Dopamine signaling via astrocytic D1 receptors regulates nucleus accumbens synaptic remodeling and cocaine seeking

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

doi:10.1172/JCI206794

¹Department of Neuroscience, University of Pittsburgh, Pittsburgh, United States of America

²Department of Neuroscience, University of pittburgh, Pittsburgh, United States of America

³Center for Genomics, School of Medicine, Loma Linda University, Loma Linda, United States of America

⁴Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany

⁵Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, United States of America

⁶Center for Genomics, School of Medicine, Loma Linda University, California, United States of America

⁷Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

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¹Department of Neuroscience, University of Pittsburgh, Pittsburgh, United States of America

²Department of Neuroscience, University of pittburgh, Pittsburgh, United States of America

³Center for Genomics, School of Medicine, Loma Linda University, Loma Linda, United States of America

⁴Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany

⁵Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, United States of America

⁶Center for Genomics, School of Medicine, Loma Linda University, California, United States of America

⁷Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

Find articles by Li, Q. in: PubMed | Google Scholar

¹Department of Neuroscience, University of Pittsburgh, Pittsburgh, United States of America

²Department of Neuroscience, University of pittburgh, Pittsburgh, United States of America

³Center for Genomics, School of Medicine, Loma Linda University, Loma Linda, United States of America

⁴Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany

⁵Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, United States of America

⁶Center for Genomics, School of Medicine, Loma Linda University, California, United States of America

⁷Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

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¹Department of Neuroscience, University of Pittsburgh, Pittsburgh, United States of America

²Department of Neuroscience, University of pittburgh, Pittsburgh, United States of America

³Center for Genomics, School of Medicine, Loma Linda University, Loma Linda, United States of America

⁴Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany

⁵Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, United States of America

⁶Center for Genomics, School of Medicine, Loma Linda University, California, United States of America

⁷Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

Find articles by Chen, W. in: PubMed | Google Scholar

¹Department of Neuroscience, University of Pittsburgh, Pittsburgh, United States of America

²Department of Neuroscience, University of pittburgh, Pittsburgh, United States of America

³Center for Genomics, School of Medicine, Loma Linda University, Loma Linda, United States of America

⁴Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany

⁵Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, United States of America

⁶Center for Genomics, School of Medicine, Loma Linda University, California, United States of America

⁷Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

Find articles by Chen, Z. in: PubMed | Google Scholar

¹Department of Neuroscience, University of Pittsburgh, Pittsburgh, United States of America

²Department of Neuroscience, University of pittburgh, Pittsburgh, United States of America

³Center for Genomics, School of Medicine, Loma Linda University, Loma Linda, United States of America

⁴Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany

⁵Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, United States of America

⁶Center for Genomics, School of Medicine, Loma Linda University, California, United States of America

⁷Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

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¹Department of Neuroscience, University of Pittsburgh, Pittsburgh, United States of America

²Department of Neuroscience, University of pittburgh, Pittsburgh, United States of America

³Center for Genomics, School of Medicine, Loma Linda University, Loma Linda, United States of America

⁴Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany

⁵Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, United States of America

⁶Center for Genomics, School of Medicine, Loma Linda University, California, United States of America

⁷Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

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¹Department of Neuroscience, University of Pittsburgh, Pittsburgh, United States of America

²Department of Neuroscience, University of pittburgh, Pittsburgh, United States of America

³Center for Genomics, School of Medicine, Loma Linda University, Loma Linda, United States of America

⁴Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany

⁵Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, United States of America

⁶Center for Genomics, School of Medicine, Loma Linda University, California, United States of America

⁷Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

Find articles by Lu, Z. in: PubMed | Google Scholar

¹Department of Neuroscience, University of Pittsburgh, Pittsburgh, United States of America

²Department of Neuroscience, University of pittburgh, Pittsburgh, United States of America

³Center for Genomics, School of Medicine, Loma Linda University, Loma Linda, United States of America

⁴Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany

⁵Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, United States of America

⁶Center for Genomics, School of Medicine, Loma Linda University, California, United States of America

⁷Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

Find articles by Qi, X. in: PubMed | Google Scholar

¹Department of Neuroscience, University of Pittsburgh, Pittsburgh, United States of America

²Department of Neuroscience, University of pittburgh, Pittsburgh, United States of America

³Center for Genomics, School of Medicine, Loma Linda University, Loma Linda, United States of America

⁴Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany

⁵Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, United States of America

⁶Center for Genomics, School of Medicine, Loma Linda University, California, United States of America

⁷Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

Find articles by Xu, Z. in: PubMed | Google Scholar

¹Department of Neuroscience, University of Pittsburgh, Pittsburgh, United States of America

