Cortisol administration after extinction in a fear-conditioning paradigm with traumatic film clips prevents return of fear

Brueckner, Alexandra H.; Lass‐Hennemann, Johanna; Wilhelm, Frank H.; Sá, Diana S. Ferreira de; Michael, Tanja

doi:10.1038/s41398-019-0455-0

Cited by 21 publications

(15 citation statements)

References 49 publications

(61 reference statements)

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“…Noradrenaline has been shown to enhance extinction learning and consolidation in animals (Abraham et al 2012) and administrations of cortisol affect human extinction learning (Merz et al 2017) and enhance extinction memory consolidation in humans (Brueckner et al 2019).…”

Section: Introductionmentioning

confidence: 99%

Post-extinction L-DOPA administration to reduce the return of fear in humans

Gerlicher¹,

Ilhan-Bayrakcı²,

Tüscher³

et al. 2022

Preprint

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The dopamine precursor L-DOPA is a promising adjunct to exposure therapy in anxiety disorders. In two magnetic resonance imaging (MRI) studies we previously showed that a post-extinction administration of L-DOPA reduces the return of fear. However, when aiming to replicate these results outside the MRI scanner, we found weaker effects – albeit with an adjusted paradigm. In order to discern whether the discrepant results can be explained by the experimental environment (in- vs. outside MRI scanner) or the differences in the paradigms, we here replicated a previous MRI paradigm outside the MRI scanner. In total, N=50 male participants underwent fear conditioning on day 1 and extinction on day 2. We tested the effect of post-extinction L-DOPA compared to placebo administration on differential skin conductance responses (SCR) during test on day 3. In contrast to previous findings in the MRI scanner, there was no reduction of differential SCRs after L-DOPA compared to placebo intake at test. Resembling previous findings outside the MRI scanner, there was a significant relationship between differential SCRs at the end of extinction on day 2 and test on day 3 in the L-DOPA group. This relationship did, however, not differ between groups. Summarizing, our results rather speak against an effect of paradigm and in favour of an effect of MRI environment. Contextual arousal, likely to be elevated in the MRI environment, may influence the effect of L-DOPA. These findings call for future work to investigate the interaction between arousal and catecholamines in the context of extinction memory consolidation.

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Section: Introductionmentioning

confidence: 99%

Post-extinction L-DOPA administration to reduce the return of fear in humans

Gerlicher¹,

Ilhan-Bayrakcı²,

Tüscher³

et al. 2022

Preprint

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“…Acute MDMA administration also causes up to a 200% increase in plasma cortisol levels (Harris et al, 2002; Parrott et al, 2014) and a significant elevation in blood oxytocin through stimulation of 5‐HT 1A receptors of hypothalamic oxytocin‐producing neurons (Hunt et al, 2011; Figure 1). As we have already mentioned, preextinction administration of cortisol diminished fear recall (Merz et al, 2018), whereas post‐training application reinforced consolidation of extinction memory (Brueckner et al, 2019). Clinical studies have also shown that heightened cortisol levels enhance the effectiveness of ET in patients with PTSD (Yehuda et al, 2015) and phobic fear (de Quervain et al, 2011; Soravia et al, 2006).…”

Section: Hallucinogenic Drugsmentioning

confidence: 78%

“…This triggers GR's translocation to the nucleus, where it acts as a transcription regulator of numerous genes, while the release of GR accessory proteins mediates glucocorticoids' nongenomic actions that rely on the activity of MAPK, PI3K, and Akt kinases (Oakley & Cidlowski, 2013; Scheschowitsch et al, 2017). Depending on the time point of their application, both oxytocin and cortisol can facilitate FE processes (Brueckner et al, 2019; Lahoud & Maroun, 2013; Merz et al, 2018; Triana‐Del Rio et al, 2019). While oxytocin mainly augments extinction learning when administered after a fear recall session (Lahoud & Maroun, 2013; Triana‐Del Rio et al, 2019), cortisol can strengthen extinction memory when it is applied both before (Merz et al, 2018) and immediately after FE training (Brueckner et al, 2019).…”

Section: Molecular Mechanisms Of Fear Extinctionmentioning

confidence: 99%

“…Depending on the time point of their application, both oxytocin and cortisol can facilitate FE processes (Brueckner et al, 2019; Lahoud & Maroun, 2013; Merz et al, 2018; Triana‐Del Rio et al, 2019). While oxytocin mainly augments extinction learning when administered after a fear recall session (Lahoud & Maroun, 2013; Triana‐Del Rio et al, 2019), cortisol can strengthen extinction memory when it is applied both before (Merz et al, 2018) and immediately after FE training (Brueckner et al, 2019).…”

Section: Molecular Mechanisms Of Fear Extinctionmentioning

confidence: 99%

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Hallucinogenic drugs and their potential for treating fear‐related disorders: Through the lens of fear extinction

