Skip to main content
    • Aa
    • Aa

Human amygdala reactivity is diminished by the β-noradrenergic antagonist propranolol

  • R. Hurlemann (a1) (a2), H. Walter (a1) (a3), A. K. Rehme (a1), J. Kukolja (a1) (a2), S. C. Santoro (a1), C. Schmidt (a1), K. Schnell (a1) (a3), F. Musshoff (a4), C. Keysers (a5), W. Maier (a1), K. M. Kendrick (a6) and O. A. Onur (a1) (a2)...

Animal models of anxiety disorders emphasize the crucial role of locus ceruleus–noradrenergic (norepinephrine, NE) signaling, the basolateral amygdala (BLA) and their interactions in the expression of anxiety-like behavioral responses to stress. Despite clinical evidence for the efficacy of a β-noradrenergic receptor blockade with propranolol in the alleviation of anxiety symptoms and the secondary prevention of post traumatic stress disorder, preclinical evidence for a β-noradrenergic modulation of BLA activity in humans is missing.


We combined functional magnetic resonance imaging in healthy volunteers with probabilistic mapping of intra-amygdalar responses to fearful, neutral and happy facial expressions to test the hypothesis that a β-noradrenergic receptor blockade with propranolol would inactivate the BLA.


Consistent with our a priori hypothesis, propranolol diminished BLA responses to facial expressions, independent of their emotional valence. The absence of activity changes in probabilistically defined visual control regions underscores the specific action of propranolol in the BLA.


Our findings provide the missing link between the anxiolytic potential of propranolol and the biological basis of β-noradrenergic activation in the human BLA as a key target for the pharmacological inhibition of anxiety neurocircuitry. Moreover, our findings add to emerging evidence that NE modulates both the reactivity (sensitivity) and the operating characteristics (specificity) of the BLA via β-noradrenergic receptors.

Corresponding author
*Address for correspondence: Dr R. Hurlemann, Department of Psychiatry, University of Bonn, Sigmund-Freud-Str. 25, 53105Bonn, Germany. (Email:
Linked references
Hide All

This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

R Adolphs , M Spezio (2006). Role of the amygdala in processing visual social stimuli. Progress in Brain Research 156, 363378.

JK Alexander , A Hillier , RM Smith , ME Tivarus , DQ Beversdorf (2007). Beta-adrenergic modulation of cognitive flexibility during stress. Journal of Cognitive Neuroscience 19, 468478.

J Amat , MV Baratta , E Paul , ST Bland , LR Watkins , SF Maier (2005). Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus. Nature Neuroscience 8, 365371.

K Amunts , O Kedo , M Kindler , P Pieperhoff , H Mohlberg , NJ Shah , U Habel , S Schneider , K Zilles (2005). Cytoarchitectonic mapping of the human amygdala, hippocampal region and entorhinal cortex: intersubject variability and probability maps. Anatomy and Embryology (Berlin) 210, 343352.

E Arce , AN Simmons , KL Lovero , MB Stein , MP Paulus (2008). Escitalopram effects on insula and amygdala BOLD activation during emotional processing. Psychopharmacology (Berlin) 196, 661672.

E Asan (1998). The catecholaminergic innervation of the rat amygdala. Advances in Anatomy, Embryology and Cell Biology 142, L1L118.

J Ashburner , KJ Friston (2005). Unified segmentation. Neuroimage 26, 839851.

G Aston-Jones , JD Cohen (2005). An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance. Annual Review – Neuroscience 28, 403540.

CW Berridge , BD Waterhouse (2003). The locus coeruleus–noradrenergic system: modulation of behavioral state and state-dependent cognitive processes. Brain Research. Brain Research Reviews 42, 3384.

CO Brantigan , TA Brantigan , N Joseph (1982). Effect of beta-blockade and beta-stimulation on stage fright. American Journal of Medicine 72, 8894.

JD Bremner , JH Krystal , SM Southwick , DS Charney (1996 b). Noradrenergic mechanisms in stress and anxiety: II. Clinical studies. Synapse 23, 3951.

DM Buffalari , AA Grace (2007). Noradrenergic modulation of basolateral amygdala neuronal activity: opposing influences of alpha-2 and beta receptor activation. Journal of Neuroscience 27, 1235812366.

L Cahill , B Prins , M Weber , JL McGaugh (1994). Beta-adrenergic activation and memory for emotional events. Nature 371, 702704.