²Department of Neuroscience, University of pittburgh, Pittsburgh, United States of America

³Center for Genomics, School of Medicine, Loma Linda University, Loma Linda, United States of America

⁴Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany

⁵Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, United States of America

⁶Center for Genomics, School of Medicine, Loma Linda University, California, United States of America

⁷Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

Find articles by Han, Y. in: PubMed | Google Scholar

¹Department of Neuroscience, University of Pittsburgh, Pittsburgh, United States of America

²Department of Neuroscience, University of pittburgh, Pittsburgh, United States of America

³Center for Genomics, School of Medicine, Loma Linda University, Loma Linda, United States of America

⁴Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany

⁵Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, United States of America

⁶Center for Genomics, School of Medicine, Loma Linda University, California, United States of America

⁷Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

Find articles by Sharma, G. in: PubMed | Google Scholar

¹Department of Neuroscience, University of Pittsburgh, Pittsburgh, United States of America

²Department of Neuroscience, University of pittburgh, Pittsburgh, United States of America

³Center for Genomics, School of Medicine, Loma Linda University, Loma Linda, United States of America

⁴Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany

⁵Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, United States of America

⁶Center for Genomics, School of Medicine, Loma Linda University, California, United States of America

⁷Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

Find articles by Wang, C. in: PubMed | Google Scholar

¹Department of Neuroscience, University of Pittsburgh, Pittsburgh, United States of America

²Department of Neuroscience, University of pittburgh, Pittsburgh, United States of America

³Center for Genomics, School of Medicine, Loma Linda University, Loma Linda, United States of America

⁴Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany

⁵Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, United States of America

⁶Center for Genomics, School of Medicine, Loma Linda University, California, United States of America

⁷Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

Find articles by Nestler, E. in: PubMed | Google Scholar

¹Department of Neuroscience, University of Pittsburgh, Pittsburgh, United States of America

²Department of Neuroscience, University of pittburgh, Pittsburgh, United States of America

³Center for Genomics, School of Medicine, Loma Linda University, Loma Linda, United States of America

⁴Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany

⁵Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, United States of America

⁶Center for Genomics, School of Medicine, Loma Linda University, California, United States of America

⁷Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

Find articles by Schlüter, O. in: PubMed | Google Scholar

¹Department of Neuroscience, University of Pittsburgh, Pittsburgh, United States of America

²Department of Neuroscience, University of pittburgh, Pittsburgh, United States of America

³Center for Genomics, School of Medicine, Loma Linda University, Loma Linda, United States of America

⁴Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany

⁵Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, United States of America

⁶Center for Genomics, School of Medicine, Loma Linda University, California, United States of America

⁷Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

Find articles by Dong, Y. in: PubMed | Google Scholar

J Clin Invest. https://doi.org/10.1172/JCI206794.
Copyright © 2026, Yan et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published October 22, 2026 - Version history

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.

Dopamine signaling via astrocytic D1 receptors regulates nucleus accumbens synaptic remodeling and cocaine seeking

Shi Yan,¹ Qize Li,² Yao Wang,¹ Wanqiu Chen,³ Zhong Chen,³ Alexander K. Zinsmaier,¹ Paloma R. Huguet,⁴ Zhengsong Lu,¹ Xiguang Qi,⁵ Zheng Xu,¹ Yi Han,¹ Gouri Sharma,¹ Charles Wang,³ Eric J. Nestler,⁷ Oliver M. Schlüter,¹ and Yan Dong¹

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Dopamine signaling via astrocytic D1 receptors regulates nucleus accumbens synaptic remodeling and cocaine seeking

Shi Yan,1 Qize Li,2 Yao Wang,1 Wanqiu Chen,3 Zhong Chen,3 Alexander K. Zinsmaier,1 Paloma R. Huguet,4 Zhengsong Lu,1 Xiguang Qi,5 Zheng Xu,1 Yi Han,1 Gouri Sharma,1 Charles Wang,3 Eric J. Nestler,7 Oliver M. Schlüter,1 and Yan Dong1

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Shi Yan,¹ Qize Li,² Yao Wang,¹ Wanqiu Chen,³ Zhong Chen,³ Alexander K. Zinsmaier,¹ Paloma R. Huguet,⁴ Zhengsong Lu,¹ Xiguang Qi,⁵ Zheng Xu,¹ Yi Han,¹ Gouri Sharma,¹ Charles Wang,³ Eric J. Nestler,⁷ Oliver M. Schlüter,¹ and Yan Dong¹