Glavonic

Mitić

Adžić

2022

J of Neuroscience Research

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Fear‐related disorders, mainly phobias and post‐traumatic stress disorder, are highly prevalent, debilitating disorders that pose a significant public health problem. They are characterized by aberrant processing of aversive experiences and dysregulated fear extinction, leading to excessive expression of fear and diminished quality of life. The gold standard for treating fear‐related disorders is extinction‐based exposure therapy (ET), shown to be ineffective for up to 35% of subjects. Moreover, ET combined with traditional pharmacological treatments for fear‐related disorders, such as selective serotonin reuptake inhibitors, offers no further advantage to patients. This prompted the search for ways to improve ET outcomes, with current research focused on pharmacological agents that can augment ET by strengthening fear extinction learning. Hallucinogenic drugs promote reprocessing of fear‐imbued memories and induce positive mood and openness, relieving anxiety and enabling the necessary emotional engagement during psychotherapeutic interventions. Mechanistically, hallucinogens induce dynamic structural and functional neuroplastic changes across the fear extinction circuitry and temper amygdala's hyperreactivity to threat‐related stimuli, effectively mitigating one of the hallmarks of fear‐related disorders. This paper provides the first comprehensive review of hallucinogens' potential to alleviate symptoms of fear‐related disorders by focusing on their effects on fear extinction and the underlying molecular mechanisms. We overview both preclinical and clinical studies and emphasize the advantages of hallucinogenic drugs over current first‐line treatments. We highlight 3,4‐methylenedioxymethamphetamine and ketamine as the most effective therapeutics for fear‐related disorders and discuss the potential molecular mechanisms responsible for their potency with implications for improving hallucinogen‐assisted psychotherapy.

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“…These cortisol effects on learning and memory processes are key to our understanding of the pathogenesis and treatment of various mental disorders, including anxiety disorders and posttraumatic stress disorder ( Bentz et al, 2010 ; de Quervain et al, 2017 ). For example, cortisol itself might comprise the potential to overcome stress-induced relapses: cortisol administered prior to extinction training is supposed to strengthen the extinction memory trace, which in turn counteracts the return of fear in healthy participants as well as patients with anxiety disorders ( Soravia et al, 2006 , 2014 ; Bentz et al, 2010 , 2013 ; Brueckner et al, 2019 ). Additionally, further strategies enhancing the recall of the extinction memory trace, for example deepened extinction or occasional reinforced extinction ( Craske et al, 2014 , 2018 ), could be applied to reduce the risk of stress-induced relapses, potentially in combination with extinction generalization.…”

Section: Discussionmentioning

confidence: 99%

Stimulus-Based Extinction Generalization: Neural Correlates and Modulation by Cortisol

Hagedorn

Wolf

Merz

2020

International Journal of Neuropsychopharmacology

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Background While healthy individuals and patients with anxiety disorders easily generalize fear responses, extinction learning is more stimulus-specific. Treatments aiming to generalize extinction learning are urgently needed, since they comprise the potential to overcome stimulus-specificity and reduce relapses, particularly in the face of stressful events. Methods In the current three-day fMRI fear conditioning paradigm, we aimed to create a generalized extinction memory trace in 60 healthy men and women by presenting multiple sizes of one conditioned stimulus during extinction training (CS+G; generalized), whereas the other conditioned stimulus was solely presented in its original size (CS+N; non-generalized). Recall was tested on the third day either after pharmacological administration of the stress hormone cortisol or placebo. Results After successful fear acquisition, prolonged activation of the amygdala and insula and deactivation of the ventromedial prefrontal cortex for CS+G compared to CS+N during extinction learning indicated sustained fear to the generalization stimuli. In line with our hypotheses, reduced amygdala activation was observed after extinction generalization on the third day in the contrast CS+G minus CS+N, possibly reflecting an attenuated return of fear. Cortisol administration before recall, however, blocked this effect. Conclusions Taken together, extinction generalization was associated with decreased activation of the fear network during recall after prolonged activation of the fear network during extinction learning. However, the generalization of the extinction memory did not counteract the detrimental effects of stress hormones on recall. Thus, stimulus-based extinction generalization may not be sufficient to reduce relapses after stressful experiences.

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Cortisol administration after extinction in a fear-conditioning paradigm with traumatic film clips prevents return of fear

Cited by 21 publications

References 49 publications

Post-extinction L-DOPA administration to reduce the return of fear in humans

Post-extinction L-DOPA administration to reduce the return of fear in humans

Hallucinogenic drugs and their potential for treating fear‐related disorders: Through the lens of fear extinction

Stimulus-Based Extinction Generalization: Neural Correlates and Modulation by Cortisol

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