Archival Report| Volume 8, ISSUE 3, P262-270, March 2023

Angiotensin II Regulates the Neural Expression of Subjective Fear in Humans: A Precision Pharmaco-Neuroimaging Approach

  • Ran Zhang
    Center of Psychosomatic Medicine, Sichuan Provincial Center for Mental Health, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China

    Ministry of Education, Key Laboratory for Neuroinformation, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
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  • Weihua Zhao
    Ministry of Education, Key Laboratory for Neuroinformation, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
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  • Ziyu Qi
    Center of Psychosomatic Medicine, Sichuan Provincial Center for Mental Health, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China

    Ministry of Education, Key Laboratory for Neuroinformation, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
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  • Ting Xu
    Center of Psychosomatic Medicine, Sichuan Provincial Center for Mental Health, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China

    Ministry of Education, Key Laboratory for Neuroinformation, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
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  • Feng Zhou
    Address correspondence to Feng Zhou, Ph.D.
    Faculty of Psychology, Southwest University, ChongQing, China

    Key Laboratory of Cognition and Personality, Ministry of Education, ChongQing, China
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  • Benjamin Becker
    Benjamin Becker, Ph.D.
    Center of Psychosomatic Medicine, Sichuan Provincial Center for Mental Health, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China

    Ministry of Education, Key Laboratory for Neuroinformation, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
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Published:September 26, 2022DOI:



      Rodent models and pharmacological neuroimaging studies in humans have been used to test novel pharmacological agents to reduce fear. However, these strategies are limited with respect to determining process-specific effects on the actual subjective experience of fear, which represents the key symptom that motivates patients to seek treatment. In this study, we used a novel precision pharmacological functional magnetic resonance imaging approach based on process-specific neuroaffective signatures to determine effects of the selective angiotensin II type 1 receptor (AT1R) antagonist losartan on the subjective experience of fear.


      In a double-blind, placebo-controlled, randomized pharmacological functional magnetic resonance imaging design, healthy participants (N = 87) were administered 50 mg losartan or placebo before they underwent an oddball paradigm that included neutral, novel, and fear oddballs. Effects of losartan on brain activity and connectivity as well as on process-specific multivariate neural signatures were examined.


      AT1R blockade selectively reduced neurofunctional reactivity to fear-inducing visual oddballs in terms of attenuating dorsolateral prefrontal activity and amygdala-ventral anterior cingulate communication. Neurofunctional decoding further demonstrated fear-specific effects in that AT1R blockade reduced the neural expression of subjective fear but not of threat or nonspecific negative affect and did not influence reactivity to novel oddballs.


      These results show a specific role of the AT1R in regulating the subjective fear experience and demonstrate the feasibility of a precision pharmacological functional magnetic resonance imaging approach to the affective characterization of novel receptor targets for fear in humans.


