Article | Published:

Role of the mesolimbic dopamine system in relief learning

Neuropsychopharmacologyvolume 43pages16511659 (2018) | Download Citation


The relief from an aversive event is rewarding. Since organisms are able to learn which environmental cues can cease an aversive event, relief learning helps to better cope with future aversive events. Literature data suggest that relief learning is affected in various psychopathological conditions, such as anxiety disorders. Here, we investigated the role of the mesolimbic dopamine system in relief learning. Using a relief learning procedure in Sprague Dawley rats, we applied a combination of behavioral experiments with anatomical tracing, c-Fos immunohistochemistry, and local chemogenetic and pharmacological interventions to broadly characterize the role of the mesolimbic dopamine system. The present study shows that a specific part of the mesolimbic dopamine system, the projection from the posterior medial ventral tegmental area (pmVTA) to the nucleus accumbens shell (AcbSh), is activated by aversive electric stimuli. 6-OHDA lesions of the pmVTA blocked relief learning but fear learning and safety learning were not affected. Chemogenetic silencing of the pmVTA-AcbSh projection using the DREADD approach, as well as intra-AcbSh injections of the dopamine D2/3 receptor antagonist raclopride inhibited relief learning. Taken together, the present data demonstrate that the dopaminergic pmVTA-AcbSh projection is critical for relief learning but not for similar learning phenomena. This novel finding may have clinical implications since the processing of signals predicting relief and safety is often impaired in patients suffering from anxiety disorders. Furthermore, it may help to better understand psychological conditions like non-suicidal self-injury, which are associated with pain offset relief.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Additional information

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


  1. 1.

    Solomon RL. The opponent-process theory of acquired motivation—the costs of pleasure and the benefits of pain. Am Psychol. 1980;35:691–712.

  2. 2.

    Solomon RL, Corbit JD. Opponent-process theory of motivation .1. Temporal dynamics of affect. Psychol Rev. 1974;81:119–45.

  3. 3.

    Gerber B, Yarali A, Diegelmann S, Wotjak CT, Pauli P, Fendt M. Pain-relief learning in flies, rats, and man: basic research and applied perspectives. Learn Mem. 2014;21:232–52.

  4. 4.

    LeDoux J. Rethinking the emotional brain. Neuron. 2012;73:653–76.

  5. 5.

    Fendt M, Fanselow MS. The neuroanatomical and neurochemical basis of conditioned fear. Neurosci Biobehav Rev. 1999;23:743–60.

  6. 6.

    Johansen JP, Cain CK, Ostroff LE, LeDoux JE. Molecular mechanisms of fear learning and memory. Cell. 2011;147:509–24.

  7. 7.

    Denny MR. Relaxation theory and experiments. In: Brush FR editors. Aversive conditioning and learning. New York, NY: Academic Press; 1971. p. 235–95.

  8. 8.

    Navratilova E, Atcherley CW, Porreca F. Brain circuits encoding reward from pain relief. Trends Neurosci. 2015;38:741–50.

  9. 9.

    Christianson JP, Fernando ABP, Kazama AM, Jovanovic T, Ostroff LE, Sangha S. Inhibition of fear by learned safety signals: a mini-symposium review. J Neurosci. 2012;32:14118–24.

  10. 10.

    Pollak DD, Monje FJ, Lubec G. The learned safety paradigm as a mouse model for neuropsychiatric research. Nat Protoc. 2010;5:954–62.

  11. 11.

    Lohr JM, Olatunji BO, Sawchuk CN. A functional analysis of danger and safety signals in anxiety disorders. Clin Psychol Rev. 2007;27:114–26.

  12. 12.

    Lissek S, Powers AS, McClure EB, Phelps EA. Classical fear conditioning in the anxiety disorders: a meta-analysis. Behav Res Ther. 2005;43:1424.

  13. 13.

    Lissek S, Rabin S, Heller RE, Lukenbaugh D, Geraci M, Pine DS, Grillon C. Overgeneralization of conditioned fear as a pathogenic marker of panic disorder. Am J Psychiatry. 2010;167:47–55.

  14. 14.

    Öhman A, Mineka S. Fears, phobias, and preparedness: toward an evolved module of fear and fear learning. Psychol Rev. 2001;108:483–522.

  15. 15.

