As mentioned above drug-evoked synaptic plasticity at this synapse persists for about a week after a single injection. Beyond this time, the receptor redistribution is reversed and the initial state of the synapse restored (Fig. 2). Several lines of evidence implicate metabotropic mGluR1 receptors in this reversal. In fact, pharmacological or synaptic activation of mGluR1 in slices from cocaine treated mice quickly removes GluA2-lacking AMPARs and replaces them by GluA2 containing ones, leading to an overall depression of synaptic transmission (Bellone and Lüscher, 2006; Bellone and Lüscher, 2005). Such mGluR-LTD relies on mammalian target of rapamycin (mToR) signaling and rapid synthesis of GluA2 subunits, via local translation from prefabricated mRNA present in dendrites of DA neurons (Mameli et al., 2007). Moreover interfering with mGluR1 function in vivo by introducing a TAT conjugated dominant negative peptide that disrupts mGluR1-Homer interaction selectively in the VTA significantly prolongs the persistence of cocaine-evoked plasticity (Mameli et al., 2009). Taken together, these results suggest that mGluR1 triggers an endogenous defense mechanism that ensures the removal of calcium permeable AMPARs, which were inserted in response to