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        • Kessler R.C.
        • Berglund P.
        • Demler O.
        • Jin R.
        • Merikangas K.R.
        • Walters E.E.
        Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National comorbidity Survey Replication.
        Arch Gen Psychiatry. 2005; 62: 593-602
        • Correll C.U.
        • Solmi M.
        • Veronese N.
        • Bortolato B.
        • Rosson S.
        • Santonastaso P.
        • et al.
        Prevalence, incidence and mortality from cardiovascular disease in patients with pooled and specific severe mental illness: A large-scale meta-analysis of 3,211,768 patients and 113,383,368 controls.
        World Psychiatry. 2017; 16: 163-180
        • Santomauro D.F.
        • Herrera A.M.M.
        • Shadid J.
        • Zheng P.
        • Ashbaugh C.
        • Pigott D.M.
        Global prevalence and burden of depressive and anxiety disorders in 204 countries and territories in 2020 due to the COVID-19 pandemic.
        Lancet. 2021; 398: 1700-1712
        • Farach F.J.
        • Pruitt L.D.
        • Jun J.J.
        • Jerud A.B.
        • Zoellner L.A.
        • Roy-Byrne P.P.
        Pharmacological treatment of anxiety disorders: Current treatments and future directions.
        J Anxiety Disord. 2012; 26: 833-843
        • Insel T.R.
        • Wang P.S.
        The STAR∗ D trial: Revealing the need for better treatments.
        Psychiatr Serv. 2009; 60: 1466-1467
        • Liu X.
        • Klugah-Brown B.
        • Zhang R.
        • Zhang J.
        • Becker B.
        Distinct neurostructural signatures of anxiety-, fear-related and depressive disorders: A comparative voxel-based meta-analysis.
        Transl Psychiatry. 2022; 12: 405
        • Garcia R.
        Neurobiology of fear and specific phobias.
        Learn Mem. 2017; 24: 462-471
        • Milad M.R.
        • Rauch S.L.
        • Pitman R.K.
        • Quirk G.J.
        Fear extinction in rats: Implications for human brain imaging and anxiety disorders.
        Biol Psychol. 2006; 73: 61-71
        • Becker B.
        • Zhou F.
        Neural Processing of Fear–From Animal Models to Human Research.
        in: Della Sala S. Encyclopedia of Behavioral Neuroscience. 2nd edition (Second Edition). Elsevier, Oxford2022: 454-459
        • Paulus M.P.
        • Stein M.B.
        Role of functional magnetic resonance imaging in drug discovery.
        Neuropsychol Rev. 2007; 17: 179-188
        • Marvar P.J.
        • Andero R.
        • Hurlemann R.
        • Lago T.R.
        • Zelikowsky M.
        • Dabrowska J.
        Limbic neuropeptidergic modulators of emotion and their therapeutic potential for anxiety and post-traumatic stress disorder.
        J Neurosci. 2021; 41: 901-910
        • Quintana D.S.
        • Lischke A.
        • Grace S.
        • Scheele D.
        • Ma Y.
        • Becker B.
        Advances in the field of intranasal oxytocin research: Lessons learned and future directions for clinical research.
        Mol Psychiatry. 2021; 26: 80-91
        • Reinecke A.
        • Browning M.
        • Klein Breteler J.K.
        • Kappelmann N.
        • Ressler K.J.
        • Harmer C.J.
        • Craske M.G.
        Angiotensin regulation of amygdala response to threat in high-trait-anxiety individuals.
        Biol Psychiatry Cogn Neurosci Neuroimaging. 2018; 3: 826-835
        • Chrissobolis S.
        • Luu A.N.
        • Waldschmidt R.A.
        • Yoakum M.E.
        • D’Souza M.S.
        Targeting the renin angiotensin system for the treatment of anxiety and depression.
        Pharmacol Biochem Behav. 2020; 199173063
        • Morrison F.G.
        • Ressler K.J.
        From the neurobiology of extinction to improved clinical treatments.
        Depress Anxiety. 2014; 31: 279-290
        • Seligowski A.V.
        • Duffy L.A.
        • Merker J.B.
        • Michopoulos V.
        • Gillespie C.F.