DL Collins , P Neelin , TM Peters , AC Evans (1994). Automatic 3D intersubject registration of MR volumetric data in standardized Talairach space. Journal of Computer Assisted Tomography 18, 192205.

J Debiec , JE Ledoux (2004). Disruption of reconsolidation but not consolidation of auditory fear conditioning by noradrenergic blockade in the amygdala. Neuroscience 129, 267272.

J Debiec , JE LeDoux (2006). Noradrenergic signaling in the amygdala contributes to the reconsolidation of fear memory: treatment implications for PTSD. Annals of the New York Academy of Sciences 1071, 521524.

SB Eickhoff , S Heim , K Zilles , K Amunts (2006). Testing anatomically specified hypotheses in functional imaging using cytoarchitectonic maps. Neuroimage 32, 570582.

SB Eickhoff , T Paus , S Caspers , MH Grosbras , A Evans , K Zilles , K Amunts (2007). Assignment of functional activations to probabilistic cytoarchitectonic areas revisited. Neuroimage 36, 511521.

SB Eickhoff , KE Stephan , H Mohlberg , C Grefkes , GR Fink , K Amunts , K Zilles (2005). A new SPM toolbox for combining probabilistic cytoarchitectonic maps and functional imaging data. Neuroimage 25, 13251335.

A Etkin , TD Wager (2007). Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. American Journal of Psychiatry 164, 14761488.

AC Evans , M Kamber , DL Collins , D MacDonald (1994). An MRI based probabilistic atlas of neuroanatomy. In Magnetic Resonance Scanning and Epilepsy (ed. S. Shorvon , D. Fish , F. Andermann , G. M. Bydder ), pp. 263274. Plenum Press: New York.

AC Evans , S Marrett , P Neelin , L Collins , K Worsley , W Dai , S Milot , E Meyer , D Bub (1992). Anatomical mapping of functional activation in stereotactic coordinate space. Neuroimage 1, 4353.

KO Fagerstrom , K Hugdahl , N Lundstrom (1985). Effect of beta-receptor blockade on anxiety with reference to the three-systems model of phobic behavior. Neuropsychobiology 13, 187193.

HC Faigel (1991). The effect of beta blockade on stress-induced cognitive dysfunction in adolescents. Clinical Pediatrics 30, 441445.

DA Fitzgerald , M Angstadt , LM Jelsone , PJ Nathan , KL Phan (2006). Beyond threat: amygdala reactivity across multiple expressions of facial affect. Neuroimage 30, 14411448.

KJ Friston , A Holmes , KJ Worsley , JB Poline , CD Frith , RSJ Frackowiak (1995). Statistical parametric maps in functional imaging: a general linear approach. Human Brain Mapping 2, 189210.

R Galvez , MH Mesches , JL McGaugh (1996). Norepinephrine release in the amygdala in response to footshock stimulation. Neurobiology of Learning and Memory 66, 253257.

C Grillon , J Cordova , CA Morgan , DS Charney , M Davis (2004). Effects of the beta-blocker propranolol on cued and contextual fear conditioning in humans. Psychopharmacology (Berlin) 175, 342352.

U Hasson , Y Nir , I Levy , G Fuhrmann , R Malach (2004). Intersubject synchronization of cortical activity during natural vision. Science 303, 16341640.

T Hatfield , JL McGaugh (1999). Norepinephrine infused into the basolateral amygdala posttraining enhances retention in a spatial water maze task. Neurobiology of Learning and Memory 71, 232239.

T Hatfield , C Spanis , JL McGaugh (1999). Response of amygdalar norepinephrine to footshock and GABAergic drugs using in vivo microdialysis and HPLC. Brain Research 835, 340345.

PE Hayes , SC Schulz (1987). Beta-blockers in anxiety disorders. Journal of Affective Disorders 13, 119130.

CJ Holmes , R Hoge , L Collins , R Woods , AW Toga , AC Evans (1998). Enhancement of MR images using registration for signal averaging. Journal of Computer Assisted Tomography 22, 324333.

R Hurlemann (2008). Noradrenergic-glucococorticoid mechanisms in emotion-induced amnesia: from adaptation to disease. Psychopharmacology (Berlin) 197, 1323.

R Hurlemann , B Hawellek , A Matusch , H Kolsch , H Wollersen , B Madea , K Vogeley , W Maier , RJ Dolan (2005). Noradrenergic modulation of emotion-induced forgetting and remembering. Journal of Neuroscience 25, 63436349.

