Abstract
Social status has a profound impact on mental health and propensity towards drug addiction. However, the neural mechanisms underlying the effects of social rank on drug-seeking behavior remain unclear. Here we found that dominant male rodents (based on the tube test) had denser mesocortical dopaminergic projections and were more resistant to methamphetamine (METH)-seeking, whereas subordinates had heightened dopaminergic function in the mesolimbic pathway and were more vulnerable to METH seeking. Optogenetic activation of the mesocortical dopaminergic pathway promoted winning and suppressed METH seeking in subordinates, whereas lesions of the mesocortical pathway increased METH seeking in dominants. Elevation of social rank with forced win training in subordinates led to remodeling of the dopaminergic system and prevented METH-seeking behavior. In females, however, both ranks were susceptible to METH seeking, with mesocorticolimbic pathways comparable to those in subordinate males. These results provide a framework for understanding the neural basis of the impact of social status on drug-seeking.
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Acknowledgements
We thank E. Neher, X. Chen and M. Han for critical comments and suggestions, G. Bi and F. Xu for assistance in VISoR experiments, F.Q. Xu (Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences) for providing sparse labeling virus, and Y. Sun and C. Jiang for preliminary explorations. We also acknowledge Q. Luo, Z.Y. Yang and H. Gu for their help with mass spectrometry analysis. This work was supported by the Major Project of the Science and Technology Innovation 2030 of China (2021ZD0202103 and 2021ZD0203500), Strategic Priority Research Program of the Chinese Academy of Sciences (XDB0930000), the National Natural Science Foundation of China (82425023, 82171492, 32300846, 82101569 and 32400840), Guangdong Basic and Applied Basic Research Foundation (2023B1515040009 and 2023A1515012122), the Technology and Innovation Commission of Shenzhen (RCJC20200714114556103, ZDSYS20190902093601675, JCYJ20210324141201003, KCXFZ20211020164543007 and KCXFZ20230731100901004), the Shenzhen Medical Research Funding (SMRFA2303034) and the Yunnan Technological Innovation Centre of Drug Addiction Medicine (202305AK340001). We also thank the support from the Innovative Research Team of High-level Local Universities in Shanghai.
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Y.Z. and X.D. conceptualized the project. X.D., Y.L., G.C. and K.S. developed the methodology. X.D., W.X., Y.L., H.J., J.Z., K.S., W.C., S.J., G.C., Y.Z., R.Z., L.X., X.W. and B.Z. conducted the investigation. Y.Z., X.D., W.X., Y.L. and G.C. acquired funding. Y.Z. supervised the project. Y.Z. and X.D. wrote the original draft of the paper. Y.Z., X.D., W.X. and Y.L. contributed to writing, reviewing and editing of the paper.
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Extended data
Extended Data Fig. 1 Other behavioral and physiological results.
a,b, Schematic and behavioral outcomes of the agonistic behavior assay (a) and the warm spot test (b) in male mice (n = 18 pairs). Paired t test. c, Average futile pokes during the last three sessions of METH self-administration for the dominant (n = 13) and subordinate (n = 13) rats. Paired t test. Futile pokes = active pokes − infusions. d, Winning probability across trials and total wins in mice (n = 28 pairs). Paired t test. e, Schematic of METH self-administration in mice. f–h, Nose pokes (f) and infusions (g) across session and their average number (h) during the last three sessions in the dominant (n = 11) and subordinate (n = 12) mice. f,g, Two-way ANOVA; h, paired t test. i, Hyperlocomotion induced by 2.5 mg kg−1 METH injection in mice (n = 8 pairs). Two-way ANOVA followed by Sidak’s test. j, Morphine CPP scores in mice (n = 5 pairs). Unpaired t test. k, Body weight change. Two-way ANOVA. l, Distance traveled and central time during open-field test in rats (n = 11 pairs). Unpaired t test. m–o, Immobility time in the forced swimming test (m) and the tail suspension test (n) and preference ratio (o) in the sucrose preference test in mice (n = 12 pairs). Paired t test. p, Serum corticosterone levels in rats (sub, n = 10; dom, n = 9). Unpaired t test. q, Serum testosterone levels in rats (female sub, n = 5; female dom, n = 4; male sub, n = 10; male dom, n = 8). Two-way ANOVA. r, Serum estrogen levels in rats (females, n = 4/group; male sub, n = 5; male dom, n = 4). Two-way ANOVA. s, Timeline of the mass spectrometry analysis. t,u, Serum concentrations (t) and half-life (u) of METH following METH injection in rats (n = 5 pairs). x, two-way ANOVA; y, paired t test. Data are represented as mean ± s.e.m. *P < 0.05, **P < 0.01, ***P < 0.01, ****P < 0.0001. Detailed statistical information is available in Supplementary Table 1.