        • Marvar P.J.
        • et al.
        The renin–angiotensin system in PTSD: A replication and extension.
        Neuropsychopharmacology. 2021; 46: 750-755
        • Marvar P.J.
        • Goodman J.
        • Fuchs S.
        • Choi D.C.
        • Banerjee S.
        • Ressler K.J.
        Angiotensin type 1 receptor inhibition enhances the extinction of fear memory.
        Biol Psychiatry. 2014; 75: 864-872
        • Zhou F.
        • Geng Y.
        • Xin F.
        • Li J.
        • Feng P.
        • Liu C.
        • et al.
        Human extinction learning is accelerated by an angiotensin antagonist via ventromedial prefrontal cortex and its connections with basolateral amygdala.
        Biol Psychiatry. 2019; 86: 910-920
        • Xu T.
        • Zhou X.
        • Jiao G.
        • Zeng Y.
        • Zhao W.
        • Li J.
        • et al.
        Angiotensin antagonist inhibits preferential negative memory encoding via decreasing hippocampus activation and its coupling with the amygdala.
        Biol Psychiatry Cogn Neurosci Neuroimaging. 2022; 7: 970-978
        • Mihov Y.
        • Kendrick K.M.
        • Becker B.
        • Zschernack J.
        • Reich H.
        • Maier W.
        • et al.
        Mirroring fear in the absence of a functional amygdala.
        Biol Psychiatry. 2013; 73: e9-e11
        • Janak P.H.
        • Tye K.M.
        From circuits to behaviour in the amygdala.
        Nature. 2015; 517: 284-292
        • LeDoux J.E.
        • Pine D.S.
        Using neuroscience to help understand fear and anxiety: A two-system framework.
        Am J Psychiatry. 2016; 173: 1083-1093
        • Zhou F.
        • Zhao W.
        • Qi Z.
        • Geng Y.
        • Yao S.
        • Kendrick K.M.
        • et al.
        A distributed fMRI-based signature for the subjective experience of fear.
        Nat Commun. 2021; 12: 6643
        • Woo C.W.
        • Chang L.J.
        • Lindquist M.A.
        • Wager T.D.
        Building better biomarkers: Brain models in translational neuroimaging.
        Nat Neurosci. 2017; 20: 365-377
        • Taschereau-Dumouchel V.
        • Michel M.
        • Lau H.
        • Hofmann S.G.
        • LeDoux J.E.
        Putting the “mental” back in “mental disorders”: A perspective from research on fear and anxiety.
        Mol Psychiatry. 2022; 3: 322-1330
        • Poldrack R.A.
        • Baker C.I.
        • Durnez J.
        • Gorgolewski K.J.
        • Matthews P.M.
        • Munafò M.R.
        • et al.
        Scanning the horizon: Towards transparent and reproducible neuroimaging research.
        Nat Rev Neurosci. 2017; 18: 115-126
        • Xin F.
        • Zhou X.
        • Dong D.
        • Zhao Z.
        • Yang X.
        • Wang Q.
        • et al.
        Oxytocin differentially modulates amygdala responses during top-down and bottom-up aversive anticipation.
        Adv Sci (Weinh). 2020; 72001077
        • Paulus M.P.
        • Stein M.B.
        • Simmons A.N.
        • Risbrough V.B.
        • Halter R.
        • Chaplan S.R.
        The effects of FAAH inhibition on the neural basis of anxiety-related processing in healthy male subjects: A randomized clinical trial.
        Neuropsychopharmacology. 2021; 46: 1011-1019
        • Geng Y.
        • Zhao W.
        • Zhou F.
        • Ma X.
        • Yao S.
        • Becker B.
        • Kendrick K.M.
        Oxytocin facilitates empathic- and self-embarrassment ratings by attenuating amygdala and anterior insula responses.
        Front Endocrinol. 2018; 9: 572
        • Ma X.
        • Zhao W.
        • Luo R.
        • Zhou F.
        • Geng Y.
        • Xu L.
        • et al.
        Sex- and context-dependent effects of oxytocin on social sharing.
        Neuroimage. 2018; 183: 62-72
        • Becker B.
        • Mihov Y.
        • Scheele D.
        • Kendrick K.M.
        • Feinstein J.S.
        • Matusch A.
        • et al.
