Retrieval-extinction of drug memory requires AMPA receptor trafficking.

Disruption of drug-associated memory reduces relapse. Transient memory retrieval facilitates the upcoming extinction of addiction memory, while the neural basis for this beneficial outcome remains unelucidated. Here, we report that AMPA receptor trafficking acts as the central component for retrieval-extinction-based drug memory intervention. Drug memory retrieval transiently reduces AMPA receptor-mediated synaptic transmission in prefrontal cortical neurons (lasting for 2 to 4 hours) through rapid removal of calcium-permeable AMPA receptors from the synapse, which returned to basal state level after 6 hours. The receptor trafficking is orchestrated by dopamine D1 but not D2 receptor signaling. Blocking AMPA receptor trafficking abolishes retrieval-extinction-mediated addiction memory degradation. These results reveal the molecular mechanism underlying the efficacy of transient memory retrieval on helping to erase addiction memory and support targeting the prefrontal cortex to reduce relapse (e.g., with noninvasive brain stimulation).