Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Pain induces adaptations in ventral tegmental area dopamine neurons to drive anhedonia-like behavior

Subjects

Abstract

The persistence of negative affect in pain leads to co-morbid symptoms such as anhedonia and depression—major health issues in the United States. The neuronal circuitry and contribution of specific cellular populations underlying these behavioral adaptations remains unknown. A common characteristic of negative affect is a decrease in motivation to initiate and complete goal-directed behavior, known as anhedonia. We report that in rodents, inflammatory pain decreased the activity of ventral tegmental area (VTA) dopamine (DA) neurons, which are critical mediators of motivational states. Pain increased rostromedial tegmental nucleus inhibitory tone onto VTA DA neurons, making them less excitable. Furthermore, the decreased activity of DA neurons was associated with reduced motivation for natural rewards, consistent with anhedonia-like behavior. Selective activation of VTA DA neurons was sufficient to restore baseline motivation and hedonic responses to natural rewards. These findings reveal pain-induced adaptations within VTA DA neurons that underlie anhedonia-like behavior.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: CFA decreases the frequency of VTA DA neuron calcium transients but amplifies the phasic response to reward.
Fig. 2: VTA DA cells are hyperpolarized in CFA-injected animals, exhibiting decreased intrinsic excitability and increased inhibitory drive onto them.
Fig. 3: Chemogenetic activation of VTA DA neurons, or the VTA–NAc pathway, reverses the CFA-induced decrease in motivation.
Fig. 4: Chemogenetic activation of NAcSh-projecting VTA DA neurons mitigates the effect of CFA on motivated behavior.
Fig. 5: Increasing the concentration of sucrose reward overcomes the effects of CFA on sucrose consumption.
Fig. 6: RMTg GABAergic neuronal projections have higher release probability in CFA-treated animals.

Similar content being viewed by others

Data availability

The data that support the findings of this study are available from the corresponding authors upon request.

Code availability

Custom Matlab scripts generated during and/or analyzed during the current study are publicly available from the following link: https://github.com/christianepedersen. Custom-written analysis software Igor Pro 7 and mafPC is publicly available from the following links: https://bitbucket.org/r-bock/vigor/src/master/, https://bitbucket.org/r-bock/common-igor-functions/src/master/ and https://www.xufriedman.org/mafpc.

References

  1. Leknes, S. & Tracey, I. A common neurobiology for pain and pleasure. Nat. Rev. Neurosci. 9, 314–320 (2008).

    Article  CAS  PubMed  Google Scholar 

  2. Bair, M. J., Robinson, R. L., Katon, W. & Kroenke, K. Depression and pain comorbidity: a literature review. Arch. Intern. Med. 163, 2433–2445 (2003).

    Article  PubMed  Google Scholar 

  3. McWilliams, L. A., Goodwin, R. D. & Cox, B. J. Depression and anxiety associated with three pain conditions: results from a nationally representative sample. Pain 111, 77–83 (2004).

    Article  PubMed  Google Scholar 

  4. Campbell, L. C., Clauw, D. J. & Keefe, F. J. Persistent pain and depression: a biopsychosocial perspective. Biol. Psychiatry 54, 399–409 (2003).

    Article  PubMed  Google Scholar 

  5. Volkow, N. D. & McLellan, A. T. Opioid abuse in chronic pain—misconceptions and mitigation strategies. N. Engl. J. Med. 374, 1253–1263 (2016).

    Article  CAS  PubMed  Google Scholar 

  6. Apkarian, A. V. et al. Chronic pain patients are impaired on an emotional decision-making task. Pain 108, 129–136 (2004).

    Article  PubMed  Google Scholar 

  7. Verdejo-García, A., López-Torrecillas, F., Calandre, E. P., Delgado-Rodríguez, A. & Bechara, A. Executive function and decision-making in women with fibromyalgia. Arch. Clin. Neuropsychol. 24, 113–122 (2009).

    Article  PubMed  Google Scholar 

  8. Wiech, K. et al. Influence of prior information on pain involves biased perceptual decision-making. Curr. Biol. 24, R679–R681 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Seixas, D., Palace, J. & Tracey, I. Chronic pain disrupts the reward circuitry in multiple sclerosis. Eur. J. Neurosci. 44, 1928–1934 (2016).

