, 2008 and Harnett et al., 2009). mGluRs-I are localized perisynaptically but can modulate transmission of AMPARs and NMDARs (Bellone et al., 2008, Lüscher and Huber, 2010, Bellone et al., 2011 and Matta et al., 2011). Cocaine exposure profoundly changes AMPAR transmission at excitatory synapses onto DA neurons in the VTA. The induction of cocaine-evoked synaptic plasticity of AMPAR transmission depends on the concomitant activation of D1Rs (Brown et al., 2010) and NMDARs (Ungless et al., 2001 and Engblom et al., 2008). Its expression I BET151 relies on an exchange of GluA2-containing for

GluA2-lacking, Ca2+-permeable AMPARs (CP-AMPARs). Since CP-AMPARs have a higher single-channel conductance, AMPA transmission

at resting membrane potentials is potentiated following a single cocaine injection. One week after a single exposure to cocaine, the drug-evoked plasticity of AMPAR transmission returns to baseline and the mechanisms of this reversal phenomenon Selleck JQ1 have been characterized (Bellone and Lüscher, 2006 and Mameli et al., 2007). The recovery of baseline transmission is driven by mGluR1, manifests as a form of long-term depression (LTD), and involves an exchange of CP-AMPARs for Ca2+-impermeable AMPARs (CI-AMPARs, Bellone and Lüscher, 2006). This exchange requires fast and local protein synthesis (Mameli et al., 2007), and reversal of cocaine-evoked synaptic plasticity in the VTA has relevance within the context of drug-seeking behavior (Mameli et al., 2009). Interestingly, recent evidence suggests that 24 hr after a single cocaine exposure in vivo, the amplitude of unitary NMDAR-EPSC is reduced (Mameli et al., 2011). This indicates that the increased AMPA/NMDA ratio observed ex vivo in many studies (Ungless et al., 2001 and Bellone and Lüscher, 2006) results

from a larger AMPAR-mediated component along with a reduced amplitude of NMDAR-mediated component (Mameli et al., 2011). While drug-evoked changes in AMPAR-mediated transmission at excitatory Astemizole synapses of VTA DA neurons have been extensively studied, little is known about mechanisms that underlie the expression and reversal of plasticity of NMDAR transmission. NMDARs are heterotetrameric receptors typically containing two GluN1 subunits together with a combination of two GluN2 (A-D) or one GluN2 and one GluN3 (A, B) subunit (Traynelis et al., 2010). Thus, multiple NMDAR subtypes can exist and accumulating evidence indicates that subunit composition determines the receptor’s biophysical and pharmacological properties, the quality of synaptic transmission, and the rules for plasticity (Paoletti et al., 2013). Among the GluN2 subunit family, GluN2A and GluN2B subunits are the most abundant in the forebrain.