Extended Data Fig. 2 Other fiber photometry results for DA release in the NAc and mPFC.
a,b, Schematics of viral expression and optic fiber placement in the NAc shell (a) and core (b) for fiber photometry. c–g, Representative image of viral expression in the NAc shell (c) and core (e). Scale bar = 0.5 mm. DA release in the NAc shell (d) and core (f) and AUC comparison (g) after METH (0.1 mg kg−1) infusion in mice (shell: sub, n = 9; dom: n = 10; core: sub, n = 7; dom, n = 6). Two-way ANOVA followed by Sidak’s post-hoc test, *P < 0.05, **P < 0.01. h–k, Schematics for viral expression and optic fiber placement in the NAc (h) and mPFC (j) for fiber photometry experiments. Saline-induced DA release in the NAc (i) and mPFC (k) in mice (NAc: n = 13/group; mPFC: n = 9/group). Two-sided unpaired t test. l, Timeline and schematic showing the METH self-administration with simultaneous fiber photometry recording. m,n, Schematics showing viral expression and optic fiber placement in the NAc (m) and mPFC (n) for fiber photometry in a free-moving self-administration. o,p, DA release in the NAc (o) and mPFC (p) following active and inactive pokes in a free-moving METH self-administration (NAc: n = 10 per group; mPFC: sub, n = 8; dom, n = 9). Two-sided unpaired t test, *P < 0.05, **P < 0.01. Each row in the heatmap represents averaged DA dynamics over trials from individual mouse (ranked by AUC). Data are represented as mean ± s.e.m. Detailed statistical information is available in Supplementary Table 1.
Extended Data Fig. 3 Activity of VTADA neurons following METH infusion between dominants and subordinates.
a, Schematic of the virus strategy and a representative image showing GCaMP expression and optic fiber placement (top). Scale bar = 200 µm. Diagrams showing viral expression and optic fiber ___location in the VTA for the fiber photometry experiments (bottom). b–e, Activity of VTADA neurons following i.v. injection of saline (b), 0.1 mg kg−1 (c) and 0.3 mg kg−1 METH (d) and sucrose licking (e) in mice (saline and 0.1 METH: n = 5/group; 0.3 METH: sub, n = 4; dom, n = 3; sucrose: sub, n = 5; dom, n = 4). Mann–Whitney test. f, Schematic of the viral strategy to specifically record the NAc-projecting VTA neurons and a representative image (top). Scale bar = 200 µm. Diagrams showing viral expression and optic fiber ___location in the VTA for the fiber photometry experiments (bottom). g,h, Activity of NAc-projecting VTADA neurons following i.v. injection of 0.1 mg kg−1 (g) and 0.3 (h) mg kg−1 METH in mice (sub, n = 5; dom, n = 6). Two-sided unpaired t test. Each row in the heatmap represents averaged DA dynamics over trials from individual mouse (ranked by AUC). Data are represented as mean ± s.e.m. Detailed statistical information is available in Supplementary Table 1.