        Fear processing and social networking in the absence of a functional amygdala.
        Biol Psychiatry. 2012; 72: 70-77
        • Anderson A.K.
        • Phelps E.A.
        Is the human amygdala critical for the subjective experience of emotion? Evidence of intact dispositional affect in patients with amygdala lesions.
        J Cogn Neurosci. 2002; 14: 709-720
        • Zhao Z.
        • Yao S.
        • Li K.
        • Sindermann C.
        • Zhou F.
        • Zhao W.
        • et al.
        Real-time functional connectivity-informed neurofeedback of amygdala-frontal pathways reduces anxiety.
        Psychother Psychosom. 2019; 88: 5-15
        • Diemer J.
        • Zwanzger P.
        • Fohrbeck I.
        • Zavorotnyy M.
        • Notzon S.
        • Silling K.
        • et al.
        Influence of single-dose quetiapine on fear network activity–A pharmaco-imaging study.
        Prog Neuropsychopharmacol Biol Psychiatry. 2017; 76: 80-87
        • Kragel P.A.
        • Koban L.
        • Barrett L.F.
        • Wager T.D.
        Representation, pattern information, and brain signatures: From neurons to neuroimaging.
        Neuron. 2018; 99: 257-273
        • Wager T.D.
        • Atlas L.Y.
        • Lindquist M.A.
        • Roy M.
        • Woo C.W.
        • Kross E.
        An fMRI-based neurologic signature of physical pain.
        N Engl J Med. 2013; 368: 1388-1397
        • Chang L.J.
        • Gianaros P.J.
        • Manuck S.B.
        • Krishnan A.
        • Wager T.D.
        A sensitive and specific neural signature for picture-induced negative affect.
        PLoS Biol. 2015; 13e1002180
        • Reddan M.C.
        • Wager T.D.
        • Schiller D.
        Attenuating neural threat expression with imagination.
        Neuron. 2018; 100: 994-1005.e4
        • Huettel S.A.
        • McCarthy G.
        What is odd in the oddball task? Prefrontal cortex is activated by dynamic changes in response strategy.
        Neuropsychologia. 2004; 42: 379-386
        • Genaro K.
        • Juliano M.A.
        • Prado W.A.
        • Brandão M.L.
        • Martins A.R.
        Effects of angiotensin (5–8) microinfusions into the ventrolateral periaqueductal gray on defensive behaviors in rats.
        Behav Brain Res. 2013; 256: 537-544
        • Swiercz A.P.
        • Iyer L.
        • Yu Z.
        • Edwards A.
        • Prashant N.M.
        • Nguyen B.N.
        • et al.
        Evaluation of an angiotensin Type 1 receptor blocker on the reconsolidation of fear memory.
        Transl Psychiatry. 2020; 10: 363
        • Winter A.
        • Ahlbrand R.
        • Sah R.
        Recruitment of central angiotensin II type 1 receptor associated neurocircuits in carbon dioxide associated fear.
        Prog Neuropsychopharmacol Biol Psychiatry. 2019; 92: 378-386
        • Pulcu E.
        • Shkreli L.
        • Holst C.G.
        • Woud M.L.
        • Craske M.G.
        • Browning M.
        • Reinecke A.
        The effects of the angiotensin II receptor antagonist losartan on appetitive versus aversive learning: A randomized controlled trial.
        Biol Psychiatry. 2019; 86: 397-404
        • Lo M.W.
        • Goldberg M.R.
        • McCrea J.B.
        • Lu H.
        • Furtek C.I.
        • Bjornsson T.D.
        Pharmacokinetics of losartan, an angiotensin II receptor antagonist, and its active metabolite EXP3174 in humans.
        Clin Pharmacol Ther. 1995; 58: 641-649
        • Ohtawa M.
        • Takayama F.
        • Saitoh K.
        • Yoshinaga T.
        • Nakashima M.
        Pharmacokinetics and biochemical efficacy after single and multiple oral administration of losartan, an orally active nonpeptide angiotensin II receptor antagonist, in humans.
        Br J Clin Pharmacol. 1993; 35: 290-297
        • Marchewka A.
        • Żurawski Ł.
        • Jednoróg K.
        • Grabowska A.
        The Nencki Affective Picture System (NAPS): Introduction to a novel, standardized, wide-range, high-quality, realistic picture database.
