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Role of the mesolimbic dopamine system in relief learning

Neuropsychopharmacologyvolume 43pages16511659 (2018) | Download Citation

Abstract

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.

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Acknowledgements

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.

Funding

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

Affiliations

  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

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Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Markus Fendt.

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DOI

https://doi.org/10.1038/s41386-018-0020-1

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