Extended Data Fig. 4 DA pathways from the VTA projecting to mPFC and NAc are structurally and functionally distinct.
a, Schematic showing the CTB-mediated retrograde tracing experiment in DAT::Ai14 mice (top). Representative images of CTB488 in the mPFC (bottom left) and CTB647 in the NAc (bottom right). Scale bar = 0.5 mm. b, Representative images showing DA neurons, mPFC-projecting and NAc-projecting neurons in the VTA. Scale bar = 0.2 mm. c, Venn diagram illustrating the overlap of CTB-labeled VTADA neuron projecting to the mPFC and NAc (n = 5 mice). d, Distribution of CTB-labeled mPFC-projecting and NAc-projecting VTADA neurons across different anteroposterior coordinates. e,f, Optogenetically activation of the mesolimbic (e) and mesocortical (f) DA pathway in mice during a real-time place preference experiment (EYFP, n = 5; ChR2, n = 10). Two-sided unpaired t test, **P < 0.01. Data are represented as mean ± s.e.m. Detailed statistical information is available in Supplementary Table 1.
Extended Data Fig. 5 Additional DA-related protein and immunofluorescence data.
a, Overlay of images of DA terminals in the NAc (n = 9 mouse pairs). Scale bar = 400 μm. b, Schematic of patch clamp. c, Representative traces showing action potential firing of VTADA neurons. d, Intrinsic excitability of VTADA neurons from dominant (n = 4 cells) and subordinate (n = 3 cells) mice. Two-way ANOVA. APS, action potentials. e,f, Representative western blot images (e) and relative levels (f) of ERK/pERK in the NAc (n = 8 rat pairs). Two-sided paired t test, *P < 0.05. g, Overlay of images showing TH-positive terminals in the mPFC (n = 9 mouse pairs). Scale bar = 400 μm. h, The percentage of the PrL area covered by DA terminals across different layers. Two-sided paired t test, *P < 0.05, **P < 0.01. i, Representative images (i) and quantification (j) of DA varicosities in the PrL layer 2–5 (n = 18 slices from four mouse pairs) and along DA axon branches (n = 26 axon branches from three mouse pairs). Two-sided unpaired t test, ***P < 0.001. k, Schematic showing sparsely labeling DA neurons in the VTA. l, Representative sections showing VTADA neurons, and DA terminals in the NAc and mPFC by VISoR. Scale bar = 2 mm. m, Overlay of seven reconstructed mPFC-projecting neurons (one neuron from a subordinate; six neurons from four dominants) registered to a reference brain. n, Number of labeled VTADA neurons in the subordinate (n = 4) and dominant (n = 3) mice. Two-sided unpaired t test. o, Proportion of mPFC-projecting VTADA neurons in the dominant (n = 3 mice) and subordinate (n = 4 mice) mice. Two-sided unpaired t test, *P < 0.05. p,q, GFP-labeled fluorescence in the NAc (p) and mPFC (q) in the dominant (n = 5) and subordinate (n = 5) mice. Two-sided unpaired t test, **P < 0.01. Data are represented as mean ± s.e.m. Detailed statistical information is available in Supplementary Table 1.
Extended Data Fig. 6 Additional results of pharmacological and optogenetic manipulation in the mesolimbic pathway.
a, Timeline for intracranial injections followed by behavioral assessments (top). Schematic showing intracranial infusions of GDC/API-1 into the NAc followed by METH CPP (bottom). b, CPP scores for subordinate mice with infusion of GDC (n = 6) and vehicle (n = 6). Two-sided unpaired t test, *P < 0.05. c, CPP scores for dominant mice with infusion of API-1 (n = 6) and vehicle (n = 6). Two-sided unpaired t test. d, Changes of social rank before and after intracranial infusion of GDC in subordinates (d) and API-1 in dominants (e) into the NAc (GDC, n = 6; API-1, n = 8; vehicle, n = 6). Two-sided unpaired t test. f, Timeline for mesolimbic activation experiments. g, Schematic of the viral strategy and diagram of optogenetic stimulation during the tube test (left). Representative image in the NAc (right). Scale bar = 200 µm. h, Confirmed positions of optic fibers in the NAc. i,j, Changes of social rank during and after mesolimbic activation in dominant mice; individual data (i) and averaged data (j; ChR2, n = 6; EYFP, n = 6). Two-sided unpaired t test. k, Schematic illustrating mesolimbic activation during METH self-administration in dominant mice. Light was delivered at 20 Hz for 1 s, following an active nose poke. l–n, Nose pokes (l) and infusions (m) across ten sessions and their average number during the last three sessions (n) in the dominant + ChR2 (n = 9) and dominant + EYFP (n = 9) mice. l, Two-way ANOVA, ****P < 0.0001, followed by Tukey’s post-hoc test, ****P < 0.0001; m, ****P < 0.0001; n, two-sided unpaired t test, ****P < 0.0001. Data are represented as mean ± s.e.m. Detailed statistical information is available in Supplementary Table 1.
