Elsevier

Biological Psychiatry

Volume 78, Issue 3, 1 August 2015, Pages 194-202
Biological Psychiatry

Archival Report
Oxytocin Facilitates the Extinction of Conditioned Fear in Humans

https://doi.org/10.1016/j.biopsych.2014.10.015Get rights and content

Abstract

Background

Current neurocircuitry models of anxiety disorders posit a lack of inhibitory tone in the amygdala during acquisition of Pavlovian fear responses and deficient encoding of extinction responses in amygdala–medial prefrontal cortex circuits. Competition between these two responses often results in a return of fear, limiting control over anxiety. However, one hypothesis holds that a pharmacologic strategy aimed at reducing amygdala activity while simultaneously augmenting medial prefrontal cortex function could facilitate the extinction of conditioned fear.

Methods

Key among the endogenous inhibitors of amygdala activity in response to social fear signals is the hypothalamic peptide oxytocin. To address the question whether oxytocin can strengthen Pavlovian extinction beyond its role in controlling social fear, we conducted a functional magnetic resonance imaging experiment with 62 healthy male participants in a randomized, double-blind, parallel-group, placebo-controlled design. Specifically, subjects were exposed to a Pavlovian fear conditioning paradigm before receiving an intranasal dose (24 IU) of synthetic oxytocin or placebo.

Results

Oxytocin, when administered intranasally after Pavlovian fear conditioning, was found to increase electrodermal responses and prefrontal cortex signals to conditioned fear in the early phase of extinction and to enhance the decline of skin conductance responses in the late phase of extinction. Oxytocin also evoked an unspecific inhibition of amygdalar responses in both phases.

Conclusions

Collectively, our findings identify oxytocin as a differentially acting modulator of neural hubs involved in Pavlovian extinction. This specific profile of oxytocin action may open up new avenues for enhancing extinction-based therapies for anxiety disorders.

Section snippets

Participants

Participants included 62 healthy, right-handed men (mean age ± SD, 24.61 ± 4.28 years) who gave written, informed consent. The study was approved by the institutional review board (Identifier: 329/12) and carried out in compliance with the latest revision of the Declaration of Helsinki. The study was registered in the ClinicalTrials.gov database (Identifier: NCT02156661) provided by the U.S. National Institutes of Health. Subjects were free of current and past physical or psychiatric illness,

Physiologic Parameters

Results of the conditioning session before OXT treatment are reported in Supplement 1. For the extinction procedure, a 2 × 2 × 2 repeated measures ANOVA with the within-subject factors “stimulus type” (CS+, CS−) and “phase” (early phase, late phase), the between-subject variable “treatment” (OXT, PLC), and the SCR as dependent variable was performed. The analysis revealed significant main effects of stimulus type [F1,34 = 2.99, p = .046 one-tailed, η2 = .08] and phase [F1,34 = 7.08, p = .01, η2

Discussion

The present study was designed to examine the modulatory effects of intranasal OXT on the neural and psychophysiologic substrates of Pavlovian extinction. Analysis of the SCR profiles revealed that in the early phase of extinction, the sensitivity to both danger (CS+) and safety (CS−) cues was increased by OXT, and this was followed by a greater decline in regard to the late phase. Treatment with OXT also induced higher BOLD responses to the danger cue (CS+) in right prefrontal areas during the

Acknowledgments and Disclosures

This work was supported by a Starting Independent Researcher Grant (Neuromodulation of Emotion research group) jointly provided by the Ministry of Innovation, Science, Research & Technology of the German State of North Rhine–Westphalia and the University of Bonn (RH) and the National Natural Science Foundation of China Grant No. 91132720 (KMK).

Author contributions are as follows: ME, BB, VG, and RH designed the experiments; ME, CS, and KP conducted the experiments; ME, CS, BB, DS, and RH

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