ABSTRACT
BACKGROUND
Exaggerated arousal and dysregulated emotion-memory interactions are key pathological
dysregulations that accompany the development of post-traumatic stress disorder (PTSD).
Current treatments for PTSD are of moderate efficacy and preventing the dysregulations
already during exposure to threatening events may attenuate the development of PTSD-symptomatology.
METHODS
In a preregistered double-blind, between-subject, placebo-controlled pharmaco-fMRI
design, the present proof-of-concept study examined the potential of a single dose
of angiotensin II type 1 receptor (AT1R) antagonist losartan (LT) to attenuate the
mnemonic advantage of threatening stimuli and the underlying neural mechanism via
combining an emotional subsequent memory paradigm with LT (n=29) or placebo treatment
(n=30) and a surprise memory test after 24h washout.
RESULTS
LT generally improved memory performance and abolished emotional memory enhancement
for negative yet not positive material while emotional experience during encoding
remained intact. LT further suppressed hippocampus activity during encoding of subsequently
remembered negative stimuli. On the network level LT reduced coupling between hippocampus
and basolateral amygdala during successful memory formation of negative stimuli.
CONCLUSIONS
Our findings suggest that LT may have the potential to attenuate memory formation
for negative yet not positive information by decreasing hippocampus activity and its
functional coupling strength with amygdala. These findings suggest a promising potential
of LT to prevent preferential encoding and remembering of negative events, a mechanism
that could prevent the emotion-memory dysregulations underlying the development of
PTSD-symptomatology.
Keywords
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References
- Enhanced emotional memory: Cognitive and neural mechanisms.Current Directions in Psychological Science. 2013; 22: 430-436
- Memory bias for threatening information in anxiety and anxiety disorders: a meta-analytic review.Psychological Bulletin. 2008; 134: 886
- Emotional memory in post-traumatic stress disorder: A systematic PRISMA review of controlled studies.Frontiers in psychology. 2019; 10: 303
- Modification of cognitive biases related to posttraumatic stress: A systematic review and research agenda.Clinical psychology review. 2017; 54: 81-95
- Trauma and PTSD in the WHO world mental health surveys.European journal of psychotraumatology. 2017; 81353383
Edition, F. (2013). Diagnostic and statistical manual of mental disorders. Am Psychiatric Assoc, 21.
- A cognitive action theory of post-traumatic stress disorder.Journal of anxiety disorders. 1988; 2: 253-275
- Emotion and cognition interactions in PTSD: a review of neurocognitive and neuroimaging studies.Frontiers in integrative neuroscience. 2012; 6: 89
- New avenues for treating emotional memory disorders: towards a reconsolidation intervention for posttraumatic stress disorder.Therapeutic advances in psychopharmacology. 2016; 6: 283-295
- Mechanisms of fear extinction.Molecular psychiatry. 2007; 12: 120-150
- Neural and cellular mechanisms of fear and extinction memory formation.Neuroscience & Biobehavioral Reviews. 2012; 36: 1773-1802
- Cognitive behavioral therapy for anxiety and related disorders: A meta‐analysis of randomized placebo‐controlled trials.Depression and anxiety. 2018; 35: 502-514
- Pharmacological prevention of post-traumatic stress disorder and acute stress disorder: a systematic review and meta-analysis.The Lancet Psychiatry. 2015; 2: 413-421
- Pharmacological prevention and early treatment of post-traumatic stress disorder and acute stress disorder: a systematic review and meta-analysis.Translational psychiatry. 2019; 9: 1-10
- Inhibition of central angiotensin II enhances memory function and reduces oxidative stress status in rat hippocampus.Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2013; 43: 79-88
- Angiotensin type 1 receptor inhibition enhances the extinction of fear memory.Biological psychiatry. 2014; 75: 864-872
- Human extinction learning is accelerated by an angiotensin antagonist via ventromedial prefrontal cortex and its connections with basolateral amygdala.Biological psychiatry. 2019; 86: 910-920
- Associations of trauma exposure and post-traumatic stress disorder with the activity of the renin–angiotensin–aldosterone-system in the general population.Psychological medicine. 2019; 49: 843-851
Khoury, N. M., Marvar, P. J., Gillespie, C. F., Wingo, A., Schwartz, A., Bradley, B., . . . Ressler, K. J. (2012). The renin-angiotensin pathway in posttraumatic stress disorder: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are associated with fewer traumatic stress symptoms. The Journal of clinical psychiatry, 73(6), 0-0.
