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.
Data availability
All the data generated in this study are provided in the article and the Supplementary Information. The relevant raw data are provided as a Source data file. Source data are provided with this paper.
Code availability
Raw Ca²⁺ imaging data were processed using commercial software (Thinkerbiotech, Nanjing, China). The custom MATLAB scripts developed for this data processing are publicly available on Zenodo (https://doi.org/10.5281/zenodo.18279500).
References
Lüscher, C., Robbins, T. W. & Everitt, B. J. The transition to compulsion in addiction. Nat. Rev. Neurosci. 21, 247–263 (2020).
Tan, B. et al. Drugs of abuse hijack a mesolimbic pathway that processes homeostatic need. Science 384, eadk6742 (2024).
DiLeone, R. J., Taylor, J. R. & Picciotto, M. R. The drive to eat: comparisons and distinctions between mechanisms of food reward and drug addiction. Nat. Neurosci. 15, 1330–1335 (2012).
Venniro, M. et al. The protective effect of social reward on opioid and psychostimulant reward and relapse: behavior, pharmacology, and brain regions. J. Neurosci. 42, 9298–9314 (2022).
Deng, X. et al. Social rank modulates methamphetamine-seeking in dominant and subordinate male rodents via distinct dopaminergic pathways. Nat. Neurosci. 28, 1268–1279 (2025).
Fritz, M. et al. Reversal of cocaine-conditioned place preference and mesocorticolimbic zif268 expression by social interaction in rats. Addict. Biol. 16, 273–284 (2011).
Venniro, M. et al. Volitional social interaction prevents drug addiction in rat models. Nat. Neurosci. 21, 1520–1529 (2018).
Solié, C., Girard, B., Righetti, B., Tapparel, M. & Bellone, C. VTA dopamine neuron activity encodes social interaction and promotes reinforcement learning through social prediction error. Nat. Neurosci. 25, 86–97 (2022).
Gunaydin, L. A. et al. Natural neural projection dynamics underlying social behavior. Cell 157, 1535–1551 (2014).
Willmore, L. et al. Overlapping representations of food and social stimuli in mouse VTA dopamine neurons. Neuron 111, 3541–3553.e3548 (2023).
Liu, Q. S., Pu, L. & Poo, M. M. Repeated cocaine exposure in vivo facilitates LTP induction in midbrain dopamine neurons. Nature 437, 1027–1031 (2005).
Pascoli, V., Terrier, J., Hiver, A. & Lüscher, C. Sufficiency of mesolimbic dopamine neuron stimulation for the progression to addiction. Neuron 88, 1054–1066 (2015).
Azcorra, M. et al. Unique functional responses differentially map onto genetic subtypes of dopamine neurons. Nat. Neurosci. 26, 1762–1774 (2023).
Matsumoto, M. & Hikosaka, O. Two types of dopamine neuron distinctly convey positive and negative motivational signals. Nature 459, 837–841 (2009).
Lei, B. et al. Adult newborn granule cells confer emotional state-dependent adaptability in memory retrieval. Sci. Adv. 8, eabn2136 (2022).
Dölen, G., Darvishzadeh, A., Huang, K. W. & Malenka, R. C. Social reward requires coordinated activity of nucleus accumbens oxytocin and serotonin. Nature 501, 179–184 (2013).
Xue, Y. X. et al. A memory retrieval-extinction procedure to prevent drug craving and relapse. Science 336, 241–245 (2012).
Beier, K. T. et al. Circuit architecture of VTA dopamine neurons revealed by systematic input-output mapping. Cell 162, 622–634 (2015).
Schultz, W., Dayan, P. & Montague, P. R. A neural substrate of prediction and reward. Science 275, 1593–1599 (1997).
Engelhard, B. et al. Specialized coding of sensory, motor, and cognitive variables in VTA dopamine neurons. Nature 570, 509–513 (2019).
Yuste, R., Cossart, R. & Yaksi, E. Neuronal ensembles: Building blocks of neural circuits. Neuron 112, 875–892 (2024).
Tritsch, N. X., Ding, J. B. & Sabatini, B. L. Dopaminergic neurons inhibit striatal output through non-canonical release of GABA. Nature 490, 262–266 (2012).
Kim, J. I. et al. Aldehyde dehydrogenase 1a1 mediates a GABA synthesis pathway in midbrain dopaminergic neurons. Science 350, 102–106 (2015).
Pomrenze, M. B. et al. Modulation of 5-ht release by dynorphin mediates social deficits during opioid withdrawal. Neuron 110, 4125–4143.e4126 (2022).
