Social reward outcompetes drug seeking dopaminergic ensembles to prevent relapse PMID: 41932919

ADC Targets in Oncology

2026-04-10

Social reward outcompetes drug seeking dopaminergic ensembles to prevent relapse

Nat Commun. 2026 Apr 3;17(1):3462. doi: 10.1038/s41467-026-71357-4.

Wei Zheng ^# ¹ , Xiaoxing Liu ^# ² , Tangsheng Lu ^# ³ , Xinyou Lv ⁴ , Xuefang Guan ⁵ , Yifan Yu ² , Xue Li ³ , Zhe Wang ⁶ , Kai Yuan ² , Jeffrey W Grimm ⁷ , Trevor W Robbins ⁸ ⁹ , Jie Shi ¹⁰ , Lin Lu ¹¹ ¹² ¹³ ¹⁴ , Yan-Xue Xue ¹⁵ ¹⁶

Affiliations

1. Peking-Tsinghua Center for Life Sciences, PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China.
2. Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China.
3. National Institute on Drug Dependence, Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, China.
4. Department of Psychology, School of Humanities and Social Sciences, University of Science and Technology of China, Hefei, China.
5. Henan Academy of Innovation in Medical Science, Henan University, Kaifeng, China.
6. Institute of Brain Science and Brain-inspired Research, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China.
7. Department of Psychology and Program in Behavioral Neuroscience, Western Washington University, Bellingham, WA, USA.
8. Behavioural and Clinical Neuroscience Institute, Department of Psychology, University of Cambridge, Cambridge, UK.
9. Institute of Science and Technology for Brain-Inspired Intelligence, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China.
10. National Institute on Drug Dependence, Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, China. [email protected].
11. Peking-Tsinghua Center for Life Sciences, PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China. [email protected].
12. Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China. [email protected].
13. National Institute on Drug Dependence, Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, China. [email protected].
14. Institute of Brain Science and Brain-inspired Research, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China. [email protected].
15. National Institute on Drug Dependence, Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, China. [email protected].
16. Chinese Institute for Brain Research, Beijing, Beijing, China. [email protected].
# Contributed equally.

Abstract

Drugs of abuse promote substance use disorder (SUD) by hijacking mesolimbic circuits that normally process natural rewards. Among these, social rewards exhibit therapeutic potential, but the underlying neural substrates remain unclear. Using a multimodal approach integrating in vivo single-neuron calcium imaging, optogenetic manipulation, and electrophysiology in male rats, we identified two distinct dopaminergic ensembles in the ventral tegmental area (VTA) that respectively encode social reward and drug seeking. Notably, these antagonistic ensembles exert reciprocal influence through competitive interactions that shape behavioral outcomes. Furthermore, circuit mapping revealed divergent connectivity patterns, with social reward-responsive dopaminergic ensembles receiving preferential input from the dorsal raphe nucleus (DRN). Activation of the DRN-VTA pathway recapitulates the protective effects of social reward against drug seeking. In this study, we uncovered a dynamic competition between functionally specialized dopaminergic ensembles through which social reward attenuates drug seeking, offering insights that may inform development of novel strategies for SUD treatment.