoring activity to the prefrontal cortex, N-acetylcysteine could decrease action potential-mediated synaptic glutamate release and elicit homeostatic down-regulation of AMPA receptors (41).…”

“…In this way, chronic cocaine use reduces basal levels of extracellular glutamate, thereby decreasing tone upon perisynaptic metabotropic glutamate receptors (mGluR) known to regulate glutamatergic synaptic transmission (22)(23)(24). Supporting involvement of this adaptation in relapse, administering cystine prodrugs to acutely activate the exchanger inhibits reinstated cocaine-seeking in animal models (20,25,26).Despite the value of acutely administered pharmacotherapies, a drug regimen that induces long-lasting repair of cocaine-induced neuropathologies and enduring protection from relapse would have greater therapeutic utility. Thus, we sought to determine (i) whether chronic treatment with a cystine prodrug causes enduring repair of cocaine-induced neuropathologies in prefrontal-toaccumbens glutamatergic synapses, (ii) how the repair of the extrasynaptic and synaptic neuropathologies are mechanistically linked, and (iii) whether synaptic restoration translates into reduced cocaine-seeking in an animal model of relapse.…”

“…Cystine-glutamate exchange regulates extrasynaptic glutamate levels by providing a 1:1 stoichiometric exchange of extracellular cystine for intracellular glutamate (17)(18)(19), and along with glutamate transport, it is down-regulated following repeated cocaine administration (20,21). In this way, chronic cocaine use reduces basal levels of extracellular glutamate, thereby decreasing tone upon perisynaptic metabotropic glutamate receptors (mGluR) known to regulate glutamatergic synaptic transmission (22)(23)(24).…”

“…In this way, chronic cocaine use reduces basal levels of extracellular glutamate, thereby decreasing tone upon perisynaptic metabotropic glutamate receptors (mGluR) known to regulate glutamatergic synaptic transmission (22)(23)(24). Supporting involvement of this adaptation in relapse, administering cystine prodrugs to acutely activate the exchanger inhibits reinstated cocaine-seeking in animal models (20,25,26).…”