Central administration of oxytocin receptor ligands affects cued fear extinction in rats and mice in a timepoint-dependent manner
Abstract
Rationale Oxytocin (OXT) has been proposed as a potential therapeutic agent for post-traumatic stress disorder (PTSD).Objectives We aimed to verify whether pharmacological manipulation of the brain OXT system affects cued fear conditioning and fear extinction.Methods Male rats and mice were intracerebroventricularly administered synthetic OXT (rats, 0.1 or 1.0 μg/5 μl; mice, 0.1 or 0.5 μg/2 μl) and/or an OXT receptor antagonist (OXTR-A; rats, 0.75 μg/5 μl) either prior to fear conditioning or extinction training.Results Preconditioning administration of OXT did not affect fear conditioning in rats, but decreased fear expression and facilitated fear extinction. In contrast, preconditioning blockade of OXT neurotransmission by OXTR-A did not affect fear conditioning or fear expression, but impaired fear extinction. When administered before extinction training, OXT impaired fear extinction in both rats and mice, indicating that the effects of OXT on fear extinction are conserved across species. This impairment was OXTR-mediated, as the inhibitory effect of OXT on fear extinction was abolished by prior treatment with OXTR-A. The impaired fear extinction was not a result of reduced locomotion in rats, whereas an apparent decrease in fear expression and facilitation of fear extinction with the higher OXT dose in mice was the result of behavioral hyperactivity.Conclusions These results suggest that increasing OXT neurotransmission during traumatic events is likely to prevent the formation of aversive memories. In contrast, OXT treatment before fear extinction training, which would be the comparable timepoint for psychotherapy in PTSD patients, rather delays fear extinction and, therefore, caution is needed before recommending OXT for the treatment of PTSD.
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In rodents, administration of OT before fear conditioning facilitated fear extinction.
“administration of OT before fear conditioning decreased fear expression and facilitated fear extinction”
From A precision medicine approach to oxytocin trials (2017) · cites this paper as Toth et al. 2012
In mice and rats, infusion of OT after fear conditioning and before extinction impaired fear extinction.
“the infusion of OT after fear conditioning and before extinction instead impaired fear extinction in mice and rats”
From A precision medicine approach to oxytocin trials (2017) · cites this paper as Toth et al. 2012
In rodents, blockage of OT neurotransmission before conditioning impaired fear extinction.
“blockage of OT neurotransmission before conditioning impaired fear extinction”
From A precision medicine approach to oxytocin trials (2017) · cites this paper as Toth et al. 2012
In rodents, administration of OT before fear conditioning decreased fear expression.
“administration of OT before fear conditioning decreased fear expression”
From A precision medicine approach to oxytocin trials (2017) · cites this paper as Toth et al. 2012
In rodents, central oxytocin administration before conditioned fear extinction improved social fear extinction but impaired nonsocial fear extinction.
“in rodents, central oxytocin administration before conditioned fear extinction improved social fear extinction (68) but impaired nonsocial fear extinction (69).”
From Intranasal Oxytocin to Prevent Posttraumatic Stress Disorder Symptoms: A Randomized Controlled Trial in Emergency Department Patients (2017) · cites this paper as [69]
Central oxytocin administered 10 minutes prior to extinction training (at 1 day after fear acquisition) inhibited fear extinction, indicating that timing of oxytocin administration relative to traumatic memory consolidation may be important in determining whether oxytocin promotes or inhibits fear extinction.
“The same study showed that central oxytocin administrated 10 minutes prior to extinction training (at 1 day after fear acquisition) inhibited fear extinction, indicating that timing of oxytocin administration relative to traumatic memory consolidation may be important in determining whether oxytocin promotes or inhibits fear extinction.”
From Efficacy of oxytocin administration early after psychotrauma in preventing the development of PTSD: study protocol of a randomized controlled trial (2014) · cites this paper as [54]
Central oxytocin administration in rats 10 minutes prior to fear conditioning did not affect fear conditioning, but subsequently decreased fear expression and facilitated fear extinction.
“Furthermore, central oxytocin administration in rats 10 minutes prior to fear conditioning did not affect fear conditioning, but did subsequently decrease fear expression and facilitated fear extinction [54].”
From Efficacy of oxytocin administration early after psychotrauma in preventing the development of PTSD: study protocol of a randomized controlled trial (2014) · cites this paper as [54]
Preclinical studies differ in whether the timing of oxytocin intervention in relation to severe stress exposure does not influence the outcome or determines whether the intervention results in beneficial or adverse effects.
“As discussed above, preclinical studies differ in whether the timing of the oxytocin intervention in relation to severe stress exposure either does not influence the outcome [53] or determines whether the intervention results in beneficial or adverse effects [54].”
From Efficacy of oxytocin administration early after psychotrauma in preventing the development of PTSD: study protocol of a randomized controlled trial (2014) · cites this paper as [54]
Effects of oxytocin may depend on contextual and interindividual differences.
“A strength of the current trial is that we assess a wide range of variables that may moderate the effect of the OT intervention [54].”
From Efficacy of oxytocin administration early after psychotrauma in preventing the development of PTSD: study protocol of a randomized controlled trial (2014) · cites this paper as [54]
Animal studies reported that OT abolished the impact of negative outcomes on subsequent behaviors in rats and mice.
“Animal studies also reported that OT abolished the impact of negative outcomes (such as traumatic events and aversive conditioning) on subsequent behaviors in rats and mice (57, 58).”
From Distinct oxytocin effects on belief updating in response to desirable and undesirable feedback (2016) · cites this paper as [58]
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- Authors
- Toth, I., Neumann, I. D., & Slattery, D. A.
- Affiliations
- University of Regensburg (DE)
- Corresponding author
- Slattery, David A.
- Venue
- Psychopharmacology
- Published
- 2012-04-20
- Volume
- 223
- Issue
- 2
- Pages
- 149-158
- ISSN
- 0033-3158 (ISSN-L)
- 1432-2072
- OpenAlex
- W2074960279
- Cited by
- 107
- References
- 80
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 6 · 2023: 2 · 2022: 5 · 2021: 9 · 2020: 10 · 2019: 6 · 2018: 7 · 2017: 8 · 2016: 11 · 2015: 14 · 2014: 12 · 2013: 8 · 2012: 2
- FWCI
- 5.89
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Psychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- University of Regensburg Publication Server (University of Regensburg) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung
- Bayerische Forschungsstiftung
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- oxytocin, oxytocin receptor antagonist, fear extinction, fear conditioning, post-traumatic stress disorder, intracerebroventricular administration, timing of drug administration, behavioral hyperactivity
- MeSH terms
- Animals, Behavior, Animal, Conditioning, Psychological, Cues, Dose-Response Relationship, Drug, Extinction, Psychological, Fear, Injections, Intraventricular, Ligands, Male, Mice, Inbred Strains, Motor Activity, Oxytocin, Retention, Psychology, Species Specificity, Stress Disorders, Post-Traumatic, Time Factors, Rats, Wistar, Receptors, Oxytocin, Mice, Rats
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