R Hurlemann , AK Rehme , M Diessel , J Kukolja , W Maier , H Walter , MX Cohen (2008). Segregating intra-amygdalar responses to dynamic facial emotion with cytoarchitectonic maximum probability maps. Journal of Neuroscience Methods 172, 1320.

Y Ikegaya , K Nakanishi , H Saito , K Abe (1997). Amygdala beta-noradrenergic influence on hippocampal long-term potentiation in vivo. Neuroreport 8, 31433146.

K Itoi (2008). Ablation of the central noradrenergic neurons for unraveling their roles in stress and anxiety. Annals of the New York Academy of Sciences 1129, 4754.

RC Kessler , WT Chiu , O Demler , KR Merikangas , EE Walters (2005). Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Archives of General Psychiatry 62, 617627.

M Kindt , M Soeter , B Vervliet (2009). Beyond extinction: erasing human fear responses and preventing the return of fear. Nature Neuroscience 12, 256258.

J Kornischka , J Cordes , MW Agelink (2007). 40 years beta-adrenoceptor blockers in psychiatry. Fortschritte der Neurologie-Psychiatrie 75, 199210.

J Kukolja , TE Schlaepfer , C Keysers , D Klingmuller , W Maier , GR Fink , R Hurlemann (2008). Modeling a negative response bias in the human amygdala by noradrenergic-glucocorticoid interactions. Journal of Neuroscience 28, 1286812876.

K Kuraoka , K Nakamura (2007). Responses of single neurons in monkey amygdala to facial and vocal emotions. Journal of Neurophysiology 97, 13791387.

KS LaBar , MJ Crupain , JT Voyvodic , G McCarthy (2003). Dynamic perception of facial affect and identity in the human brain. Cerebral Cortex 13, 10231033.

KC Liang , RG Juler , JL McGaugh (1986). Modulating effects of posttraining epinephrine on memory: involvement of the amygdala noradrenergic system. Brain Research 368, 125133.

HH Liu , P Milgrom , L Fiset (1991). Effect of a beta-adrenergic blocking agent on dental anxiety. Journal of Dental Research 70, 13061308.

DA Morilak , G Barrera , DJ Echevarria , AS Garcia , A Hernandez , S Ma , CO Petre (2005). Role of brain norepinephrine in the behavioral response to stress. Progress in Neuropsychopharmacology and Biological Psychiatry 29, 12141224.

SE Murphy , R Norbury , U O'Sullivan , PJ Cowen , CJ Harmer (2009) Effect of a single dose of citalopram on amygdala response to emotional faces. British Journal of Psychiatry 194, 535540.

OA Onur , H Walter , TE Schlaepfer , AK Rehme , C Schmidt , C Keysers , W Maier , R Hurlemann (2009). Noradrenergic enhancement of amygdala responses to fear. Social Cognitive and Affective Neuroscience 4, 119126.

MP Paulus , JS Feinstein , G Castillo , AN Simmons , MB Stein (2005). Dose-dependent decrease of activation in bilateral amygdala and insula by lorazepam during emotion processing. Archives of General Psychiatry 62, 282288.

A Pitkanen , M Pikkarainen , N Nurminen , A Ylinen (2000). Reciprocal connections between the amygdala and the hippocampal formation, perirhinal cortex, and postrhinal cortex in rat. A review. Annals of the New York Academy of Sciences 911, 369391.

RK Pitman , KM Sanders , RM Zusman , AR Healy , F Cheema , NB Lasko , L Cahill , SP Orr (2002). Pilot study of secondary prevention of posttraumatic stress disorder with propranolol. Biological Psychiatry 51, 189192.

TC Rainbow , B Parsons , BB Wolfe (1984). Quantitative autoradiography of beta 1- and beta 2-adrenergic receptors in rat brain. Proceedings of the National Academy of Sciences USA 81, 15851589.

RM Raitan (1958). Validity of the trail making test as an indication of organic brain damage. Perceptual and Motor Skills 8, 271276.

AA Reinders , J Gläscher , JR de Jong , AT Willemsen , JA den Boer , C Büchel (2006). Detecting fearful and neutral faces: BOLD latency differences in amygdala-hippocampal junction. Neuroimage 33, 805814.

GJ Quirk , DR Gehlert (2003). Inhibition of the amygdala: key to pathological states? Annals of the New York Academy of Sciences 985, 263272.

CL Ravaris , MJ Friedman , PJ Hauri , GJ McHugo (1991). A controlled study of alprazolam and propranolol in panic-disordered and agoraphobic outpatients. Journal of Clinical Psychopharmacology 11, 344350.