    Bouton ME, Mineka S, Barlow DH. A modern learning theory perspective on the etiology of panic disorder. Psychol Rev. 2001;108:4–32.

  16. 16.

    Jovanovic T, Kazama A, Bachevalier J, Davis M. Impaired safety signal learning may be a biomarker of PTSD. Neuropharmacology. 2012;62:695–704.

  17. 17.

    Lissek S, Rabin SJ, McDowell DJ, Dvir S, Bradford DE, Geraci M, Pine DS, Grillon C. Impaired discriminative fear-conditioning resulting from elevated fear responding to learned safety cues among individuals with panic disorder. Behav Res Ther. 2009;47:111–8.

  18. 18.

    Kong E, Monje FJ, Hirsch J, Pollak DD. Learning not to fear: neural correlates of learned safety. Neuropsychopharmacology. 2014;39:515–27.

  19. 19.

    Rogan MT, Leon KS, Perez DL, Kandel ER. Distinct neural signatures for safety and danger in the amygdala and striatum of the mouse. Neuron. 2005;46:309–20.

  20. 20.

    Schiller D, Levy I, Niv Y, LeDoux JE, Phelps EA. From fear to safety and back: reversal of fear in the human brain. J Neurosci. 2008;28:11517–25.

  21. 21.

    Becerra L, Navratilova E, Porreca F, Borsook D. Analogous responses in the nucleus accumbens and cingulate cortex to pain onset (aversion) and offset (relief) in rats and humans. J Neurophysiol. 2013;110:1221–6.

  22. 22.

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

  23. 23.

    Andreatta M, Fendt M, Mühlberger A, Wieser MJ, Imobersteg S, Yarali A, Gerber B, Pauli P. Onset and offset of aversive events establish distinct memories requiring fear- and reward networks. Learn Mem. 2012;19:518–26.

  24. 24.

    Seymour B, O’Doherty JP, Koltzenburg M, Wiech K, Frackowiak R, Friston K, Dolan R. Opponent appetitive-aversive neural processes underlie predictive learning of pain relief. Nat Neurosci. 2005;8:1234–40.

  25. 25.

    Mohammadi M, Bergado Acosta JR, Fendt M. Relief learning is distinguished from safety learning by the requirement of the nucleus accumbens. Behav Brain Res. 2014;272:40–45.

  26. 26.

    Navratilova E, Xie JY, Okun A, Qu CL, Eyde N, Ci S, Ossipov MH, King T, Fields HL, Porreca F. Pain relief produces negative reinforcement through activation of mesolimbic reward-valuation circuitry. Proc Natl Acad Sci USA. 2012;109:20709–13.

  27. 27.

    Kahl E, Fendt M. Metabotropic glutamate receptors 7 within the nucleus accumbens are involved in relief learning in rats. Curr Neuropharmacol. 2016;14:405–12.

  28. 28.

    Bergado Acosta JR, Kahl E, Kogias G, Uzuneser TC, Fendt M. Relief learning requires a coincident activation of dopamine D1 and NMDA receptors within the nucleus accumbens. Neuropharmacology. 2017;114:58–66.

  29. 29.

    Mohammadi M, Fendt M. Relief learning is dependent on NMDA receptor activation in the nucleus accumbens. Br J Pharmacol. 2015;172:2419–26.

  30. 30.

    Leknes S, Brooks JCW, Wiech K, Tracey I. Pain relief as an opponent process: a psychophysical investigation. Eur J Neurosci. 2008;28:794–801.

  31. 31.

    Ikemoto S. Dopamine reward circuitry: two projection systems from the ventral midbrain to the nucleus accumbens-olfactory tubercle complex. Brain Res Rev. 2007;56:27–78.

  32. 32.

    Brischoux F, Chakraborty S, Brierley DI, Ungless MA. Phasic excitation of dopamine neurons in ventral VTA by noxious stimuli. Proc Natl Acad Sci USA. 2009;106:4894–9.

  33. 33.

    Paxinos G, Watson C. The rat brain in stereotaxic coordinates. San Diego: Academic Press; 2014.

  34. 34.

    Lin HY, Yeh WL, Huang BR, Lin CJ, Lai CH, Lin H, Lu DY. Desipramine protects neuronal cell death and induces heme oxygenase-1 expression in Mes23.5 dopaminergic neurons. PLoS ONE. 2012;7:e50138.

