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

Authors

Xueyi Xie, Xuehua Wang, Jun Wang

Published in

Addiction biology. Volume 31. Issue 9. Pages e70191.

Abstract

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.

PMID:
42732882
Bibliographic data and abstract were imported from PubMed on 14 Sep 2026.

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