We report a signaling pathway that dynamically regulates the coupling of group 1 metabotropic receptor mGluR5 with the NMDA receptor channel, and demonstrate its contribution to cocaine-induced plasticity. Two coordinate events are required; dynamic phosphorylation of the Homer binding site in the C-terminus of mGluR5, and induction of the immediate early gene Homer 1a. Phosphorylation of mGluR5 is required for binding of the prolyl isomerase, Pin1. Homer 1a is also required as it competes with cross-linking forms of Homer, thereby enhancing Pin1 binding to mGluR5. Once bound, Pin1 accelerates the isomerization of the pS-P bond within the Homer binding site of mGluR5, and this is necessary to potentiate an mGluR5 activated slow inward current mediated by NMDA receptors. In mouse genetic models that either prevent phosphorylation of mGluR5, prevent the induction Homer 1a or reduce Pin1 expression, cocaine fails to induce normal motor sensitization. The mGluR5-Pin1 mechanism requires coordinated events at disparate locations, the synapse and the nucleus, and thereby serves as a robust molecular switch to link effects of neuromodulators and growth factors with use-dependent neuronal plasticity.