  35. 35.

    Kahl E, Fendt M. Injections of the somatostatin receptor type 2 agonist L-054,264 into the amygdala block expression but not acquisition of conditioned fear in rats. Behav Brain Res. 2014;265:49–52.

  36. 36.

    Mahler SV, Vazey EM, Beckley JT, Keistler CR, McGlinchey EM, Kaufling J, Wilson SP, Deisseroth K, Woodward JJ, Aston-Jones G. Designer receptors show role for ventral pallidum input to ventral tegmental area in cocaine seeking. Nat Neurosci. 2014;17:577–85.

  37. 37.

    Lex A, Hauber W. Dopamine D1 and D2 receptors in the nucleus accumbens core and shell mediate Pavlovian-instrumental transfer. Learn Mem. 2008;15:483–91.

  38. 38.

    Schulz S, Schreff M, Koch T, Zimprich A, Gramsch C, Elde R, Höllt V. Immunolocalization of two mu-opioid receptor isoforms (MOR1 and MOR1B) in the rat central nervous system. Neuroscience. 1998;82:613–22.

  39. 39.

    Morgan JI, Curran T. Stimulus-transcription coupling in the nervous system: involvement of the inducible proto-oncogenes fos and jun. Annu Rev Neurosci. 1991;14:421–51.

  40. 40.

    Björklund A, Dunnett SB. Dopamine neuron systems in the brain: an update. Trends Neurosci. 2007;30:194–202.

  41. 41.

    Roth BL. DREADDs for neuroscientists. Neuron. 2016;89:683–94.

  42. 42.

    Bergado Acosta JR, Schneider M, Fendt M. Intra-accumbal blockade of endocannabinoid CB1 receptors impairs learning but not retention of conditioned relief. Neurobiol Learn Mem. 2017;144:48–52.

  43. 43.

    Grillon C. Models and mechanisms of anxiety: evidence from startle studies. Psychopharmacology (Berl). 2008;199:421–37.

  44. 44.

    Koch M. The neurobiology of startle. Prog Neurobiol. 1999;59:107–28.

  45. 45.

    Davis M, Astrachan DI. Conditioned fear and startle magnitude: effects of different footshock or backshock intensities used in training. J Exp Psychol: Anim Behav Proc. 1978;4:95–103.

  46. 46.

    Christianson JP, Benison AM, Jennings J, Sandsmark EK, Amat J, Kaufman RD, Baratta MV, Paul ED, Campeau S, Watkins LR, Barth DS, Maier SF. The sensory insular cortex mediates the stress-buffering effects of safety signals but not behavioral control. J Neurosci. 2008;28:13703–11.

  47. 47.

    Bruning JEA, Breitfeld T, Kahl E, Bergado-Acosta JR, Fendt M. Relief memory consolidation requires protein synthesis within the nucleus accumbens. Neuropharmacology. 2016;105:10–14.

  48. 48.

    Herdegen T, Leah JD. Inducible and constitutive transcription factors in the mammalian nervous system: control of gene expression by Jun, Fos and Krox, and CREB/ATF proteins. Brain Res Rev. 1998;28:370–490.

  49. 49.

    Roberts DCS, Koob GF. Disruption of cocaine self-administration following 6-hydroxydopamine lesions of the ventral tegmental area in rats. Pharmacol Biochem Behav. 1982;17:901–4.

  50. 50.

    Shibata R, Kameishi M, Kondoh T, Torii K. Bilateral dopaminergic lesions in the ventral tegmental area of rats influence sucrose intake, but not umami and amino acid intake. Physiol Behav. 2009;96:667–74.

  51. 51.

    Smith KS, Bucci DJ, Luikart BW, Mahler SV. DREADDs: use and application in behavioral neuroscience. Behav Neurosci. 2016;130:137–55.

  52. 52.

    Gomez JL, Bonaventura J, Lesniak W, Mathews WB, Sysa-Shah P, Rodriguez LA, Ellis RJ, Richie CT, Harvey BK, Dannals RF, Pomper MG, Bonci A, Michaelides M. Chemogenetics revealed: DREADD occupancy and activation via converted clozapine. Science. 2017;357:503.

  53. 53.

    Coward DM. General pharmacology of clozapine. Br J Pharmacol. 1992;17:5–11.

  54. 54.

