A confusing aspect of the results summarized thus far is that an extensive body of evidence suggests that activation, not inhibition, of NAc MSNs by prefrontal cortical afferents is important for the reinstatement of drug seeking (Knackstedt and Kalivas, 2009). Indeed, surface levels of AMPARs in the NAc are increased for several weeks during withdrawal following repeated non-contingent cocaine administration (Boudreau et al., 2007; Boudreau and Wolf, 2005) and the AMPAR/NMDAR ratio recorded from NAc shell MSNs was increased 10–14 days following 5 days of repetitive cocaine administration (Kourrich et al., 2007). Importantly, in all these studies, a challenge dose of cocaine was not administered 24 hours before the electrophysiological recordings. A day after a challenge dose of cocaine terminating a protracted withdrawal period both the surface levels of AMPARs and the AMPAR/NMDAR ratio in NAc MSNs are decreased (Boudreau et al., 2007; Kourrich et al., 2007; Wolf and Ferrario, 2010; Bachtell and Self, 2008). Within a week the surface levels of AMPARs recovered and eventually stabilized at an enhanced level.