    PubMed  Google Scholar 

  10. Nestler, E. J. & Carlezon, W. A. The mesolimbic dopamine reward circuit in depression. Biol. Psychiatry 59, 1151–1159 (2006).

    Article  CAS  PubMed  Google Scholar 

  11. Schultz, W. Behavioral dopamine signals. Trends Neurosci. 30, 203–210 (2007).

    Article  CAS  PubMed  Google Scholar 

  12. Berridge, K. C. & Robinson, T. E. What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience? Brain Res. Rev. 28, 309–369 (1998).

    Article  CAS  PubMed  Google Scholar 

  13. Bromberg-Martin, E. S., Matsumoto, M. & Hikosaka, O. Dopamine in motivational control: rewarding, aversive, and alerting. Neuron 68, 815–834 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Martikainen, I. K. et al. Chronic back pain is associated with alterations in dopamine neurotransmission in the ventral striatum. J. Neurosci. 35, 9957–9965 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Scott, D. J., Heitzeg, M. M., Koeppe, R. A., Stohler, C. S. & Zubieta, J.-K. Variations in the human pain stress experience mediated by ventral and dorsal basal ganglia dopamine activity. J. Neurosci. 26, 10789–10795 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Benarroch, E. E. Involvement of the nucleus accumbens and dopamine system in chronic pain. Neurology 87, 1720–1726 (2016).

    Article  PubMed  Google Scholar 

  17. Hipolito, L. et al. Inflammatory pain promotes increased opioid self-administration: role of dysregulated ventral tegmental area opioid receptors. J. Neurosci. 35, 12217–12231 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Taylor, A. M. W. et al. Microglia disrupt mesolimbic reward circuitry in chronic pain. J. Neurosci. 35, 8442–8450 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Massaly, N. et al. Pain-induced negative affect is mediated via recruitment of the nucleus accumbens kappa opioid system. Neuron 102, 564–573.e6 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Schwartz, N. et al. Decreased motivation during chronic pain requires long-term depression in the nucleus accumbens. Science 345, 535–542 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Matsui, A., Jarvie, B. C., Robinson, B. G., Hentges, S. T. & Williams, J. T. Separate GABA afferents to dopamine neurons mediate acute action of opioids, development of tolerance and expression of withdrawal. Neuron 82, 1346–1356 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ozaki, S. et al. Suppression of the morphine-induced rewarding effect in the rat with neuropathic pain: implication of the reduction in µ-opioid receptor functions in the ventral tegmental area. J. Neurochem. 82, 1192–1198 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. Hodos, W. Progressive ratio as a measure of reward strength. Science 134, 943–944 (1961).

    Article  CAS  PubMed  Google Scholar 

  24. Brennan, K., Roberts, D. C., Anisman, H. & Merali, Z. Individual differences in sucrose consumption in the rat: motivational and neurochemical correlates of hedonia. Psychopharmacology (Berl.) 157, 269–276 (2001).

    Article  CAS  Google Scholar 

  25. Kitai, S. T., Shepard, P. D., Callaway, J. C. & Scroggs, R. Afferent modulation of dopamine neuron firing patterns. Curr. Opin. Neurobiol. 9, 690–697 (1999).

    Article  CAS  PubMed  Google Scholar 

  26. Neuhoff, H., Neu, A., Liss, B. & Roeper, J. Ih channels contribute to the different functional properties of identified dopaminergic subpopulations in the midbrain. J. Neurosci. 22, 1290–1302 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Saddoris, M. P., Cacciapaglia, F., Wightman, R. M. & Carelli, R. M. Differential dopamine release dynamics in the nucleus accumbens core and shell reveal complementary signals for error prediction and incentive motivation. J. Neurosci. 35, 11572–11582 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Boekhoudt, L. et al. Enhancing excitability of dopamine neurons promotes motivational behaviour through increased action initiation. Eur. Neuropsychopharmacol. 28, 171–184 (2018).

