Environmental Enrichment Attenuates Fentanyl-Seeking Behavior and Protects against Stress-Induced Reinstatement in Both Male and Female Rats.

Environmental enrichment (EE) reduces vulnerability to multiple drugs of abuse, yet its impact on fentanyl use and relapse-like behavior remains unclear. Here, we tested whether long-term, nonsocial, object-based EE alters fentanyl self-administration, extinction, and stress-induced reinstatement in male and female rats. Rats were individually housed in either standard nonenriched (NE) conditions or in EE cages containing a rotating set of novel objects beginning at least 3 d prior to self-administration. EE did not impact acquisition of fentanyl self-administration but reduced fentanyl intake during maintenance of self-administration and reduced the persistence of drug-seeking in extinction. Following extinction, yohimbine robustly reinstated drug-seeking behavior in NE rats but reinstatement in EE rats was markedly attenuated, indicating reduced sensitivity to stress-induced relapse triggers. Circulating corticosterone levels were lower in EE rats across the experiment and were positively correlated with reinstatement responding, suggesting that enrichment's protective effects may be mediated in part by reduced hypothalamic-pituitary-adrenal (HPA) axis activation. These findings demonstrate that object-based EE, even in the absence of social enrichment, is sufficient to blunt fentanyl use, facilitate extinction, and constrain stress-induced reinstatement. The results highlight the role of environmental context and stress regulation in fentanyl vulnerability and suggest that enrichment-inspired, nonsocial interventions may offer a scalable strategy to reduce opioid use and relapse risk.