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Emotion-induced retrograde amnesia varies as a function of noradrenergic-glucocorticoid activity

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Abstract

Rationale

Privileged episodic encoding of an aversive event often comes at a cost of neutral events flanking the aversive event, resulting in decreased episodic memory for these neutral events. This peri-emotional amnesia is amygdala-dependent and varies as a function of norepinephrine activity. However, less is known about the amnesiogenic potential of cortisol.

Objective

We used a strategy of pharmacologically potentiating cortisol and norepinephrine activity to probe the putative neurochemical substrates of peri-emotional amnesia.

Materials and methods

Fifty-four healthy individuals participated in a randomized double-blind placebo-controlled study. Within the experimental context of an established peri-emotional amnesia paradigm, we tested the amnesiogenic potential of hydrocortisone (30 mg p.o.) in the presence or absence of the norepinephrine-reuptake inhibitor reboxetine (4 mg p.o.).

Results

Under dual challenge conditions, we observed a linear dose–response relationship in the magnitude and duration of emotion-induced retrograde amnesia.

Conclusions

Our results are consistent with a phenotypic expression of retrograde amnesia varying as a function of norepinephrine and cortisol coactivation during episodic encoding of aversive events. Our study demonstrates that the adverse cognitive and behavioral sequelae of aversive emotion can be experimentally modeled by a pharmacological manipulation of its putative neurochemical substrates.

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Acknowledgments

The authors wish to thank R.-E. Berg and C. Santoro for excellent assistance and T. Schlaepfer for his valuable comments on a previous version of the manuscript. R. Hurlemann was supported by a German Federal Ministry of Education and Research (BMBF) grant (01GW0671) and a BONFOR fellowship.

Disclosure/Conflict of interest statement

The authors have no conflicts of interest to report, nor any involvement to disclose, financial or otherwise, that may bias the conduct, interpretation, or presentation of this work.

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Authors and Affiliations

  1. Department of Psychiatry, University of Bonn, Sigmund-Freud-Str. 25, 53105, Bonn, Germany

    René Hurlemann, Barbara Hawellek, Heike Kolsch & Wolfgang Maier

  2. Department of Clinical Biochemistry, Division of Endocrinology, University of Bonn, 53105, Bonn, Germany

    Dietrich Klingmuller

  3. Brain Imaging Center West, Research Center Juelich, 52425, Juelich, Germany

    René Hurlemann & Andreas Matusch

  4. Wellcome Trust Centre for Neuroimaging, University College London, London, WC1N 3BG, UK

    Raymond J. Dolan

Authors
  1. René Hurlemann
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  2. Andreas Matusch
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Corresponding author

Correspondence to René Hurlemann.

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Supplementary Fig. 5

Pharmacokinetic interference of reboxetine and cortisol. To detect potential methodological influences on reboxetine (RBX) plasma levels in the presence orabsence of cortisol (CORT), we performed a series of in vitro assays. Initially, one RBX 4-mg tablet was dissolved in 40 mL of water. Then, 80 μL of different dilutions from this stock solution were added to 1920 μL of fresh human plasma yielding concentrations of 0, 25, 50, 75, 100, 125, 150, 175, and 200 μg/L, incubated for 180 min at 37°C, and subsequently analyzed in the same way as the in vivo samples. The measured RBX plasma concentrations were 0, 25, 46, 72, 104, 132, 165, 181, and 211 μg/L, respectively, yielding the relationship: RBXmeasured = 1.09 × RBXnominal − 5.3 μg / L. In a second series of plasma standards, 40 μL of analyte solution were added to several aliquots of 1920 μL plasma yielding a concentration of 100 μg/L and incubated for 60 min at 37°C. Then, either 40 μL of water or CORT solution were added resulting in concentrations of 0 (3 vials), 200, 400, 600, 800 μg/L CORT, respectively, and incubated for additional 120 min. The measured analyte concentrations were 95, 97, 103, 108, and 112 μg/L, respectively, resulting in the depicted calibration curve for RBX as a function of CORT plasma levels. For the purpose of external quality control, 2 of the 3 blank plasma standards containing 100 μg/L RBX alone underwent HPLC-tandem mass spectroscopy (HPLC-MS/MS) after addition of a deuterated calibrator (Medical Laboratory of Bremen, 28357 Bremen,Germany), which yielded RBX concentrations of 90 and 94 μg/L as compared to 95 μg/L determined in our in-house analysis. We conclude that CORT dose dependently increased the recovery of the analyte RBX in the present study (GIF 60.1 kb)

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Hurlemann, R., Matusch, A., Hawellek, B. et al. Emotion-induced retrograde amnesia varies as a function of noradrenergic-glucocorticoid activity. Psychopharmacology 194, 261–269 (2007). https://doi.org/10.1007/s00213-007-0836-6

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