Abstract
D1-type receptor (D1R)-mediated dopaminergic signaling within the nucleus accumbens shell (NAcSh) is essential for forming adaptive circuit changes that embed persistent memories associated with drug seeking and craving. While D1R is expressed in both NAcSh neurons and astrocytes, the specific contribution of astrocytic D1R to drug-related circuit plasticity remains poorly understood. Here, we demonstrated in mouse NAcSh slices that D1R agonists increased astrocytic Ca2+ activity, an effect that was attenuated by astrocyte-specific D1R knockdown. Furthermore, selective knockdown of astrocytic D1R in the NAcSh prior to cocaine self-administration inhibited cocaine-induced generation of silent synapses, thereby hampering the associated remodeling of NAcSh circuits. Behaviorally, knockdown of NAcSh astrocytic D1R expedited the extinction of cocaine seeking and reduced cue-induced reinstatement. These results identified astrocytic D1R as a fundamental component of NAcSh dopamine signaling during cocaine experience that remodeled synaptic connections and neural networks underlying drug seeking and relapse.
Authors
Shi Yan, Qize Li, Yao Wang, Wanqiu Chen, Zhong Chen, Alexander K. Zinsmaier, Paloma R. Huguet, Zhengsong Lu, Xiguang Qi, Zheng Xu, Yi Han, Gouri Sharma, Charles Wang, Eric J. Nestler, Oliver M. Schlüter, Yan Dong
Full Text PDF
Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)