- The renin–angiotensin system in PTSD: a replication and extension.Neuropsychopharmacology. 2021; 46: 750-755
- Angiotensin involvement in trauma processing—exploring candidate neurocognitive mechanisms of preventing post-traumatic stress symptoms.Neuropsychopharmacology. 2020; 45: 507-514
- The effects of the angiotensin II receptor antagonist losartan on appetitive versus aversive learning: a randomized controlled trial.Biological psychiatry. 2019; 86: 397-404
Zhou, X., Xu, T., Zeng, Y., Zhang, R., Qi, Z., Zhao, W., . . . Becker, B. (2021). The angiotensin antagonist Losartan shifts social reward motivation and punishment feedback sensitivity via modulating midbrain-striato-frontal circuits. bioRxiv.
- Adaptive emotional memory: the key hippocampal–amygdalar interaction.Stress. 2015; 18: 297-308
- Encoding of emotional memories depends on amygdala and hippocampus and their interactions.Nature neuroscience. 2004; 7: 278-285
Suarez-Jimenez, B., Albajes-Eizagirre, A., Lazarov, A., Zhu, X., Harrison, B. J., Radua, J., . . . Fullana, M. A. (2020). Neural signatures of conditioning, extinction learning, and extinction recall in posttraumatic stress disorder: a meta-analysis of functional magnetic resonance imaging studies. Psychological medicine, 50(9), 1442-1451.
- Smaller hippocampal volume in posttraumatic stress disorder: a multisite ENIGMA-PGC study: subcortical volumetry results from posttraumatic stress disorder consortia.Biological psychiatry. 2018; 83: 244-253
- Posttraumatic stress disorder symptom severity is associated with left hippocampal volume reduction: a meta-analytic study.CNS spectrums. 2017; 22: 363-372
- Longitudinal changes in brain function associated with symptom improvement in youth with PTSD.Journal of psychiatric research. 2019; 114: 161-169
Zhu, X., Suarez‐Jimenez, B., Lazarov, A., Helpman, L., Papini, S., Lowell, A., . . . Schneier, F. (2018). Exposure‐based therapy changes amygdala and hippocampus resting‐state functional connectivity in patients with posttraumatic stress disorder. Depression and anxiety, 35(10), 974-984.
- β-Adrenergic modulation of emotional memory-evoked human amygdala and hippocampal responses.Proceedings of the National Academy of Sciences. 2004; 101: 11454-11458
- Neural plasticity and the brain renin–angiotensin system.Neuroscience & Biobehavioral Reviews. 2002; 26: 529-552
- Recruitment of central angiotensin II type 1 receptor associated neurocircuits in carbon dioxide associated fear.Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2019; 92: 378-386
Yu, Z., Swiercz, A. P., Moshfegh, C. M., Hopkins, L., Wiaderkiewicz, J., Speth, R. C., . . . Marvar, P. J. (2019). Angiotensin II type 2 receptor–expressing neurons in the central amygdala influence fear-related behavior. Biological psychiatry, 86(12), 899-909.
- Angiotensin regulation of amygdala response to threat in high-trait-anxiety individuals.Biological Psychiatry: Cognitive Neuroscience and Neuroimaging. 2018; 3: 826-835
- Oxytocin facilitates protective responses to aversive social stimuli in males.Proceedings of the National Academy of Sciences. 2012; 109: 18144-18149
- Angiotensin-(1-7)/Mas axis modulates fear memory and extinction in mice.Neurobiology of learning and memory. 2016; 127: 27-33
- Estradiol modulation of the renin–angiotensin system and the regulation of fear extinction.Translational psychiatry. 2019; 9: 1-12
- Gender differences in the renal response to renin-angiotensin system blockade.Journal of the American Society of Nephrology. 2006; 17: 2554-2560
- Sex-related difference in amygdala activity during emotionally influenced memory storage.Neurobiology of learning and memory. 2001; 75: 1-9
- Sex differences in the neural basis of emotional memories.Proceedings of the National Academy of Sciences. 2002; 99: 10789-10794
- Effects of systemic treatment with irbesartan and losartan on central responses to angiotensin II in conscious, normotensive rats.European Journal of Pharmacology. 1999; 367: 255-265
- Functional evidence that the angiotensin antagonist losartan crosses the blood-brain barrier in the rat.Brain research bulletin. 1993; 30: 33-39
- Formulation and evaluation of non-effervescent floating tablets of losartan potassium.Current drug delivery. 2013; 10: 620-629
- Clinical pharmacokinetics of losartan.Clinical pharmacokinetics. 2005; 44: 797-814
- The Nencki Affective Picture System (NAPS): Introduction to a novel, standardized, wide-range, high-quality, realistic picture database.Behavior research methods. 2014; 46: 596-610
- International affective picture system (IAPS): Technical manual and affective ratings.NIMH Center for the Study of Emotion and Attention. 1997; 1: 3
