Renewal and reacquisition of substance-associated relapse

Renewal and reacquisition (R/R) of drug-seeking behaviors are key drivers of relapse in substance use disorders (SUDs). These processes emerge from interactions among learning, memory, and reward-related neural circuits that are engaged when individuals encounter drug-associated contexts, cues, stressors, or restored drug availability. Advances in animal models and experimental tools have improved our understanding of the neurobiological mechanisms that cause relapse, including how substance-associated memories are formed and retrieved, how context-dependent renewal happens after extinction or punishment-based interventions, and how substance seeking and taking restarts rapidly when reinforcement is restored. In this review, we synthesize evidence on behavioral, circuit-level and molecular processes that contribute to R/R across substances, highlighting translational and clinical parallels, and identifying mechanistic gaps that constrain intervention development. We conclude by outlining mechanism-informed strategies that integrate behavioral, pharmacological, and genetic interventions to strengthen the generalization (transference) and durability of extinction learning and memory updating, to reduce relapse vulnerability, particularly driven by R/R.