The cocaine-driven subunit switch of NMDAR subunits mimics observations made during development (Williams et al., 1993, Sheng et al., 1994 and Sanchez

et al., 2010). During the first postnatal week, GluN2B-containing NMDARs are replaced by GluN2A-containing ones in most glutamatergic synapses, including excitatory synapses onto VTA DA neurons (Sheng et al., 1994, Sans et al., 2000 and Bellone and Nicoll, 2007). This postnatal subunit switch is activity dependent, regulates AMPAR expression, and depends on the activation of group I mGluRs both in the hippocampus and in the VTA (Bellone et al., 2011, Matta et al., 2011 and Gray et al., 2011). The GluN3A subunit also has a developmental distribution profile (Wong et al., 2002 and Henson find more et al., 2010). Because of its expression profile, GluN3A may represent a molecular break for synaptic maturation (Roberts et al., 2009). In agreement with this idea, GluN3A overexpression decreases spine density and attenuates LTP induction at Trametinib price CA1 hippocampal synapses (Roberts et al., 2009). Moreover, deletion of GluN3A accelerates the expression of markers

of synaptic maturation (Henson et al., 2012). Faster synaptic maturation could result from the loss of GluN1/GluN2B/GluN3A heterotrimers and the insertion of GluN2A-containing NMDARs. This scenario is further supported by the observation that, in the VTA, neonatal synapses onto DA neurons are characterized by Ca2+-impermeable NMDARs with high ifenprodil sensitivity and slow decay time kinetics (Bellone et al., 2011). We therefore favor a scenario where at

neonatal synapses after the birth, NMDAR synaptic transmission is mediated by GluN3A- and GluN2B-containing subunits that are replaced by GluN2A-containing ones within the third postnatal week. At juvenile and adult synapses, a single cocaine injection triggers receptor redistribution with the reappearance of subunits typically present in immature synapses. Such observations lead us to propose that addictive drugs may reopen a critical period of synapse development (Bellone and Lüscher, 2012). The role of mGluR1s in orchestrating both AMPARs and NMDARs is of particular interest. We have previously shown that mGluR1 drives the postnatal maturation of AMPARs and NMDARs (Bellone et al., 2011). In the present study we show that mGluR1 activation restores below baseline transmission after cocaine exposure. mGluR1-mediated restoration of baseline transmission is not limited to NMDARs in the VTA, but may also provide an efficient mechanism to reverse cocaine-evoked plasticity in other brain structures within the mesocorticolimbic system (Mameli et al., 2007, Mameli et al., 2009, McCutcheon et al., 2011 and Loweth et al., 2013). Collectively, these data point to mGluR1 as an important modulator of the synaptic transmission and a potential target for drug development (Loweth et al., 2013). In the present study, we have explored the signaling pathway recruited following mGluR1 stimulation.