Glutamatergic signal transduction is mediated by glutamate receptors (GluRs), such as ionotropic α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), N-methyl-D-aspartic acid, (NMDA) and metabotropic glutamate receptors (mGluR), that are specifically targeted and clustered at the post-synaptic membrane by various scaffolding and adaptor proteins (3). Post-synaptic density protein 95 (PSD-95) is a prominent scaffolding protein in the PSD that complexes with NMDA and AMPA [via stargazin (TARP)] receptors (4). In addition to being required for AMPA and NMDA receptor stabilization, signaling, activity and trafficking (5–9), PSD-95 is also required for the control of AMPA glutamate receptor subunit (GluA)1 incorporation during experience-driven synaptic plasticity (6), which is crucial for drug-induced strengthening of excitatory synapses (10). Several studies evaluating gene deletion or transgenic mouse models support the notion of AMPA, NMDA receptors and PSD-95 as important contributors to glutamate plasticity and the development and persistence of addiction (11, 12).
