Oxytocin facilitates the extinction of conditioned fear in humans
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.
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Oxytocin strengthens top-down cognitive control by increasing middle frontal gyrus activity.
“Additionally, OXT strengthens top-down cognitive control strengthens top-down cognitive control by enhancing activity in the middle frontal gyrus (MFG) (Eckstein et al., 2015;Striepens et al., 2016).”
From Oxytocin enhances the pain‐relieving effects of social support in romantic couples (2019) · cites this paper as Eckstein et al., 2015
An oxytocin-induced increase in prefrontal cortex activity may reflect enhanced top-down cognitive control.
“Additionally, an OXT-induced increase in activity in the PFC, where OXT receptors are highly expressed (Boccia, Petrusz, Suzuki, Marson, & Pedersen, 2013), may reflect enhanced top-down cognitive control that has been previously observed in the context of food craving behavior (Striepens et al., 2016) and fear extinction (Eckstein et al., 2015).”
From Oxytocin enhances the pain‐relieving effects of social support in romantic couples (2019) · cites this paper as Eckstein et al., 2015
Oxytocin-induced inhibition of fear enables the ability to reorganize experiences and memories.
“An important consequence of oxytocin-induced inhibition of fear is the ability to reorganize experiences and memories.”
From The Oxytocinergic System as a Mediator of Anti-stress and Instorative Effects Induced by Nature: The Calm and Connection Theory (2021) · cites this paper as Eckstein et al., 2015
When fear is absent, it is possible to introduce new ways of thinking and even exchange emotional links to memories.
“When fear is absent, it is possible to introduce new ways of thinking and even exchange emotional links to memories (Eckstein et al., 2015; Engert et al., 2016).”
From The Oxytocinergic System as a Mediator of Anti-stress and Instorative Effects Induced by Nature: The Calm and Connection Theory (2021) · cites this paper as Eckstein et al., 2015
mPFC/aMCC activities are modulated by administered OT.
“and mPFC/aMCC activities are modulated by administered OT (Sabihi et al., 2014; Eckstein et al., 2015; Liu et al., 2017; Wang et al., 2017).”
From A neurobiological association of revenge propensity during intergroup conflict (2020) · cites this paper as Eckstein et al., 2015
Oxytocin has demonstrated the ability to enhance fear extinction in preclinical models and among healthy individuals.
“Oxytocin has demonstrated the ability to enhance fear extinction in preclinical models (Eskandarian et al., 2013) and among healthy individuals (Acheson et al., 2013; Eckstein et al., 2014).”
From Augmenting Prolonged Exposure therapy for PTSD with intranasal oxytocin: a randomized, placebo-controlled pilot trial (2018) · cites this paper as Eckstein et al., 2014
A similar pattern was shown in healthy individuals administered oxytocin after fear conditioning: participants showed increased fear expression during early-stage extinction and then facilitated decline of physiological distress at the late stage of extinction.
“A similar pattern was shown in healthy individuals administered oxytocin after fear conditioning: participants showed increased fear expression during early-stage extinction and then facilitated decline of physiological distress at the late stage of extinction (Eckstein et al., 2014).”
From Augmenting Prolonged Exposure therapy for PTSD with intranasal oxytocin: a randomized, placebo-controlled pilot trial (2018) · cites this paper as Eckstein et al., 2014
In healthy participants, intranasal OXT has been shown to facilitate the extinction of conditioned fear.
“In healthy participants, intranasal OXT has been shown to facilitate the extinction of conditioned fear (Acheson et al., 2013;Eckstein et al., 2015).”
From Novel pharmacological targets in drug development for the treatment of anxiety and anxiety-related disorders (2019) · cites this paper as Eckstein et al., 2015
Three studies investigated the effects of oxytocin on startle response to learned threat cues after conditioning and on learned threat following extinction.
“Three studies investigated the effects of oxytocin on startle response to learned threat cues after conditioning and on learned threat following extinction (Acheson et al., 2013;Eckstein et al., 2015;Eckstein et al., 2016).”
From Meta-analytic review of the effects of a single dose of intranasal oxytocin on threat processing in humans (2018) · cites this paper as Eckstein et al., 2015
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- Authors
- Eckstein, M., Becker, B., Scheele, D., Scholz, C., Preckel, K., Schlaepfer, T. E., Grinevich, V., Kendrick, K. M., Maier, W., & Hurlemann, R.
- Affiliations
- University of Bonn (DE)
- German Cancer Research Center (DE)
- University of Electronic Science and Technology of China (CN)
- ORCID
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2015-08
- Volume
- 78
- Issue
- 3
- Pages
- 194-202
- ISSN
- 0006-3223 (ISSN-L)
- OpenAlex
- W2159597393
- Semantic Scholar
- a0d214dc18ff76b08062d373649a6e6f49fafabf
- Cited by
- 210
- References
- 76
- Citations by year
- 2026: 9 · 2025: 11 · 2024: 10 · 2023: 11 · 2022: 19 · 2021: 16 · 2020: 24 · 2019: 21 · 2018: 25 · 2017: 21 · 2016: 20 · 2015: 23
- FWCI
- 31.56
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- DZNE Pub (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Ministry of Innovation, Science, Research and Technology of the State of North Rhine-Westphalia
- Rheinische Friedrich-Wilhelms-Universität Bonn
- National Natural Science Foundation of China (91132720)
- Topics
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- oxytocin, fear extinction, fear conditioning, amygdala, medial prefrontal cortex, anxiety disorders, skin conductance response, intranasal administration, social fear
- MeSH terms
- Adult, Amygdala, Conditioning, Classical, Double-Blind Method, Fear, Galvanic Skin Response, Humans, Magnetic Resonance Imaging, Male, Oxytocin, Prefrontal Cortex, Young Adult, Healthy Volunteers
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