In line with this prediction, the typical NMDAR-dependent LTP of AMPARs is also absent after cocaine (Argilli et al., 2008, Luu and Malenka, 2008 and Mameli et al., 2011), probably due to a change in NMDARs that are no longer able to induce plasticity. The observation that targeted deletion of GluN3A abolished the cocaine-driven NMDA subunit redistribution indicates that GluN3A is necessary for the expression of cocaine-evoked plasticity of both AMPAR- and NMDAR-mediated

transmission. A critical step will be to understand the role for GluN3 in behavioral changes triggered by cocaine experience. Previous studies have explored the link between cocaine-evoked plasticity and addiction-relevant behaviors Paclitaxel solubility dmso (Engblom et al., 2008 and Mameli et al., 2009). Notably, deletion of the GluN1 subunit specifically in dopamine neurons, using a NR1 floxed x DAT cre mouse line, was found to impair reinstatement of cocaine seeking in both conditioned place BYL719 in vivo preference and drug self-administration paradigms (Engblom et al., 2008, Zweifel et al., 2008 and Mameli et al., 2009). In light of our findings, one possibility is that impaired reinstatement was due in part to a loss of GluN3-containing NMDAR subunits in VTA neurons. Although we saw no differences in both behavioral sensitization to cocaine and CPP using an ShRNA approach, we might predict that GluN3A plays an important role in the ability of cocaine-associated

stimuli to trigger relapse to drug seeking. The tight coupling of NMDAR and AMPAR redistribution also raises the possibility that at other synapses, where GluA2-lacking AMPARs have been observed, the NMDA transmission may be affected. For example, CP-AMPARs are present at excitatory synapses

onto interneurons in the cortex and hippocampus (Liu and Zukin, 2007). In these cells, an anti-Hebbian form of LTP that is induced by Ca2+ entering the cells through AMPARs can be observed (Lamsa et al., 2007). Whether Ca2+-impermeable NMDAR are also present at these synapses has not been investigated. As described above, both CP-AMPARs and GluN3A-containing NMDARs are present at many synapses during the early postnatal development (Ho et al., 2007, Henson et al., 2010 and Bellone et al., 2011) and may be permissive for circuit formation in Urease the developing brain and for activity-dependent changes in the mature brain. Regardless of the identity of the molecular linker, the subunit switch for NMDARs and AMPARs represents a form of metaplasticity. Rather than encoding specific events, cocaine sets the rules for subsequent activity-dependent synaptic plasticity (Mameli et al., 2011). After cocaine, NMDAR activation no longer induces LTP (because of the insignificant Ca2+ permeability), which, however, can be rescued when hyperpolarizing the cell during the induction protocol (thus favoring Ca2+ entry via GluA2-lacking inwardly rectifiying AMPARs).