- Measuring emotion: the self-assessment manikin and the semantic differential.Journal of behavior therapy and experimental psychiatry. 1994; 25: 49-59
- Emotion and memory: A recognition advantage for positive and negative words independent of arousal.Cognition. 2013; 129: 530-535
- The effect of emotional arousal and retention delay on subsequent-memory effects.Cognitive neuroscience. 2012; 3: 150-159
- General and emotion-specific neural effects of ketamine during emotional memory formation.Neuroimage. 2017; 150: 308-317
- The neural correlates of emotional memory in posttraumatic stress disorder.Biological psychiatry. 2010; 68: 1023-1030
- Statistical parametric maps in functional imaging: a general linear approach.Human brain mapping. 1994; 2: 189-210
- Cytoarchitectonic mapping of the human amygdala, hippocampal region and entorhinal cortex: intersubject variability and probability maps.Anatomy and embryology. 2005; 210: 343-352
- Architectonic mapping of the human brain beyond Brodmann.Neuron. 2015; 88: 1086-1107
- Observing the transformation of experience into memory.Trends in cognitive sciences. 2002; 6: 93-102
- Effects of losartan on blood pressure, plasma renin activity, and angiotensin II in volunteers.Hypertension. 1993; 21: 704-713
- Cognitive enhancement following acute losartan in normotensive young adults.Psychopharmacology. 2011; 217: 51-60
- Influence of losartan and atenolol on memory function in very elderly hypertensive patients.J Hum Hypertens. 2003; 17: 781-785https://doi.org/10.1038/sj.jhh.1001613
- Cognitive enhancement following acute losartan in normotensive young adults.Psychopharmacology (Berl). 2011; 217: 51-60https://doi.org/10.1007/s00213-011-2257-9
Ben-Zion, Z., Shany, O., Admon, R., Keynan, N. J., Avisdris, N., Balter, S. R., . . . Hendler, T. (2021). Differential roles of positive and negative valence systems in the development of post-traumatic stress psychopathology. bioRxiv.
- Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia.American journal of Psychiatry. 2007; 164: 1476-1488
Carletto, S., Panero, M., Cavallo, M., & Pagani, M. (2021). Neurobiology of Posttraumatic Stress Disorder PET and SPECT in Psychiatry (pp. 411-435): Springer.
- An fMRI investigation of memory encoding in PTSD: influence of symptom severity.Neuropsychologia. 2008; 46: 1522-1531
- Reduced hippocampal and amygdala activity predicts memory distortions for trauma reminders in combat-related PTSD.Journal of psychiatric research. 2011; 45: 660-669
- Involvement of hippocampal angiotensin 1 receptors in anxiety-like behaviour of olfactory bulbectomized rats.Pharmacological Reports. 2018; 70: 847-852
- Fear processing and social networking in the absence of a functional amygdala.Biological psychiatry. 2012; 72: 70-77
- Intrinsic functional connectivity between amygdala and hippocampus during rest predicts enhanced memory under stress.Psychoneuroendocrinology. 2017; 75: 192-202
- Persistence of amygdala–hippocampal connectivity and multi-voxel correlation structures during awake rest after fear learning predicts long-term expression of fear.Cerebral Cortex. 2017; 27: 3028-3041
- MDMA impairs both the encoding and retrieval of emotional recollections.Neuropsychopharmacology. 2018; 43: 791-800
- Effects of sleep after experimental trauma on intrusive emotional memories.Sleep. 2016; 39: 2125-2132
- Stress, sleep, and the selective consolidation of emotional memories.Current opinion in behavioral sciences. 2018; 19: 36-43
- Cognitive neuroscience of emotional memory.Nature Reviews Neuroscience. 2006; 7: 54-64
- Peripheral administration of an angiotensin II AT1 receptor antagonist decreases the hypothalamic-pituitary-adrenal response to isolation stress.Endocrinology. 2001; 142: 3880-3889
- Associative encoding and retrieval are predicted by functional connectivity in distinct hippocampal area CA1 pathways.Journal of Neuroscience. 2014; 34: 11188-11198
Article Info
Publication History
Accepted:
May 13,
2022
Received in revised form:
May 11,
2022
Received:
February 8,
2022
Publication stage
In Press Journal Pre-ProofFootnotes
The trial was preregistered on clinicaltrials.gov
(https://clinicaltrials.gov/ct2/show/NCT04606225, ID NCT04606225)
Author contributions
TX and BB designed the study; TX, GJ, YZ, XZ conducted the experiment and collected the data. TX, XZ, FZ, FY, LJ performed the data analysis. TX and BB wrote the manuscript draft, WZ and YS critically revised the manuscript draft.
Identification
Copyright
© 2022 Published by Elsevier Inc on behalf of Society of Biological Psychiatry.