    Article  CAS  PubMed  Google Scholar 

  29. Yang, H. et al. Nucleus accumbens subnuclei regulate motivated behavior via direct inhibition and disinhibition of VTA dopamine subpopulations. Neuron 97, 434–449.e4 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Al-Hasani, R. et al. Distinct subpopulations of nucleus accumbens dynorphin neurons drive aversion and reward. Neuron 87, 1063–1077 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Boender, A. J. et al. Combined use of the canine adenovirus-2 and DREADD-technology to activate specific neural pathways in vivo. PLoS ONE 9, e95392 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Navratilova, E. et al. Pain relief produces negative reinforcement through activation of mesolimbic reward–valuation circuitry. Proc. Natl Acad. Sci. USA 109, 20709–20713 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Liu, M.-Y. et al. Sucrose preference test for measurement of stress-induced anhedonia in mice. Nat. Protoc. 13, 1686–1698 (2018).

    Article  CAS  PubMed  Google Scholar 

  34. van Zessen, R., Phillips, J. L., Budygin, E. A. & Stuber, G. D. Activation of VTA GABA neurons disrupts reward consumption. Neuron 73, 1184–1194 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Jhou, T. C., Fields, H. L., Baxter, M. G., Saper, C. B. & Holland, P. C. The rostromedial tegmental nucleus (RMTg), a GABAergic afferent to midbrain dopamine neurons, encodes aversive stimuli and inhibits motor responses. Neuron 61, 786–800 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Huang, S., Borgland, S. L. & Zamponi, G. W. Peripheral nerve injury-induced alterations in VTA neuron firing properties. Mol. Brain 12, 89 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Creed, M. C., Ntamati, N. R. & Tan, K. R. VTA GABA neurons modulate specific learning behaviors through the control of dopamine and cholinergic systems. Front. Behav. Neurosci. 8, 8 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Waung, M. W., Margolis, E. B., Charbit, A. R. & Fields, H. L. A midbrain circuit that mediates headache aversiveness in rats. Cell Rep. 28, 2739–2747.e4 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Schultz, W. Dopamine reward prediction error coding. Dialogues Clin. Neurosci. 18, 23–32 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Schultz, W., Dayan, P. & Montague, P. R. A neural substrate of prediction and reward. Science 275, 1593–1599 (1997).

    Article  CAS  PubMed  Google Scholar 

  41. Li, H. et al. Three rostromedial tegmental afferents drive triply dissociable aspects of punishment learning and aversive valence encoding. Neuron 104, 987–999.e4 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Morales, M. & Margolis, E. B. Ventral tegmental area: cellular heterogeneity, connectivity and behaviour. Nat. Rev. Neurosci. 18, 73–85 (2017).

    Article  CAS  PubMed  Google Scholar 

  43. Navratilova, E. & Porreca, F. Reward and motivation in pain and pain relief. Nat. Neurosci. 17, 1304–1312 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Leknes, S., Lee, M., Berna, C., Andersson, J. & Tracey, I. Relief as a reward: hedonic and neural responses to safety from pain. PLoS ONE 6, e17870 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Mohebi, A. et al. Dissociable dopamine dynamics for learning and motivation. Nature 570, 65–70 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Liu, S. et al. Neuropathic pain alters reward and affect via kappa opioid receptor (KOR) upregulation. FASEB J. https://doi.org/10.1096/fasebj.30.1_supplement.928.5 (2016).

  47. Hayward, M. D., Schaich-Borg, A., Pintar, J. E. & Low, M. J. Differential involvement of endogenous opioids in sucrose consumption and food reinforcement. Pharmacol. Biochem. Behav. 85, 601–611 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Nummenmaa, L. et al. μ-opioid receptor system mediates reward processing in humans. Nat. Commun. 9, 1500 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Harris, R. E. et al. Decreased central μ-opioid receptor availability in fibromyalgia. J. Neurosci. 27, 10000–10006 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Zhou, W. et al. A neural circuit for comorbid depressive symptoms in chronic pain. Nat. Neurosci. https://doi.org/10.1038/s41593-019-0468-2 (2019).