Extended Data Fig. 7 Activating the VTA–PFC pathway alone is not sufficient to change drug-seeking behavior unless it is mediated by social winning.
a, Confirmed positions of optic fibers used for optogenetic mesocortical activation. b, Schematic showing the viral strategy to record DA release during optogenetic mesocortical activation. c, DA dynamics (left) and AUC of DA release (right) in the mPFC induced by optogenetic stimulation of the mesocortical pathway at different frequencies (n = 4 mice). Friedman test, ***P < 0.001. d, Infusions across 12 METH sessions in the control subordinate (n = 9), the unchange (n = 5) and the partial win + full win (n = 5) mice. Two-way ANOVA, *P < 0.05, followed by Tukey’s test, ***P < 0.001, ****P < 0.0001. e, Correlation between the number of METH infusions and the winning probability after 4 days of optogenetic stimulation (n = 10 mice). Spearman’s correlation, r = −0.6922, *P < 0.05. f, Timeline for VTA→mPFC optogenetic stimulation experiments in subordinates. g, Rank changes in the subordinate + ChR2 (n = 7) group induced by optogenetic stimulation of the VTA→mPFC pathway. h, Comparison of winning probability before and after optogenetic stimulation in the Subordinate + ChR2 (n = 7) group. Two-sided paired t test. i–k, Active/inactive pokes (i) and infusions (j) across sessions and average number (k) during the last three sessions in the subordinate + EYFP (n = 13) and subordinate + ChR2 (n = 7) groups across ten sessions of METH self-administration. i, Two-way ANOVA, **P < 0.01, followed by Tukey’s post-hoc test; j, P > 0.05; k, two-sided unpaired t test. Data are represented as mean ± s.e.m. Detailed statistical information is available in Supplementary Table 1.
Extended Data Fig. 8 Repeated loss experiences facilitate METH-seeking behavior in dominants resistant to forced loss.
a, Timeline for forced loss procedure followed by depressive assays. b–d, Immobility time in the forced swimming test (b) and the tail suspension test (c) and preference ratio in the sucrose preference test (d) between native control (n = 16), natural loss (n = 10) and forced loss (n = 8) mice. One-way ANOVA followed by Tukey’s test, *P < 0.05, **P < 0.01. e, Rank change across sessions for subordinates resistant to forced win (defined as S-to-S, n = 8 rats). f–h, Active/inactive pokes (f) and infusions (g) across sessions and average number (h) during the last three sessions in subordinate (n = 10) and S-to-S (n = 7) rats. f, Two-way ANOVA, ***P < 0.001, followed by Tukey’s test; g, P > 0.05; h, two-sided unpaired t test. i, Rank change across sessions for dominants resistant to forced loss (defined as D-to-D, n = 12 rats). j–l, Active/inactive pokes (j) and infusions (k) across sessions and average number (l) during the last three sessions in the dominant (n = 10) and D-to-D (n = 7) rats. j, Two-way ANOVA, ****P < 0.0001, followed by Tukey’s test, ****P < 0.0001; k, **P < 0.01; l, two-sided unpaired t test, **P < 0.01. m,n, Verification of viral expression and optic fiber placement for fiber photometry in the NAc (m) and mPFC (n). o, pERK expression in the NAc before and after forced win/loss procedure, normalized to matched subordinates (n = 6 rats/groups). Two-sided unpaired t test, **P < 0.01. Data are represented as mean ± s.e.m. Detailed statistical information is available in Supplementary Table 1.
