, 2006). Likewise, the D2-like receptor agonist quinpirole did not significantly affect NMDA receptor EPSCs in L2/3 PFC pyramidal neurons (Gonzalez-Islas and Hablitz, 2003). By contrast, selective pharmacological activation of D4

receptors suppresses synaptically evoked NMDA receptor EPSCs in cortex through PKA-dependent NMDA receptor internalization (Wang et al., 2003). Thus, DA has the capacity to bidirectionally modulate synaptic NMDA receptors through D1- and D2-class receptors, but the susceptibility of individual synapses across brain areas and the intracellular pathways recruited vary greatly. As for NMDA receptors, there is a large body of evidence showing that DA bidirectionally modulates the function and membrane

trafficking of AMPA receptors. Biochemical studies have demonstrated that D1 receptor agonists and D2 receptor antagonists promote PKA-dependent phosphorylation of AMPA receptors, whereas PARP cancer D2 receptor agonists diminish it by favoring PP1 activity (Håkansson et al., 2006; Snyder et al., 2000). PKA phosphorylation increases AMPA receptor peak open probability and extrasynaptic membrane expression (Shepherd and Huganir, Rapamycin 2007). Consistent with this, D1 receptors acting through PKA increase surface AMPA receptors in neuronal cultures prepared from nucleus accumbens (Sun et al., 2008) and PFC (Sun et al., 2005), whereas D2 receptor agonists decrease surface AMPA receptor levels (Sun et al., 2005). Moreover, membrane currents and potentials evoked by local application of AMPA receptor agonists in striatal and cortical neurons are

depressed by D2 receptor stimulation (André et al., 2010; Hernández-Echeagaray et al., 2004; Levine et al., 1996a) and are either unaffected (Calabresi et al., 1995; Seamans et al., 2001a; Zheng et al., 1999) or potentiated (André et al., 2010; Levine et al., L-NAME HCl 1996a; Lin et al., 2003; Yan et al., 1999) by D1 receptor agonists. Importantly, DA receptor signaling is not sufficient to recruit AMPA receptors to postsynaptic terminals (Sun et al., 2005, 2008), probably because AMPA receptor surface expression and synaptic targeting by lateral diffusion constitute two independent and separately regulated trafficking steps (Shepherd and Huganir, 2007). Thus, modifications of AMPA receptor surface expression at extrasynaptic membranes by DA may not necessarily extend to synaptic sites. Indeed, very few studies have reported increased or decreased postsynaptic AMPA receptor currents in response stimulation of D1- or D2-class receptors, respectively (Gonzalez-Islas and Hablitz, 2003; Levine et al., 1996b). In most cases, postsynaptic AMPA receptor function was unaltered by DA or D1 receptor agonists in PFC (Gao et al., 2001; Gao and Goldman-Rakic, 2003; Seamans et al., 2001a; Zhou and Hablitz, 1999) and striatum (Bracci et al., 2002; Levine et al., 1996b; Nicola and Malenka, 1997, 1998).