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The Role of the Mineralocorticoid Receptor for Cognitive Function, Mood and Social Cognition

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The Role of the Mineralocorticoid Receptor for Cognitive Function, Mood and Social Cognition Fachbereich Erziehungswissenschaft und Psychologie der Freien Universität Berlin The Role of the Mineralocorticoid Receptor for Cognitive Function, Mood and Social Cognition – An Examination in Patients with Primary Adrenal Insufficiency and in Healthy Subjects – Dissertation zur Erlangung des akademischen Grades Doktorin der Philosophie (Dr. phil.) vorgelegt von Dipl.-Psych. Katharina Schultebraucks Berlin, 2016 Erstgutachterin (first supervisor): Prof. Dr. rer. nat. Katja Wingenfeld Zweitgutachter (second supervisor): Prof. Dr. med. Hauke Heekeren Tag der Disputation: 05.12.2016 Acknowledgements I am very grateful to my first and second supervisors Katja Wingenfeld and Hauke Heekeren. Special thanks to the extended supervision team, in particular to Christian Otte for the invaluable support and constructive review of my work. The thesis would not have been possible without their expertise, trust, encouragement and inspiration. Special thanks also to every member of the examination committee: Malek Bajbouj, Annette Kinder & Lars Schulze. Furthermore, special thanks to Marcus Quinkler and the other associates of the Department of Clinical Endocrinology at Charité Universitätsmedizin Berlin, CCM, for the fruitful cooperation and help with the recruitment of the really rare patients with Addison’s disease. Moreover, I would like to thank my colleagues from Charité Universitätsmedizin Berlin, namely Moritz Düsenberg, Juliane Fleischer, Jan Nowacki, Christian Deuter, Linn Kühl, Sabrina Golde, Helge Hasselmann, Dominique Piber, Julian Hellman-Regen, Jana Heimes, Lisa Lockenvitz, Antonia Domke and many more for the good times, the inspiring working environment and the companionship in and out the lab. Additionally, I would like to thank all of my co-authors for their contributions and cooperation as well as everyone else, who supported me to make this dissertation thesis possible. Very special thanks to Merlin, Lisa, Dominik, Manuela and Meinolf for their emotional support and for always believing in me. ii Table of Contents ACKNOWLEDGEMENTS .......................................................................................................................... II ENGLISH SUMMARY ................................................................................................................................ VI DEUTSCHE ZUSAMMENFASSUNG (GERMAN SUMMARY) ........................................................ VIII 1 THEORETICAL AND EMPIRICAL BACKGROUND .......................................................................... 1 1.1 THE NEUROENDOCRINE STRESS RESPONSE AND ITS RELATION TO MR AND GR ...................................... 3 1.2 THE MR/GR BALANCE HYPOTHESIS ................................................................................................................. 6 1.3 THE MR IN THE BRAIN ......................................................................................................................................... 8 1.3.1 The distribution of the MR in the brain ............................................................................................ 10 1.3.2 Time-dependent function of neuronal MR of cell nucleus and membrane ....................... 11 1.3.3 The MR and cognitive functioning ...................................................................................................... 14 1.3.4 The MR and mood ...................................................................................................................................... 16 1.3.5 The MR and social cognition ................................................................................................................. 17 1.3.6 The MR in patients with Addison’s disease ..................................................................................... 19 1.3.7 Pharmacokinetics and pharmacodynamics of fludrocortisone ............................................. 22 2 AIMS AND DESIGN OF THE DISSERTATION PROJECT ............................................................. 25 2.1 RESEARCH QUESTIONS AND HYPOTHESES ..................................................................................................... 25 2.1.1 Study I: Cognitive function in patients with Addison’s disease .............................................. 26 2.1.2 Study II: The role of the MR in patients with Addison’s disease ............................................. 26 2.1.3 Study III: MR stimulation and social cognition in healthy participants ............................ 27 2.2 RATIONALE OF THE THREE STUDIES ............................................................................................................... 28 2.2.1 Participant recruitment .......................................................................................................................... 29 2.2.2 Randomization process ........................................................................................................................... 29 2.2.3 Blinding .......................................................................................................................................................... 30 2.2.4 Treatment selection .................................................................................................................................. 30 2.2.5 Measurement of blood pressure .......................................................................................................... 31 2.2.6 Measurement of salivary cortisol ........................................................................................................ 31 2.2.7 Selection of the psychological tests .................................................................................................... 32 3 COGNITIVE FUNCTION IN PATIENTS WITH ADDISON’S DISEASE (STUDY I) .................. 33 ABSTRACT ................................................................................................................................................................... 34 3.1 INTRODUCTION ................................................................................................................................................... 35 3.2 METHODS AND MATERIALS .............................................................................................................................. 36 3.2.1 Participants .................................................................................................................................................. 36 3.2.2 Procedures .................................................................................................................................................... 37 iii 3.2.3 Neuropsychological assessment .......................................................................................................... 37 3.2.4 Statistical analyses .................................................................................................................................... 38 3.3 RESULTS ............................................................................................................................................................... 38 3.3.1 Demographic and clinical data ............................................................................................................ 38 3.3.2 Comparison of patients with AI with MC ......................................................................................... 40 3.4 DISCUSSION ......................................................................................................................................................... 45 4 THE ROLE OF THE MR IN PATIENTS WITH ADDISON’S DISEASE (STUDY II) .................. 48 ABSTRACT ................................................................................................................................................................... 49 4.1 INTRODUCTION ................................................................................................................................................... 50 4.2 METHODS AND MATERIALS .............................................................................................................................. 51 4.2.1 Participants .................................................................................................................................................. 51 4.2.2 Procedures .................................................................................................................................................... 52 4.2.3 Neuropsychological assessment .......................................................................................................... 53 4.2.4 Statistical analyses .................................................................................................................................... 53 4.3 RESULTS ............................................................................................................................................................... 53 4.3.1 Demographic and clinical data: .......................................................................................................... 53 4.3.2 Intraindividual comparison of high vs. low MR occupation in patients with AI ............ 54 4.4 DISCUSSION ......................................................................................................................................................... 57 5 MR STIMULATION AND SOCIAL COGNITION IN HEALTHY PARTICIPANTS (STUDY III) .....................................................................................................................................................................
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