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Single dose of l-dopa makes extinction memories context-independent and prevents the return of fear

  1. Raffael Kalischa,e,2,3
  1. aInstitute for Systems Neuroscience, University Medical Center Hamburg-Eppendorf (UKE), 20246 Hamburg, Germany;
  2. bInstitute of Physiology I (Neurophysiology), Westfaelische Wilhems-University Münster, 48149 Münster, Germany;
  3. cDeparment of Pharmacology and Toxicology, Institute of Pharmacy and Center for Molecular Biosciences (CMBI) Innsbruck, University of Innsbruck, 6020 Innsbruck, Austria;
  4. dExperimental Neuropediatrics, Center for Molecular Neurobiology Hamburg (ZNMH), University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany; and
  5. eNeuroimaging Center Mainz (NIC), Focus Program Translational Neuroscience, Johannes Gutenberg University Medical Center, 55131 Mainz, Germany

  1. Edited by Christian Grillon, National Institute of Mental Health, Bethesda, MD, and accepted by the Editorial Board May 22, 2013 (received for review February 19, 2013)

Significance

Traumatic events can engender persistent excessive fear responses to trauma reminders that may return even after successful treatment. In the psychotherapy of fear or anxiety disorders, patients make safety experiences that generate fear-inhibitory safety memories. Fear, however, frequently returns because safety memory retrieval fails. We find that safety memories can be strengthened and are more easily retrieved when adding a standard anti-Parkinson drug that augments brain levels of the neurotransmitter dopamine directly after a safety experience. In mice and humans, this treatment up-regulates an anti-fear area in the frontal cortex. Our findings open a unique avenue for improving psychotherapy.

Abstract

Traumatic events can engender persistent excessive fear responses to trauma reminders that may return even after successful treatment. Extinction, the laboratory analog of behavior therapy, does not erase conditioned fear memories but generates competing, fear-inhibitory “extinction memories” that, however, are tied to the context in which extinction occurred. Accordingly, a dominance of fear over extinction memory expression—and, thus, return of fear—is often observed if extinguished fear stimuli are encountered outside the extinction (therapy) context. We show that postextinction administration of the dopamine precursor l-dopa makes extinction memories context-independent, thus strongly reducing the return of fear in both mice and humans. Reduced fear is accompanied by decreased amygdala and enhanced ventromedial prefrontal cortex activation in both species. In humans, ventromedial prefrontal cortex activity is predicted by enhanced resting-state functional coupling of the area with the dopaminergic midbrain during the postextinction consolidation phase. Our data suggest that dopamine-dependent boosting of extinction memory consolidation is a promising avenue to improving anxiety therapy.

Footnotes

  • ↵1S.G. and A.S. contributed equally to this work.

  • ↵2F.M. and R.K. contributed equally to this work.

  • ↵3To whom correspondence should be addressed. E-mail: raffael.kalisch{at}unimedizin-mainz.de.

  • Author contributions: N.S., H.-C.P., F.M., and R.K. designed research; J.H., S.G., A.S., N.G., T.B.L., K.M., and F.M. performed research; J.H., S.G., A.S., T.B.L., F.M., and R.K. analyzed data; and J.H. and R.K. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission. C.G. is a guest editor invited by the Editorial Board.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1303061110/-/DCSupplemental.

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