Belujon, P.; Lardeux, V.; Dugast, E.; Serriere, S.; Busson, J.; Bodard, S.; Tauber, C.; Galineau, L.; Solinas, M.

Background: Environmental enrichment (EE) is a promising strategy to promote recovery from addiction, but its neurobiological mechanisms remain poorly understood. This study investigates how exposure to EE during abstinence dynamically affects brain neuroadaptations induced by voluntary intake of cocaine. Methods: Using longitudinal 18FDG microPET imaging, we examined brain metabolic activity in rats following extended access cocaine self-administration. After establishing escalation of cocaine intake, rats were housed in either enriched or standard environments during a four-week abstinence period. Brain metabolic activity was assessed after one and four weeks of abstinence. Results: Cocaine self-administration produced widespread decreases in cortical metabolic activity, particularly in regions involved in executive function (orbitofrontal cortex, anterior cingulate) and interoception (insula), while increasing activity in emotional and motivational circuits (nucleus accumbens, amygdala, mesencephalon). EE selectively normalized these alterations through temporally distinct mechanisms: rapidly restoring nucleus accumbens and amygdala function while gradually affecting prefrontal cortical activity. After four weeks, rats housed in enriched environments showed significantly normalized metabolic activity in the orbitofrontal cortex and dorsolateral striatum compared to those in standard housing, with persistent changes in anterior cingulate cortex and ventral posterior hippocampus. Conclusions: Our findings reveal circuit-specific and temporally distinct effects of environmental enrichment on cocaine-induced brain alterations. These insights could inform the development of more targeted therapeutic approaches for addiction recovery.