Josselyn, S. A. & Tonegawa, S. Memory engrams: recalling the past and imagining the future. Science 367, eaaw4325 (2020).
Beier, K. T. et al. Topological organization of ventral tegmental area connectivity revealed by viral-genetic dissection of input-output relations. Cell Rep. 26, 159–167.e156 (2019).
Zingg, B. et al. Aav-mediated anterograde transsynaptic tagging: mapping corticocollicular input-defined neural pathways for defense behaviors. Neuron 93, 33–47 (2017).
Smith, M. A. Peer influences on drug self-administration: social facilitation and social inhibition of cocaine intake in male rats. Psychopharmacol. (Berl.) 224, 81–90 (2012).
Robinson, A. M., Lacy, R. T., Strickland, J. C., Magee, C. P. & Smith, M. A. The effects of social contact on cocaine intake under extended-access conditions in male rats. Exp. Clin. Psychopharmacol. 24, 285–296 (2016).
Coughlin, L. N. et al. Contingency management for stimulant use disorder and association with mortality: a cohort study. Am. J. Psychiatry 182, 1016–1023 (2025).
Venniro, M. et al. The anterior insular cortex→central amygdala glutamatergic pathway is critical to relapse after contingency management. Neuron 96, 414–427.e418 (2017).
He, Y. et al. A red nucleus-VTA glutamate pathway underlies exercise reward and the therapeutic effect of exercise on cocaine use. Sci. Adv. 8, eabo1440 (2022).
Huo, Y. et al. Corticotropin-releasing hormone signaling from piriform cortex to amygdala mediates social homophily in opioid addiction. Neuron 113, 3632–3646.e3637 (2025).
Brischoux, F., Chakraborty, S., Brierley, D. I. & Ungless, M. A. Phasic excitation of dopamine neurons in ventral VTA by noxious stimuli. Proc. Natl. Acad. Sci. USA 106, 4894–4899 (2009).
Bromberg-Martin, E. S., Matsumoto, M. & Hikosaka, O. Dopamine in motivational control: rewarding, aversive, and alerting. Neuron 68, 815–834 (2010).
Sias, A. C. et al. Dopamine projections to the basolateral amygdala drive the encoding of identity-specific reward memories. Nat. Neurosci. 27, 728–736 (2024).
Mohebi, A. et al. Dissociable dopamine dynamics for learning and motivation. Nature 570, 65–70 (2019).
Salamone, J. D. & Correa, M. The mysterious motivational functions of mesolimbic dopamine. Neuron 76, 470–485 (2012).
Wang, L. et al. Cocaine induces locomotor sensitization through a dopamine-dependent VTA-mpfc-fra cortico-cortical pathway in male mice. Nat. Commun. 14, 1568 (2023).
Lüscher, C. The emergence of a circuit model for addiction. Annu Rev. Neurosci. 39, 257–276 (2016).
Tiklová, K. et al. Single-cell RNA sequencing reveals midbrain dopamine neuron diversity emerging during mouse brain development. Nat. Commun. 10, 581 (2019).
La Manno, G. et al. Molecular diversity of midbrain development in mouse, human, and stem cells. Cell 167, 566–580.e519 (2016).
Phillips, R. A. et al. An atlas of transcriptionally defined cell populations in the rat ventral tegmental area. Cell Rep. 39, 110616 (2022).
Wang, F. et al. Morphine- and foot shock-responsive neuronal ensembles in the VTA possess different connectivity and biased GPCR signaling pathway. Theranostics 14, 1126–1146 (2024).
Watabe-Uchida, M., Zhu, L., Ogawa, S. K., Vamanrao, A. & Uchida, N. Whole-brain mapping of direct inputs to midbrain dopamine neurons. Neuron 74, 858–873 (2012).
Tritsch, N. X., Oh, W. J., Gu, C. & Sabatini, B. L. Midbrain dopamine neurons sustain inhibitory transmission using plasma membrane uptake of gaba, not synthesis. Elife 3, e01936 (2014).
Okaty, B. W., Commons, K. G. & Dymecki, S. M. Embracing diversity in the 5-HT neuronal system. Nat. Rev. Neurosci. 20, 397–424 (2019).
McDevitt, R. A. et al. Serotonergic versus nonserotonergic dorsal raphe projection neurons: differential participation in reward circuitry. Cell Rep. 8, 1857–1869 (2014).
Walsh, J. J. et al. 5-HT release in nucleus accumbens rescues social deficits in mouse autism model. Nature 560, 589–594 (2018).
Paquelet, G. E. et al. Single-cell activity and network properties of dorsal raphe nucleus serotonin neurons during emotionally salient behaviors. Neuron 110, 2664–2679.e2668 (2022).