Extended Data Fig. 9 Both female groups exhibited high METH-seeking behavior.
a, Timeline and schematics showing the tube test and METH self-administration in female rats. b, Winning probability across trials and total wins in female rats (n = 8 pairs). Two-sided paired t test, ****P < 0.0001. c,d, Behavioral outcome in the warm spot test (c) and agonistic behavior (d) for females (n = 12 mice per group). Two-sided paired t test, *P < 0.05. e–g, Nose pokes (e) and infusions (f) across sessions and average number (g) during the last three days in female (n = 5 per group) and male rats (n = 10 per group). e, Two-way ANOVA, *P < 0.05, followed by Tukey’s test; f, **P < 0.01, followed by Tukey’s test, ****P < 0.0001. g, One-way ANOVA, **P < 0.01, followed by Sidak’s test, ***P < 0.001. h, Timeline of the fiber photometry recordings in females. i,j, Schematic (i) and verification (j) of viral injections and optic fiber placement in the mPFC. Scale bar = 0.5 mm. k,l, DA release in the mPFC following 0.1 mg kg−1 (k) and 0.3 mg kg−1 (l) METH infusion in female (0.1 METH: sub, n = 9; dom, n = 8; 0.3 METH: n = 8/group) and male (0.1 METH: sub, n = 9; dom, n = 8; 0.3 METH: sub, n = 9; dom, n = 10) mice. Two-sided unpaired t test, *P < 0.05, **P < 0.01. m, Schematic (m) and verification (n) of viral injections and optic fiber placement in the NAc. Scale bar = 0.5 mm. o,p, DA release in the NAc following 0.1 mg kg−1 (o) and 0.3 mg kg−1 (p) METH infusion in female (0.1 METH: sub, n = 9; dom, n = 8; 0.3 METH: n = 8 per group) and male (0.1 METH: sub, n = 13; dom, n = 14; 0.3 METH: sub, n = 9; dom, n = 8) mice. Two-sided unpaired t test, *P < 0.05, **P < 0.01. Each row in the heatmap represents averaged DA dynamics over trials from individual mouse (ranked by AUC). Data are represented as mean ± s.e.m. Detailed statistical information is available in Supplementary Table 1.
Extended Data Fig. 10 Both female groups showed higher pDAT in the NAc and lower mesocortical projection density in the mPFC layer 2/3 compared to male dominants.
a, Timeline for the immunofluorescence analysis. b, Representative images of TH-positive terminals in the mPFC for female mice. Scale bar = 400 μm. c, Relative fluorescence density of TH-positive signals in the PrL, ACC, IL and the entire mPFC, normalized to paired subordinate (n = 7 pairs of female mice). Two-sided paired t test, *P < 0.05, **P < 0.01. d, Percentage of PrL covered by TH-positive terminals for male (n = 9 pairs) and female (n = 7 pairs) mice. Unpaired t test, *P < 0.05. e, Representative images of TH-positive terminals in the PrL regions across different cell layers for female mice. Scale bar = 200 μm. f, Percentage of the PrL area covered by TH-positive terminals across different layers for male (n = 9 pairs) and female (n = 7 pairs) mice. Two-way ANOVA, **P < 0.01, followed by Tukey’s test, *P < 0.05, ***P < 0.001. g, Timeline for the protein dectection. h, Representative western blot image showing expression of DAT, pDAT and GAPDH from NAc tissue samples of female rats. i, Relative expression levels of proteins in the NAc of female rats, normalized to paired subordinate (n = 8 pairs). j, Relative expression levels of pDAT in the NAc for male (n = 8 per group) and female (n = 6 per group) rats, normalized to GAPDH. Unpaired t test, ***P < 0.001. Data are represented as mean ± s.e.m. Detailed statistical information is available in Supplementary Table 1.
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Deng, X., Xu, W., Liu, Y. et al. Social rank modulates methamphetamine-seeking in dominant and subordinate male rodents via distinct dopaminergic pathways. Nat Neurosci 28, 1268–1279 (2025). https://doi.org/10.1038/s41593-025-01951-0
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DOI: https://doi.org/10.1038/s41593-025-01951-0
