L-DOPA modulates activity in the vmPFC, Nucleus Accumbens and VTA during threat extinction learning in humans

  1. Roland Esser
  2. Christoph W Korn
  3. Florian Ganzer
  4. Jan Haaker  Is a corresponding author
  1. University Medical Center Hamburg-Eppendorf, Germany

Abstract

Learning to be safe is central for adaptive behaviour when threats are no longer present. Detecting the absence of an expected threat is key for threat extinction learning and an essential process for the behavioural treatment of anxiety related disorders. One possible mechanism underlying extinction learning is a dopaminergic mismatch signal that encodes the absence of an expected threat. Here we show that such a dopamine-related pathway underlies extinction learning in humans. Dopaminergic enhancement via administration of L-DOPA (vs. Placebo) was associated with reduced retention of differential psychophysiological threat responses at later test, which was mediated by activity in the ventromedial prefrontal cortex that was specific to extinction learning. L-DOPA administration enhanced signals at the time-point of an expected, but omitted threat in extinction learning within the nucleus accumbens, which were functionally coupled with the ventral tegmental area and the amygdala. Computational modelling of threat expectancies further revealed prediction error encoding in nucleus accumbens that was reduced when L-DOPA was administered. Our results thereby provide evidence that extinction learning is influenced by L-DOPA and provide a mechanistic perspective to augment extinction learning by dopaminergic enhancement in humans.

Data availability

All data for analyses and figures in this study are provided in the within the Open Science Framework

The following data sets were generated

Article and author information

Author details

  1. Roland Esser

    Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Christoph W Korn

    Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Florian Ganzer

    Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Jan Haaker

    Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
    For correspondence
    j.haaker@uke.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8366-9559

Funding

Deutsche Forschungsgemeinschaft (Project B10 (INST 211/755) of the Collaborative Research Center TRR58)

  • Roland Esser
  • Jan Haaker

Deutsche Forschungsgemeinschaft (HA 7470/3-1)

  • Jan Haaker

Deutsche Forschungsgemeinschaft (collaborative research centre SFB TRR 169)

  • Christoph W Korn

Deutsche Forschungsgemeinschaft (Emmy Noether Research Group (392443797))

  • Christoph W Korn

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: The ethical approval was obtained by the ethics committee of the Ärztekammer Hamburg (PV5158)that approved the study. Participants gave their written, informed consent to participate in the study, for the collection of the data and consent to publish.

Reviewing Editor

  1. Alexander Shackman, University of Maryland, United States

Publication history

  1. Received: November 30, 2020
  2. Preprint posted: December 7, 2020 (view preprint)
  3. Accepted: September 1, 2021
  4. Accepted Manuscript published: September 2, 2021 (version 1)
  5. Version of Record published: September 15, 2021 (version 2)

Copyright

© 2021, Esser et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Roland Esser
  2. Christoph W Korn
  3. Florian Ganzer
  4. Jan Haaker
(2021)
L-DOPA modulates activity in the vmPFC, Nucleus Accumbens and VTA during threat extinction learning in humans
eLife 10:e65280.
https://doi.org/10.7554/eLife.65280

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