    Melchior JR, Ferris MJ, Stuber GD, Riddle DR, Jones SR. Optogenetic versus electrical stimulation of dopamine terminals in the nucleus accumbens reveals local modulation of presynaptic release. J Neurochem. 2015;134:833–44.

  55. 55.

    Köhler C, Hall H, Ögren SO, Gawell L. Specific in vitro and in vivo binding of 3H-raclopride a potent substituted benzamide drug with high affinity for dopamine D-2 receptors in the rat brain. Biochem Pharmacol. 1985;34:2251–9.

  56. 56.

    Navratilova E, Porreca F. Reward and motivation in pain and pain relief. Nat Neurosci. 2014;17:1304–12.

  57. 57.

    White NM, Packard MG, Hiroi N. Place conditioning with dopamine D1 and D2 agonists injected peripherally or into nucleus accumbens. Psychopharmacol (Berl). 1991;103:271–6.

  58. 58.

    Pollak DD, Monje FJ, Zuckerman L, Denny CA, Drew MR, Kandel ER. An animal model of a behavioral intervention for depression. Neuron. 2008;60:149–61.

  59. 59.

    Rescorla RA. Pavlovian conditioned inhibition. Psychol Bull. 1969;72:77–94.

  60. 60.

    Fernando ABP, Urcelay GP, Mar AC, Dickinson A, Robbins TW. Comparison of the conditioned reinforcing properties of a safety signal and appetitive stimulus: effects of d-amphetamine and anxiolytics. Psychopharmacol (Berl). 2014;227:195–208.

  61. 61.

    Navratilova E, Xie JY, King T, Porreca F. Evaluation of reward from pain relief. Addict Rev. 2013;1282:1–11.

  62. 62.

    Jovanovic T, Norrholm SD, Blanding NQ, Davis M, Duncan E, Bradley B, Ressler KJ. Impaired fear inhibition is a biomarker of PTSD but not depression. Depress Anxiety. 2010;27:244–51.

  63. 63.

    Sailer U, Robinson S, Fischmeister FP, König D, Oppenauer C, Lueger-Schuster B, Moser E, Kryspin-Exner I, Bauer H. Altered reward processing in the nucleus accumbens and mesial prefrontal cortex of patients with posttraumatic stress disorder. Neuropsychologia. 2008;46:2836–44.

  64. 64.

    Harrison PJ, Weinberger DR. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry. 2005;10:40–68.

  65. 65.

    Koob GF, Volkow ND. Neurocircuitry of addiction. Neuropsychopharmacology. 2010;35:217–38.

  66. 66.

    Franklin JC, Lee KM, Hanna EK, Prinstein MJ. Feeling worse to feel better: Pain-offset relief simultaneously stimulates positive affect and reduces negative affect. Psychol Sci. 2013;24:521–9.

  67. 67.

    Borsook D, Linnman C, Faria V, Strassman AM, Becerra L, Elman I. Reward deficiency and anti-reward in pain chronification. Neurosci Biobehav Rev. 2016;68:282–97.

Download references


The authors are grateful to Drs. Kerstin Wernecke and Jorge Bergado Acosta for various helps during the study, Dr. Michael Lippert for the gift of pAAV2-CaMKIIa-mCherry, Dr. Thomas Endres, Judith Kreutzmann, and Nadine Faesel for critical comments to the manuscript, Judith Kreutzmann for language editing, and Kathrin Freke for animal care.


This study was supported by the German Science Foundation (DFG; SFB779/B13).

Author information

Author notes

    • Taygun C. Uzuneser

    Present address: Department for Psychiatry & Psychotherapy, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany


  1. Institute for Pharmacology and Toxicology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany

    • Dana Mayer
    • , Evelyn Kahl
    • , Taygun C. Uzuneser
    •  & Markus Fendt
  2. Integrative Neuroscience Program, Otto-von-Guericke University Magdeburg, Magdeburg, Germany

    • Taygun C. Uzuneser
  3. Center of Behavioral Brain Sciences, Otto-von-Guericke University Magdeburg, Magdeburg, Germany

    • Markus Fendt


  1. Search for Dana Mayer in:

  2. Search for Evelyn Kahl in:

  3. Search for Taygun C. Uzuneser in:

  4. Search for Markus Fendt in:

Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Markus Fendt.

Electronic supplementary material

About this article

Publication history






Further reading