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

Long-term plasticity resulting in altered excitatory neurotransmission within corticostriatal pathways has been implicated in addiction. Human cocaine abusers exposed to craving-inducing 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 rats engaged in cocaine seeking (Neisewander et al., 2000) and that transient inactivation of the prefrontal cortex or nucleus accumbens core blocks cocaine-primed reinstatement in rats (McFarland and Kalivas, 2001). Inhibition of excitatory neurotransmission in the nucleus accumbens by preventing activation of corticostriatal pathways, stimulating group II metabotropic glutamate autoreceptors, or blocking AMPA receptors also blocks cocaine-primed reinstatement in rats (Cornish and Kalivas, 2000; Park et al., 2002; Baker et al., 2003; McFarland et al., 2003; Schmidt et al., 2005; Peters and Kalivas, 2006). These data indicate that regulation of synaptic glutamate represents a novel approach in the treatment of cocaine addiction (Volkow and Fowler, 2000; Dackis, 2004). System xc- may be a key mechanism underlying cocaine-induced changes in glutamate signaling within corticostriatal pathways that contribute to pathological cocaine seeking. First, cystine-glutamate exchange via system xc- supplies nonvesicular glutamate in the extrasynaptic compartment that stimulates extrasynaptic group II metabotropic glutamate receptors (mGluR) in the nucleus accumbens and prefrontal cortex (Baker et al., 2002; Xi et al., 2002a; Moran et al., 2005). This is important because stimulation of group II mGluRs inhibits synaptic release of glutamate (Baskys and Malenka, 1991; Cochilla and Alford, 1998; Schoepp, 2001; Moran et al., 2005). Repeated cocaine blunts cystine-glutamate exchange (Baker et al., 2003; Madayag et al., 2007) which results in reduced basal glutamate levels in the nucleus accumbens (Pierce et al., 1996; Reid and Berger, 1996; Baker et al., 2003), and reduced autoregulation of synaptic glutamate by group II mGluRs (Xi et al., 2002b). Likely as a result, a cocaine challenge increases synaptic release of glutamate in cocaine-withdrawn rats (Pierce et al., 1996; Reid and Berger, 1996; Baker et al., 2003) that occurs as a result of activation of corticostriatal pathways (McFarland et al., 2003). Preclinical studies have shown N-acetylcysteine to be effective in blocking compulsive drug-seeking in rodents (Baker et al., 2003; Madayag et al., 2007; Zhou and Kalivas, 2007) and data from open-label trials have shown reduced cocaine use and craving in human cocaine abusers (Larowe et al., 2006; Mardikian et al., 2007). Although the effects of N-acetylcysteine were attributed to increased cystine-glutamate exchange by system xc-, data indicate that N-acetylcysteine may alter glutamate signaling through cellular mechanisms distinct from system xc-. Specifically, N-acetylcysteine or cysteine resulting from deacetylation of N-acetylcysteine has been shown to influence the activity of sodium-dependent glutamate transporters and glutamate receptors including NMDA and AMPA receptors (Janaky et al., 2000; Aoyama et al., 2006; Chase et al., 2007). As a result, the mechanism underlying the effects of N-acetylcysteine needs to be identified. The present study examines the therapeutic potential of targeting system xc- to reduce drug-seeking behavior. First, we examined whether the cysteine prodrug N-acetylcysteine attenuates cocaine-primed reinstatement by targeting system xc-. To do this, we examined the capacity of N-acetylcysteine to block cocaine-primed reinstatement in the presence or absence of the system xc- inhibitor (S)-4-carboxyphenylglycine (Ye et al., 1999; Patel et al., 2004) (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 xc- 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, IV; 6 hr/day). This procedure has previously been shown to prevent reduced activity of system xc- and cocaine-primed reinstatement (Madayag et al., 2007).