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Noradrenergic-glucocorticoid modulation of emotional memory encoding in the human hippocampus

  • J. Kukolja (a1) (a2) (a3), D. Klingmüller (a4), W. Maier (a1), G. R. Fink (a2) (a3) and R. Hurlemann (a1)...

Current rodent models emphasize the joint action of the stress mediators noradrenaline (NE) and cortisol (CORT) in conferring a memory advantage of emotional over neutral stimuli.


Using a pharmacological strategy of tackling this stress-related mechanism to enhance human episodic (autobiographical) memory, we measured amygdala-hippocampal responses during encoding of emotional and neutral stimuli with functional magnetic resonance imaging in 51 healthy subjects under four pharmacological conditions in a double-blind parallel group design: (i) placebo; (ii) the NE-reuptake inhibitor reboxetine (4 mg); (iii) hydrocortisone (synthetic CORT) (30 mg); or (iv) both agents in combination.


Differential drug effects were found in the left hippocampus, whereas hydrocortisone alone selectively decreased hippocampal responses to emotional relative to neutral stimuli, reboxetine potentiated hippocampal responses to these stimuli. Importantly, the inhibitory influence of hydrocortisone was reversed by co-administration of reboxetine.


Our results imply that stress levels of CORT alone attenuate hippocampal responses to emotional stimuli, an effect possibly related to a regulatory negative feedback loop. However, when simultaneously elevated to stress levels, NE and CORT act together to synergistically enhance hippocampal activity during encoding of emotional stimuli, a mechanism that may turn maladaptive under circumstances of traumatic stress.

Corresponding author
*Address for correspondence: J. Kukolja, M.D., Department of Neurology, University of Cologne, Kerpener Str. 62, 50924 Cologne, Germany. (Email:
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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.

L Goossens , J Kukolja , OA Onur , GR Fink , W Maier , E Griez , K Schruers , R Hurlemann (2009). Selective processing of social stimuli in the superficial amygdala. Human Brain Mapping 30, 33323338.

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.

OA Onur , TE Schlaepfer , J Kukolja , A Bauer , H Jeung , A Patin , DM Otte , NJ Shah , W Maier , KM Kendrick , GR Fink , R Hurlemann (2010). The N-methyl-D-aspartate receptor co-agonist D-cycloserine facilitates declarative learning and hippocampal activity in humans. Biological Psychiatry 67, 12051211.

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Psychological Medicine
  • ISSN: 0033-2917
  • EISSN: 1469-8978
  • URL: /core/journals/psychological-medicine
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