Zou, W. J. et al. A discrete serotonergic circuit regulates vulnerability to social stress. Nat. Commun. 11, 4218 (2020).
Li, Y. et al. Synaptic mechanism underlying serotonin modulation of transition to cocaine addiction. Science 373, 1252–1256 (2021).
Miyazaki, K. & Miyazaki, K. W. Increased serotonin prevents compulsion in addiction. Science 373, 1197–1198 (2021).
Lammel, S., Lim, B. K. & Malenka, R. C. Reward and aversion in a heterogeneous midbrain dopamine system. Neuropharmacology 76 Pt B, 351–359 (2014).
de Jong, J. W., Fraser, K. M. & Lammel, S. Mesoaccumbal dopamine heterogeneity: what do dopamine firing and release have to do with it? Annu Rev. Neurosci. 45, 109–129 (2022).
Reiner, D. J. et al. Role of projections between piriform cortex and orbitofrontal cortex in relapse to fentanyl seeking after palatable food choice-induced voluntary abstinence. J. Neurosci. 40, 2485–2497 (2020).
Luo, Y. X. et al. A novel UCS memory retrieval-extinction procedure to inhibit relapse to drug seeking. Nat. Commun. 6, 7675 (2015).
Lei, B., Lv, L., Hu, S., Tang, Y. & Zhong, Y. Social experiences switch states of memory engrams through regulating hippocampal rac1 activity. Proc. Natl. Acad. Sci. USA 119, e2116844119 (2022).
Deng, X., Gu, L., Sui, N., Guo, J. & Liang, J. Parvalbumin interneuron in the ventral hippocampus functions as a discriminator in social memory. Proc. Natl. Acad. Sci. USA 116, 16583–16592 (2019).
Allen, W. E. et al. Thirst-associated preoptic neurons encode an aversive motivational drive. Science 357, 1149–1155 (2017).
Wang, Q. et al. Insular cortical circuits as an executive gateway to decipher threat or extinction memory via distinct subcortical pathways. Nat. Commun. 13, 5540 (2022).
Lee, J. H., Kim, W. B., Park, E. H. & Cho, J. H. Neocortical synaptic engrams for remote contextual memories. Nat. Neurosci. 26, 259–273 (2023).
Xue, Y. X. et al. Selective inhibition of amygdala neuronal ensembles encoding nicotine-associated memories inhibits nicotine preference and relapse. Biol. Psychiatry 82, 781–793 (2017).
Chen, Y. et al. An orbitofrontal cortex-anterior insular cortex circuit gates compulsive cocaine use. Sci. Adv. 8, eabq5745 (2022).
Sheintuch, L. et al. Tracking the same neurons across multiple days in ca(2+) imaging data. Cell Rep. 21, 1102–1115 (2017).
Acknowledgements
We thank N. Sui and J.J. Zhang for advice and comments on the manuscript; Z.Y. Qi, Z.Y. Zhang, Y. Zhang, S.Y. Liu, B.Z. Gong, and S.M. Gao for comments and advice on behavioral, functional imaging, circuit, and electrophysiological experiments; W.J. Zhou and G.C. Zou for discussions. This work was supported by the National Natural Science Foundation of China (no.82288101 to L.L., no.82301681 to X.X.L., no.82071498 to Y.X.X. and no.82471514 to Y.X.X.) and the STI2030-Major Projects (no. 2021ZD0200800 to L.L. and no. 2022ZD0214500 to Y.X.X.).
Author information
Authors and Affiliations
Contributions
Conceptualization: Y.X.X., L.L., J.S., and W.Z. Behavioral, functional imaging, circuit, and electrophysiological experiments: W.Z., X.X.L., T.S.L., Y.X.L., X.F.G., Y.F.Y., X.L., Z.W., and K.Y. Formal analysis: W.Z., X.X.L., and T.S.L. Funding acquisition: Y.X.X., L.L, and X.X.L. Project administration and supervision: Y.X.X., L.L, and J.S. Writing– original draft: W.Z., X.X.L, and T.S.L. Writing– review and editing: Y.X.X., L.L, J.S., J.W.G., and T.W.R.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Peer review
Peer review information
Nature Communications thanks Yingjie Zhu and the other anonymous reviewer(s) for their contribution to the peer review of this work. A peer review file is available.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Source data
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
About this article
Cite this article
Zheng, W., Liu, X., Lu, T. et al. Social reward outcompetes drug seeking dopaminergic ensembles to prevent relapse. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71357-4
Received:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41467-026-71357-4