Download references

Acknowledgements

We would like to thank all members from the Moron-Concepcion, Bruchas, Creed and Alvarez laboratories for their help throughout the completion of the current study. In addition, we thank I. Monosov for help with statistical analysis for Fig. 3i,j,k, and A. R. Wilson-Poe for manuscript review and editing. This work was supported by US National Institutes of Health (NIH) grants DA041781 (to J.A.M.), DA042581 (to J.A.M.), DA042499 (to J.A.M.), DA041883 (to J.A.M.) and DA045463 (to J.A.M.), a NARSAD Independent Investigator Award from the Brain and Behavior Research Foundation (to J.A.M.), the Brain and Behavior Research Foundation (NARSAD Young Investigator grant 27197 to M.C.C.), National Institutes of Health National Institute on Drug Abuse R21-DA047127 (to M.C.C.) and R01-DA049924 (to M.C.C.), Whitehall Foundation grant 2017-12-54 (to M.C.C.), a Rita Allen Scholar Award in Pain (to M.C.C.), and NRSA F31DA051124 (to C.E.P.).

Author information

Authors and Affiliations

Authors

Contributions

Conceptualization: T.M., N.M., C.E.P., J.H.S., V.A.A., M.R.B., M.C.C. and J.A.M. Methodology: T.M., V.A.A., M.R.B., M.C.C. and J.A.M. Formal analysis of all data: T.M., M.C.C. and J.A.M. Photometry acquisition and data extraction: T.M. and C.E.P. Patch-clamp physiology: Y.M.V., C.A.M., K.A. and M.C.C. Operant sucrose self-administration: T.M., N.M. and H.J.Y. Locomotor studies and two-bottle choice: T.M. and J.J.G. Hargreaves tests: T.M., H.J.Y., J.J.G. and N.M. Ex vivo FSCV: J.H.S. and V.A.A. cFOS counts and immunohistochemistry: T.M., B.R. and J.J.G. Orofacial reactivity and videos: Y.M.V. Surgeries: T.M. Writing (original draft): T.M., M.C.C. and J.A.M. Writing (review and editing): T.M., N.M., C.E.P., J.H.S., B.R., Y.M.V., C.A.M., J.J.G., H.J.Y., V.A.A., M.R.B., M.C.C. and J.A.M. Funding acquisition: V.A.A., M.R.B., M.C.C. and J.A.M. Resources: V.A.A., M.R.B., M.C.C. and J.A.M. Supervision: T.M., M.R.B., M.C.C. and J.A.M.

Corresponding authors

Correspondence to Meaghan C. Creed or Jose A. Morón.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information Nature Neuroscience thanks Kate Wassum and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Spread of viral expression and fiber optic placement in the VTA.

a-c Spread of overlay of individual animal viral expression and fiber optic placement across the VTA in GCaMP6s injected TH-cre animals.

Extended Data Fig. 2 VTA DA neuron aligned to reward seeking.

a. Representative heat-maps of fluorescence aligned to the lever press (time point 0) for baseline (grey) and post-SAL (blue) PR sessions for same animal. b. Mean fluorescence aligned to lever press for baseline (grey) and post-SAL (blue) PR sessions (n = 5 rats; data presented as mean ± s.e.m) c. Representative heat-maps of fluorescence aligned to the lever press (time point 0) for baseline (grey) and post-CFA (red) PR sessions for same animal. d. Mean fluorescence aligned to lever press for baseline (grey) and post-CFA (red) PR sessions (n = 7 rats; data presented as mean ± s.e.). e. Maximum fluorescence aligned to lever press is not altered in either CFA or saline injected animals as compared to their respective baseline. f. Saline injection does not alter latency of paw withdrawal to noxious stimulus using Hargraves test. g. Latency to withdraw a paw from a noxious stimulus is decreased in CFA, resulting in hyperalgesia (two tailed Wilcoxon test, * p = 0.0156, n = 7 rats). h. Transient events per minute of VTA DA neurons throughout the PR sessions are not altered after the injection of saline. i. Saline doesn’t affect the numbers of correct lever presses during PR session. j. CFA decreases overall frequency of VTA DA neurons calcium transients during PR session (two tailed Wilcoxon test, * p = 0.0156, n = 7 rats). k. CFA decreases the number of correct lever presses during PR session (two-tailed Wilcoxon test, * p = 0.0156, n = 7 rats).