DE Redmond Jr., YH Huang , DR Snyder , JW Maas (1976). Behavioral effects of stimulation of the nucleus locus coeruleus in the stump-tailed monkey Macaca arctoides. Brain Research 116, 502510.

J Rodriguez-Romaguera , F Sotres-Bayon , D Mueller , GJ Quirk (2009). Systemic propranolol acts centrally to reduce conditioned fear in rats without impairing extinction. Biological Psychiatry 65, 887892.

WB Scoville , B Milner (1957). Loss of recent memory after bilateral hippocampal lesions. Journal of Neurology, Neurosurgery and Psychiatry 20, 1121.

SM Southwick , JH Krystal , JD Bremner , CA Morgan 3rd, AL Nicolaou , LM Nagy , DR Johnson , GR Heninger , DS Charney (1997). Noradrenergic and serotonergic function in posttraumatic stress disorder. Archives of General Psychiatry 54, 749758.

SM Southwick , JH Krystal , CA Morgan , D Johnson , LM Nagy , A Nicolaou , GR Heninger , DS Charney (1993). Abnormal noradrenergic function in posttraumatic stress disorder. Archives of General Psychiatry 50, 266274.

WN Stone , GC Gleser , LA Gottschalk (1973). Anxiety and beta-adrenergic blockade. Archives of General Psychiatry 29, 620622.

BA Strange , RJ Dolan (2004). Beta-adrenergic modulation of emotional memory-evoked human amygdala and hippocampal responses. Proceedings of the National Academy of Sciences USA 101, 1145411458.

BA Strange , RJ Dolan (2007). Beta-adrenergic modulation of oddball responses in humans. Behavioral and Brain Functions 3, 29.

BA Strange , R Hurlemann , RJ Dolan (2003). An emotion-induced retrograde amnesia in humans is amygdala- and beta-adrenergic-dependent. Proceedings of the National Academy of Sciences USA 100, 1362613631.

AF Sved , G Cano , AM Passerin , B Rabin (2002). The locus coeruleus, Barrington's nucleus, and neural circuits of stress. Physiology and Behavior 77, 737742.

P Tyrer (1988). Current status of beta-blocking drugs in the treatment of anxiety disorders. Drugs 36, 773783.

EJ van Bockstaele , D Bajic , H Proudfit , RJ Valentino (2001). Topographic architecture of stress-related pathways targeting the noradrenergic locus coeruleus. Physiology and Behavior 73, 273283.

C van der Gaag , RB Minderaa , C Keysers (2007). The BOLD signal in the amygdala does not differentiate between dynamic facial expressions. Social Cognitive and Affective Neuroscience 2, 93–103.

AH van Stegeren , W Everaerd , L Cahill , JL McGaugh , LJ Gooren (1998). Memory for emotional events: differential effects of centrally versus peripherally acting beta-blocking agents. Psychopharmacology (Berlin) 138, 305310.

AH van Stegeren , R Goekoop , W Everaerd , P Scheltens , F Barkhof , JP Kuijer , SA Rombouts (2005). Noradrenaline mediates amygdala activation in men and women during encoding of emotional material. Neuroimage 24, 898909.

AH van Stegeren , OT Wolf , W Everaerd , SA Rombouts (2008). Interaction of endogenous cortisol and noradrenaline in the human amygdala. Progress in Brain Research 167, 263268.

G Vaiva , F Ducrocq , K Jezequel , B Averland , P Lestavel , A Brunet , CR Marmar (2003). Immediate treatment with propranolol decreases posttraumatic stress disorder two months after trauma. Biological Psychiatry 54, 947949.

AJ Wood , K Carr , RE Vestal , S Belcher , GR Wilkinson , DG Shand (1978). Direct measurement of propranolol bioavailability during accumulation to steady-state. British Journal of Clinical Pharmacology 6, 345350.

DJ Woodward , HC Moises , BD Waterhouse , HH Yeh , JE Cheun (1991). Modulatory actions of norepinephrine on neural circuits. Advances in Experimental Medicine and Biology 287, 193208.

MP Young , JW Scannell , GA Burns , C Blakemore (1994). Analysis of connectivity: neural systems in the cerebral cortex. Reviews in the Neurosciences 5, 227249.

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Psychological Medicine
  • ISSN: 0033-2917
  • EISSN: 1469-8978
  • URL: /core/journals/psychological-medicine
Please enter your name
Please enter a valid email address
Who would you like to send this to? *