A growing body of literature has focused on the role of AMPA, NMDA and kainate receptor-mediated glutamatergic transmission into the NAc in the development of addiction and addictive-like behaviors (Kalivas et al., 2009). Increased glutamate receptor mRNA expression parallels increases in cell surface expression of GluR1-containing AMPA receptors following cocaine withdrawal (Boudreau et al., 2007), along with a specific population of GluR2-lacking calcium-permeable AMPA receptors (Wolf, 2010). We saw sustained up-regulation of Gria1 (GluR1) transcripts, a transient increase in Gria4 (GluR4) transcripts, and no change in Gria2 (GluR2) transcripts. While expression of kainate receptor 3 (Grik3) rose substantially, expression of Grik4 and Grik5 fell. NMDA receptors are critical for the behavioral response to drugs of abuse (Lee et al., 2010; Pascoli et al., 2011); new spines appearing in the NAc following cocaine are enriched in NMDA receptors and are not formed if NMDA receptor currents are blocked (Huang et al., 2009; Ren et al., 2010). Correspondingly, transcripts encoding several NMDA receptor subunits rose in response to cocaine. Expression of the more prevalent metabotropic glutamate receptors also increased. Perhaps the most significant finding is that expression of Slc17a7 and Slc17a6 (Vglut1 and Vglut2) exhibited sustained down-regulation after cocaine treatment and withdrawal.