Extended Data Fig. 3 Intrinsic excitability of VTA DA neurons is decreased in CFA injected animals.

a. Action potential threshold is not altered in either by CFA or upon application of PTX (n (SAL) = 21 cells from 5 rats, n (CFA) = 23 cells from 4 rats). b. Application of picrotoxin (PTX) further depolarized cells from the CFA group while it has no effect on the cells from saline injected animals (one sample t test compared to 100 percent, CFA, **** p < 0.0001, n (SAL) = 21 cells from 5 rats, n (CFA) = 23 cells from 4 rats). c. Application of picrotoxin (PTX) decreases the amount of current required to depolarize cells to fire an action potential in CFA treated animals (one sample t test compared to 100 percent, CFA, ** p = 0.0031, n (SAL) = 20 cells from 5 rats, n (CFA) = 22 cells from 4 rats). d. PTX increased input resistance in CFA but not saline treated animals (one sample t test compared to 100 percent, CFA, * p = 0.0373, n (SAL) = 21 cells from 5 rats, n (CFA) = 23 cells from 4 rats). The data are presented as the mean ± s.e.m.

Extended Data Fig. 4 Chemogenetic activation of VTA DA neurons, or VTA-NAcSh pathway reverses CFA induced decrease in number of correct lever presses for sucrose rewards in PR task.

a. Activation of DA containing neurons in the VTA reverses CFA induced decrease in number of correct lever presses in sucrose PR. Animals injected with control virus and CNO alone showed decrease in the number of correct lever presses after the CFA injection (two-way ANOVA for repeated measures, time: F1, 47 = 3.361, p = 0.0731; interaction (time x treatment): F3, 47 = 21.02, p < 0.0001; Sidak’s post hoc between groups during PR2: hM3Dq + CFA + VEH (n = 10) versus hM3Dq + SAL + CNO (n = 14), $$$$ p < 0.001, hM3Dq + CFA + VEH versus hM3Dq + CFA + CNO (n = 17), ## p = 0.002; m-Cherry + CFA + CNO (n = 10) versus hM3Dq + SAL + CNO, $$$$ p < 0.0001, m-Cherry + CFA + CNO versus hM3Dq + CFA + CNO, ## p = 0.0028), hM3Dq + CFA + CNO versus hM3Dq + SAL + CNO, $ p = 0.0188). b. Activation of NAcSh projecting VTA neurons reverses CFA induced decrease in number of correct lever presses in sucrose PR. Control CFA animals injected with either CNO or virus alone show decrease in number of correct lever presses in sucrose PR (two-way ANOVA for repeated measures, time: F1, 53 = 87.59, p < 0.0001; interaction (time x treatment): F3, 53 = 4.036, p = 0.0117; Sidak’s post hoc during PR2 between the groups: hM3Dq + CFA + VEH (n = 17) versus hM3Dq + SAL + CNO (n = 12), $$ p = 0.0021, m-Cherry + CFA + CNO (n = 11) versus hM3Dq + SAL + CNO, $ p = 0.0116). The data are presented as the mean ± s.e.m. c. Representative coronal section of VTA DREADD expressing neurons. Blue – DAPI; Red – m-Cherry (Gq DREADD); Green – TH (DA neurons). Schematic representation of viral injections for Gq DREADD injected TH cre + rats used for chemogenetic experiments in Fig. 3a–d. d. Representative coronal section of VTA Gq DREADD expressing neurons. Blue – DAPI; Red – m-Cherry (Gq DREADD); Green – TH (DA neurons). Schematic representation of viral injections for Gq DREADD injected wild type rats used in chemogenetics experiment in Fig. 3e–k. e. Representative images of low viral infection rate (red dotted line) correlated with decrease in motivation (red circle) and high viral infection rate (blue dotted line) correlated with no change in motivation (blue circle) during PR test using intersectional chemogenetics in CFA treated animals.

