Contextual unfamiliarity during drug intake induces AMPA receptors linked to relapse vulnerability

Relapse to drug use, even after years of successful rehabilitation, remains a challenge in treating substance use disorders. Drug-associated cues, stress, or the drug itself can trigger episodes of relapse. In rodent models of drug use disorders, cue-drug memories are enhanced through the expression of Ca ²⁺ -permeable AMPA receptors (CP-AMPARs) in nucleus accumbens (NAc) medium spiny neurons, emerging after prolonged withdrawal from some forms of drug-conditioned training. Inhibition or removal of these receptors dampens drug-seeking behavior. However, the specific contextual conditions that govern CP-AMPAR expression are unclear. To examine how environmental features influence drug memories, we compared three contextual settings in mice – the conditioned place preference (CPP), open-field (OF), and home-cage (HC) – using the synthetic opioid fentanyl as a model drug. Contrary to the HC condition, where CP-AMPARs were absent, synaptic CP-AMPAR expression was observed in the NAc shell of the CPP and OF groups, both of which involved immediate exposure to an unfamiliar context following drug administration. Moreover, the CPP and OF groups produced comparable increases in CP-AMPAR levels, and CPP mice presented heightened fentanyl-seeking behavior. These findings suggest that contextual unfamiliarity drove synaptic CP-AMPAR expression after drug conditioning, establishing neural substrates that mediate relapse vulnerability. The habituation or avoidance of contextual novelties during medical treatments with opioids may therefore represent a candidate therapeutic approach to reduce relapse risk by limiting the engagement of these critical cellular mechanisms.