Drug addiction is an acquired behavioral state that develops progressively through repeated drug experience and is characterized by maladaptive and compulsive behavior associated with drug seeking and taking. Cravings and subsequent drug seeking are often precipitated by the reactivation of memories associated with drug use, which are formed between various external stimuli, or cues, and the rewarding and pleasurable experience of taking the drug. As such, drug addiction is often conceptualized as a pathological form of memory that drives maladaptive behavior. This has spurred intensive investigation into the neural substrates underlying drug-associated memories, with the ultimate goal of targeting these substrates to disrupt drug seeking behaviors. To explore the synaptic underpinnings of cocaine-associated memories, we studied AMPA receptor (AMPAR)-silent excitatory synapses, which are generated in the nucleus accumbens (NAc) by cocaine experience. These synapses functionally mature during withdrawal through the recruitment of AMPARs and contribute to subsequent cocaine seeking behavior, indicating these synapses contribute to the encoding of cocaine-associated memories and behaviors. In this dissertation, we have further investigated the role of cocaine-generated silent synapses in the encoding of cocaine-associated memories by examining their role in regulating the natural dynamics of cocaine-associated memories. Our results demonstrate that dynamic changes in the functional state of cocaine-generated synapses contributes to the natural destabilization and reconsolidation of cocaine-associated memories following memory retrieval, and that disrupting these synaptic dynamics impairs subsequent cocaine seeking behaviors. In addition, we also demonstrate that cocaine-generated synapses contribute to the recruitment and activation of neurons within the NAc associated with cocaine seeking behavior during withdrawal, suggesting they may contribute to the encoding of cocaine-associated memories at the circuit level. Collectively, these findings provide further support to the hypothesis that cocaine-generated synapses serve as discrete synaptic substrates underlying aspects of cocaine-associated memories and behaviors