Extended Data Fig. 5 Spread of viral expression in the VTA.

a. Spread of overlay of individual animal viral expression across VTA in DREADD and control m-Cherry injected TH-cre animals used in Fig. 3b–d. b. Spread of overlay of individual animal viral expression across VTA in DREADD and control m-Cherry injected WT animals used in Fig. 3f–k.

Extended Data Fig. 6 Chemogenetic activation of NAcSH projecting VTA DA neurons, prevents CFA induced decrease in number of correct lever presses for sucrose rewards in PR task.

a. Activation of DA containing NAcSh projecting VTA neurons prevents CFA induced decrease in number of correct lever presses in sucrose PR. Animals injected with control virus and CNO alone showed decrease in the number of correct lever presses after the CFA injection (two-way ANOVA for repeated measures, time: F1, 27 = 8.016, p = 0.0087; interaction (time x treatment): F3, 27 = 4.966, p = 0.0071; Sidak’s post hoc between groups during PR2: hM3Dq + CFA + VEH (n = 7) versus hM3Dq + SAL + CNO (n = 8), $$$ p = 0.0005; m-Cherry + CFA + CNO (n = 8) versus hM3Dq + SAL + CNO, $$$$ p < 0.0001, m-Cherry + CFA + CNO versus hM3Dq + CFA + CNO(n = 8), # p = 0.0190). b. Schematic representation of cannula placement in the NAcSh for local delivery of aCSF or CNO. c. Spread of overlay of individual animal viral expression across VTA in DREADD and control m-Cherry injected TH-cre animals. The data are presented as the mean ± s.e.m.

Extended Data Fig. 7 CFA does not alter intake of water during the sucrose two-bottle choice experiment.

a. 5% and 30% sucrose significantly increased consummatory protrusions as compared to water, with similar trend being seeing with 60% sucrose as well (ANOVA Friedman’s test, **** p < 0.0001; two-tailed Dunn’s multiple comparisons post hoc: 5% sucrose versus water, ** p = 0.0036; 30% sucrose versus water, * p = 0.0423, n = 5 rats). No changes are observed in number of ingestive licks or the length of the lick between different concentrations. b. Volume of water consumed is not changed after the CFA injection during either 5% (CFA (n = 13 rats), SAL (n = 12 rats)), 30% (CFA (n = 12 rats) and SAL (n = 13 rats)) or 60% (CFA (n = 15 rats), SAL (n = 12 rats)) sucrose two-bottle choice. c. CFA decreases 5% sucrose preference during two-bottle choice (open bars -baseline, filled bars – 48 hours post CFA/SAL. two-way ANOVA for repeated measures, time: F1, 23 = 2.339, p = 0.1398; interaction (time x treatment): F1, 23 = 4.446, p = 0.0461; Sidak’s post hoc within group: CFA (n = 13) baseline versus 48 hours post CFA, * p = 0.03), while it has no effect on 30% or 60% sucrose preference. d. CFA decreases latency to withdrawal from a noxious stimulus resulting in hyperalgesia (two-way ANOVA for repeated measures, 5% sucrose (CFA (n = 13 rats), SAL (n = 12 rats)), time: F1,23 = 91.75, p < 0.0001; interaction (time x treatment): F1,23 = 63.86, p < 0.0001; Sidak’s post hoc for each group as compared to the group’s baseline session: **** p < 0.0001; 30% sucrose (CFA (n = 12 rats) and SAL (n = 13 rats)) time: F1,23 = 40.71, p < 0.0001; interaction (time x treatment): F1,23 = 20.02, p = 0.0002; Sidak’s post hoc for each group as compared to the group’s baseline session: **** p < 0.0001; 60% sucrose 60% (CFA (n = 15 rats), SAL (n = 12 rats)) time: F1,25 = 72.34, p < 0.0001; interaction: F1,25 = 43.85, p < 0.0001; Sidak’s post hoc for each group as compared to the group’s baseline session: **** p < 0.0001). The data are presented as the mean ± s.e.m.

