The perisynaptic Group I mGluRs and Homer scaffolding proteins are also highly implicated in synaptic plasticity relevant for addiction disorders. Constitutively active C-terminal coiled-coil long isoforms of Homer (Homer 1–3) form complexes with Group I mGluRs (13) and regulate their downstream signaling, synaptic activity and surface clustering (3, 14, 15). Homer is also tightly linked to the NMDA receptor complex via interactions with a trimeric Shank–GKAP–PSD-95 complex (16–18), thereby providing a possibility to regulate NMDA receptor activity (19). A large body of evidence supports the role of Homer proteins in addiction disorders (20). For example, Homer1 and Homer2 knockout mice exhibit enhanced cocaine-induced place conditioning and cocaine-induced locomotor activity (21). Furthermore, over-expression of long Homer isoforms in the nucleus accumbens abolish cocaine-induced sensitization of locomotor hyperactivity and prevents development of glutamate abnormalities normally elicited by cocaine (22).