        Behav Res Methods. 2014; 46: 596-610
        • Penny W.D.
        • Friston K.J.
        • Ashburner J.T.
        • Kiebel S.J.
        • Nichols T.E.
        Statistical Parametric Mapping: The Analysis of Functional Brain Images. Elsevier Science, 2011
        • LeDoux J.E.
        Coming to terms with fear.
        Proc Natl Acad Sci U S A. 2014; 111: 2871-2878
        • McLaren D.G.
        • Ries M.L.
        • Xu G.
        • Johnson S.C.
        A generalized form of context-dependent psychophysiological interactions (gPPI): A comparison to standard approaches.
        NeuroImage. 2012; 61: 1277-1286
        • Beauregard M.
        • Lévesque J.
        • Bourgouin P.
        Neural correlates of conscious self-regulation of emotion.
        J Neurosci. 2001; 21: RC165
        • Ochsner K.N.
        • Bunge S.A.
        • Gross J.J.
        • Gabrieli J.D.
        Rethinking feelings: An FMRI study of the cognitive regulation of emotion.
        J Cogn Neurosci. 2002; 14: 1215-1229
        • Lévesque J.
        • Eugène F.
        • Joanette Y.
        • Paquette V.
        • Mensour B.
        • Beaudoin G.
        • et al.
        Neural circuitry underlying voluntary suppression of sadness.
        Biol Psychiatry. 2003; 53: 502-510
        • Ochsner K.N.
        • Ray R.D.
        • Cooper J.C.
        • Robertson E.R.
        • Chopra S.
        • Gabrieli J.D.
        • Gross J.J.
        For better or for worse: Neural systems supporting the cognitive down- and up-regulation of negative emotion.
        Neuroimage. 2004; 23: 483-499
        • Phan K.L.
        • Taylor S.F.
        • Welsh R.C.
        • Ho S.H.
        • Britton J.C.
        • Liberzon I.
        Neural correlates of individual ratings of emotional salience: A trial-related fMRI study.
        Neuroimage. 2004; 21: 768-780
        • Kim S.H.
        • Hamann S.
        Neural correlates of positive and negative emotion regulation.
        J Cogn Neurosci. 2007; 19: 776-798
        • Delgado M.R.
        • Nearing K.I.
        • LeDoux J.E.
        • Phelps E.A.
        Neural circuitry underlying the regulation of conditioned fear and its relation to extinction.
        Neuron. 2008; 59: 829-838
        • Zhuang Q.
        • Xu L.
        • Zhou F.
        • Yao S.
        • Zheng X.
        • Zhou X.
        • et al.
        Segregating domain-general from emotional context-specific inhibitory control systems–ventral striatum and orbitofrontal cortex serve as emotion-cognition integration hubs.
        NeuroImage. 2021; 238118269
        • Liu C.
        • Dai J.
        • Chen Y.
        • Qi Z.
        • Xin F.
        • Zhuang Q.
        • et al.
        Disorder- and emotional context-specific neurofunctional alterations during inhibitory control in generalized anxiety and major depressive disorder.
        NeuroImage Clin. 2021; 30102661
        • Sagliano L.
        • D’Olimpio F.
        • Izzo L.
        • Trojano L.
        The effect of bicephalic stimulation of the dorsolateral prefrontal cortex on the attentional bias for threat: A transcranial direct current stimulation study.
        Cogn Affect Behav Neurosci. 2017; 17: 1048-1057
        • Peers P.V.
        • Simons J.S.
        • Lawrence A.D.
        Prefrontal control of attention to threat.
        Front Hum Neurosci. 2013; 7: 24
        • Clarke P.J.F.
        • Van Bockstaele B.
        • Marinovic W.
        • Howell J.A.
        • Boyes M.E.
        • Notebaert L.
        The effects of left DLPFC tDCS on emotion regulation, biased attention, and emotional reactivity to negative content.
        Cogn Affect Behav Neurosci. 2020; 20: 1323-1335
        • Kroes M.C.W.
        • Dunsmoor J.E.
        • Hakimi M.
        • Oosterwaal S.
        • NYU PROSPEC collaboration
        • Meager M.R.
        • Phelps E.A.
        • et al.