Extended Data Fig. 8 Chemogenetic stimulation of VTA DA neurons does not alter water intake in two-bottle choice test.

a. Chemogenetic activation of DA containing neurons in the VTA does not alter sucrose preference in two-bottle choice test. b. CFA induced hyperalgesia is not altered by activation of VTA DA neurons (two-way ANOVA for repeated measures, time: F2, 48 = 148.2, p < 0.0001; interaction (time x treatment): F6, 48 = 19.30, p < 0.0001; Sidak’s post hoc for each group as compared to the group’s baseline session: **** p < 0.0001; n (hM3Dq SAL + CNO) = 7 rats, n (hM3Dq CFA + CNO) = 7 rats, n (hM3Dq CFA + VEH) = 7 rats, n (m-Cherry CFA + CNO) = 6 rats). c. Chemogenetic activation of DA containing neurons in the VTA does not alter water consumption in two-bottle choice test. d. Representative coronal section of VTA DREADD expressing neurons. Blue – DAPI; Red – m-Cherry (Gq DREADD); Green – TH (DA neurons). e. Spread of overlay of individual animal viral expression across VTA in DREADD and control m-Cherry injected TH-cre animals. The data are presented as the mean ± s.e.m.

Extended Data Fig. 9 Chemogenetic stimulation of RMTg GABA neurons does not alter sucrose preference in two-bottle choice test.

a-d. Chemogenetic activation of RMTg GABA cells does not alter preference for 60% or 5% sucrose or water consumption in two-bottle choice test. e. Sucrose consumption presented as percent change of baseline (5% sucrose (n (m-Cherry) = 6 rats, n (hM3Dq) = 7 rats) two tailed unpaired t test, * p = 0.0105; 60% sucrose (n (m-Cherry) = 6 rats, n (hM3Dq) = 7 rats) two tailed unpaired t test p = 0.0610). f. Representative coronal section of RMTg Gq DREADD expressing neurons. Blue – DAPI; Red – m-Cherry (Gq DREADD); Green – GAD 67 (GABA neurons). g. Spread of overlay of individual animal viral expression across RMTg in DREADD and control m-Cherry injected GAD-cre animals. The data are presented as the mean ± s.e.m. h-j. PPR is not correlated with the evoked amplitude of initial response at any inter-pulse interval. The data are presented as regression line and 95% confidence interval.

Extended Data Fig. 10 Chemogenetic inhibition of RMTg-VTA GABAergic pathway does not alter sucrose preference in two-bottle choice test.

a-b. Chemogenetic inhibition of RMTg GABA cells projecting to VTA does not alter sucrose preference or water consumption in two-bottle choice test. c. Sucrose consumption presented as percent change of baseline (two-way ANOVA for repeated measures, time: F1, 20 = 20.89, p = 0.0002; interaction (time x treatment): F2,20 = 6.236, p = 0.0079; Sidak’s post hoc within group: hM3Di + CFA + CNO(n = 8) versus hM3Di + CFA + VEH (n = 8), **** p < 0.0001) d. Representative coronal section of RMTg Gi DREADD expressing neurons. Blue – DAPI; Red – m-Cherry (Gi DREADD); Green – GAD 67 (GABA neurons). e. Representative coronal section of cannula placement in the VTA. Blue – DAPI; Red – m-Cherry (Gi DREADD); Green – TH (DA neurons). f. Spread of overlay of individual animal viral expression across RMTg in DREADD and control m-Cherry injected GAD-cre animals. i. Schematic representation of cannula placement in the VTA for local delivery of aCSF or CNO. The data are presented as the mean ± s.e.m.

Supplementary information

Supplementary Information

Supplementary Figs. 1–5 with legends.

Reporting Summary

Supplementary Video 1

Hedonic protrusions, 60% sucrose.

Supplementary Video 2

Exaggerated swallowing, 60% sucrose.

Supplementary Video 3

Aversive quinine gapes.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Markovic, T., Pedersen, C.E., Massaly, N. et al. Pain induces adaptations in ventral tegmental area dopamine neurons to drive anhedonia-like behavior. Nat Neurosci 24, 1601–1613 (2021). https://doi.org/10.1038/s41593-021-00924-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41593-021-00924-3

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing