Repetitive cocaine exposure induces the generation of silent synapses in the nucleus accumbens, characterized by the presence of NMDA receptors and absence of AMPA receptors, hindering fast synaptic transmission (Huang et al, 2009). While typically abundant during early postnatal development, cocaine triggers the de novo generation of silent synapses in the adult brain, thereby establishing new synaptic connections within an already refined circuit (Huang et al, 2009; Huang et al, 2015). During withdrawal, some silent synapses undergo unsilencing by incorporating AMPARs, which crucially contribute to drug-associated behaviors (Conrad et al, 2008). In this study, utilizing the conditioned place preference (CPP) assay, we explored the involvement of silent synapses in drug-associated memories in PSD-95 KO mice, which exhibit impaired silent synapse maturation and lifelong abundance of such synapses. Contrary to wild-type mice, PSD-95 KO mice failed to express CPP following long-term cocaine withdrawal, similar to previous reports in contextual fear conditioning or alcohol-CPP, indicative of impaired long-term retention (Camp et al, 2011; Fitzgerald et al, 2014). However, we could restore long-term CPP in PSD-95 KO mice upon exposure to an additional cue, suggesting that the absence of PSD-95 primarily affects memory retrieval, and not retention, as the memory trace per se was left unaffected. This study unveils a silent synapse-based mechanism for modulating drug-associated memory retrieval, with implications for potential therapeutic interventions in addiction treatment through targeted molecular strategies. Further elucidation of molecular pathways will allow us to put forward precise therapeutic targets, offering avenues to combat drug addiction.