        Patients with dorsolateral prefrontal cortex lesions are capable of discriminatory threat learning but appear impaired in cognitive regulation of subjective fear.
        Soc Cogn Affect Neurosci. 2019; 14: 601-612
        • Ironside M.
        • O’Shea J.
        • Cowen P.J.
        • Harmer C.J.
        Frontal cortex stimulation reduces vigilance to threat: Implications for the treatment of depression and anxiety.
        Biol Psychiatry. 2016; 79: 823-830
        • Deng J.
        • Fang W.
        • Gong Y.
        • Bao Y.
        • Li H.
        • Su S.
        • et al.
        Augmentation of fear extinction by theta-burst transcranial magnetic stimulation of the prefrontal cortex in humans.
        J Psychiatry Neurosci. 2021; 46: E292-E302
        • Kober H.
        • Barrett L.F.
        • Joseph J.
        • Bliss-Moreau E.
        • Lindquist K.
        • Wager T.D.
        Functional grouping and cortical–subcortical interactions in emotion: A meta-analysis of neuroimaging studies.
        NeuroImage. 2008; 42: 998-1031
        • Toyoda H.
        • Li X.Y.
        • Wu L.J.
        • Zhao M.G.
        • Descalzi G.
        • Chen T.
        • et al.
        Interplay of amygdala and cingulate plasticity in emotional fear.
        Neural Plast. 2011; 2011813749
        • Etkin A.
        • Egner T.
        • Peraza D.M.
        • Kandel E.R.
        • Hirsch J.
        Resolving emotional conflict: A role for the rostral anterior cingulate cortex in modulating activity in the amygdala.
        Neuron. 2006; 51: 871-882
        • Etkin A.
        • Egner T.
        • Kalisch R.
        Emotional processing in anterior cingulate and medial prefrontal cortex.
        Trends Cogn Sci. 2011; 15: 85-93
        • Genaro K.
        • Fabris D.
        • Fachim H.A.
        • Prado W.A.
        Angiotensin AT1 receptors modulate the anxiogenic effects of angiotensin (5–8) injected into the rat ventrolateral periaqueductal gray.
        Peptides. 2017; 96: 8-14
        • Marinzalda M.dlA.
        • Pérez P.A.
        • Gargiulo P.A.
        • Casarsa B.S.
        • Bregonzio C.
        • Baiardi G.
        Fear-potentiated behaviour is modulated by central amygdala angiotensin II AT1 receptors stimulation..
        BioMed Res Int. 2014; 2014: 183248
        • Zhou X.
        • Xu T.
        • Zeng Y.
        • Zhang R.
        • Qi Z.
        • Zhao W.
        • et al.
        The angiotensin antagonist Losartan modulates social reward motivation and punishment sensitivity via modulating midbrain-striato-frontal circuits.
        J Neurosci. 2022; 43: 472-483
        • Zhou F.
        • Li J.
        • Zhao W.
        • Xu L.
        • Zheng X.
        • Fu M.
        • et al.
        Empathic pain evoked by sensory and emotional-communicative cues share common and process-specific neural representations.
        eLife. 2020; 9e56929
        • Li Z.
        • Bains J.S.
        • Ferguson A.V.
        Functional evidence that the angiotensin antagonist losartan crosses the blood-brain barrier in the rat.
        Brain Res Bull. 1993; 30: 33-39
        • Culman J.
        • von Heyer C.
        • Piepenburg B.
        • Rascher W.
        • Unger T.
        Effects of systemic treatment with irbesartan and losartan on central responses to angiotensin II in conscious, normotensive rats.
        Eur J Pharmacol. 1999; 367: 255-265
        • Thöne-Reineke C.
        • Steckelings U.M.
        • Unger T.
        Angiotensin receptor blockers and cerebral protection in stroke.
        J Hypertens Suppl. 2006; 24: S115-S121
        • Ulla M.R.
        • Saisivam S.
        Floating matrix tablet of losartan potassium by using hydrophilic swelling polymer and natural gum.
        Turk J Pharm Sci. 2013; 10: 435-446
        • Sica D.A.
        • Gehr T.W.
        • Ghosh S.
        Clinical pharmacokinetics of losartan.
        Clin Pharmacokinet. 2005; 44: 797-814

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