Acquisition‐Recruited and MOR‐Expressing Striatal dMSNs Differentially Regulate Extinction and Cue‐Induced Relapse of Alcohol Seeking

Relapse to alcohol use is frequently triggered by re-exposure to alcohol-associated cues, and extinction-based interventions can reduce this vulnerability. However, the striatal cellular mechanisms through which extinction alters later alcohol seeking remain unclear. Using a mouse model of operant alcohol self-administration, we examined two distinct direct-pathway medium spiny neuron (dMSN) populations in the dorsomedial striatum. Extinction reduced cue-induced alcohol seeking and decreased the probability that acquisition-recruited dMSNs were reactivated during relapse testing. Chemogenetically maintaining activity in acquisition-recruited dMSNs during extinction slowed the reduction in alcohol-seeking and enhanced subsequent relapse. In contrast, increasing activity in μ-opioid receptor (MOR)-expressing dMSNs, a striosome-enriched population, accelerated the reduction in responding and decreased later relapse without altering inactive-lever responding or locomotor activity. These findings indicate that extinction is associated with reduced re-engagement of acquisition-related dMSN ensembles, whereas enhancing activity in a MOR-defined, striosome-enriched output population can facilitate extinction-related behavioural change. Together, the results identify two complementary striatal processes that regulate alcohol extinction and relapse.