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Investigating the Role of the Central and the Peripheral Benzodiazepine Receptor on Stress and Anxiety Related Parameters

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Investigating the role of the central and the peripheral benzodiazepine receptor on stress and anxiety related parameters Inaugural-Dissertation zur Erlangung der Doktorwürde der Fakultät für Humanwissenschaften der Universität Regensburg vorgelegt von LISA-MARIE BAHR aus Hausen Regensburg 2020 Erstgutachter: Prof. Dr. rer. soc. Andreas Mühlberger Zweitgutachterin: PD Dr. med. habil. Caroline Nothdurfter I ACKNOWLEDGEMENT I wish to thank a number of people that have supported me on this exciting journey and substantially contributed to the success of this work. First of all, I want to thank my supervisors Priv.-Doz. Caroline Nothdurfter and Professor Andreas Mühlberger for always promoting me, being open for any kind of questions and teaching me to take responsibilities. Likewise, I want to thank Professor Jens Schwarzbach for the patient teaching in the fields of brain imaging and for the support in the analysis of our MRI data. Furthermore, I want to thank Professor Rainer Rupprecht for the comprehensive support in organizational and economic matters. I am thankful for the great time and the opportunities I had within my graduate school and wish to thank its spokesperson Professor Inga Neumann and all other supervisors and PhD students of the program, especially Viola Wagner and Kerstin Kuffner for going through this together. The realization of the study would not have been possible without a number of people and I want to thank Franziska Maurer and Kevin Weber for their extensive help in data acquisition, Dr. Johannes Weigl and Dr. Andre Manook for their support concerning the medical parts, Professor Thomas Wetter for the study monitoring, Doris Melchner, Anett Dörfelt, Dr. Vladimir Milenkovic, Heike Hallof-Buestrich and Tatjana Jahner for the laboratory analyses and countless hours on improving the techniques, the study nurses of the research station 18 D for the strong support at physical examinations and in organizational matters, Viola Wagner, Philipp Seidel and Marlene Tahedl for the support at the MRI scanner, Andreas Ruider and Andreas Hennings for always being achievable in technical questions as well as Dr. Theresa Wechsler, Dr. Stefanie Biehl and Michael Pfaller for the input and discussions about the analyses. Furthermore, I want to thank our collaborators that accomplished some of the laboratory analyses including the team of Georg Weinfurtner at the medbo Regensburg as well as Priv.- Doz. Jörg Reinders at the IfADo Dortmund. Further thanks go to audEERING in Gilching for providing the speech analysis component. Special thanks go to my family, especially my parents, my brother and Johannes who always supported me and all my ideas and stood behind me no matter if happy or tough times. A loving Miau goes to Gustav and Renate. Further, I want to thank my friends who always lent an ear and sometimes got me out of the rat race. Finally, a great thanks goes to all the volunteers that participated in our clinical trial and thereby even made this work possible. II III ABSTRACT Anxiety disorders belong to the most prevalent mental disorders worldwide implying a high burden of illness. Due to their complexity and variety of underlying dysfunctions, it remains a challenging task to find optimum pharmacological treatment. Benzodiazepines, which modulate the GABAA or central benzodiazepine receptor, are among the most frequently used substances in this field. However, they hold several side effects, especially at longer application. In the search for alternatives, substances that target the translocator protein (TSPO), also known as peripheral benzodiazepine receptor, yield promising candidates. Within the present work, we aimed to compare the effects of a benzodiazepine and a TSPO ligand, which further binds to GABAA receptors, on stress and anxiety related parameters. Within a randomized clinical trial, 60 healthy male subjects received either a daily dose of 1.5 mg alprazolam, 150 mg etifoxine or placebo for a period of five days. We applied the Trier Social Stress Test in Virtual Reality, the NPU Threat Test, resting-state functional imaging, and the Continuous Performance Test and assessed self-reports, physiological parameters, salivary and blood markers, objective performance parameters as well as changes of functional brain connectivity. While alprazolam blunted the response of the HPA axis to acute psychosocial stress, etifoxine increased expression of TSPO independent of additional external stimulation. There were no effects of the medication on subjective or physiological measures of the stress response. Neither alprazolam nor etifoxine had an impact on the anxiety-related startle reflex, while etifoxine attenuated the fear-potentiated startle on day 1 of treatment. Alprazolam increased functional neuronal connectivity within and between several resting-state networks. In neither group, there was strong impairment of alertness or any serious adverse event or study dropout. When focusing on symptoms related to sedation, there were more reports from subjects that had received alprazolam. The present work revealed different effects of the applied substances on molecular, physiological and neuronal markers of stress and anxiety. Thereby, especially the strength with which the GABAergic system is affected seems to play an important role, while the involvement of TSPO might be rather specific and dependent on the respective pathological state. IV ZUSAMMENFASSUNG Angststörungen gehören zu den häufigsten psychischen Erkrankungen weltweit und gehen mit einer hohen Belastung einher. Auf Grund ihrer Komplexität und Vielzahl an zugrunde liegenden Dysfunktionen bleibt es eine Herausforderung, optimale pharmakologische Behandlung zu erhalten. Benzodiazepine, welche den GABAA bzw. zentralen Benzodiazepinrezeptor modulieren, gehören zu den am häufigsten eingesetzten Substanzen in diesem Bereich. Sie verursachen jedoch, vor allem bei längerer Anwendung, zahlreiche Nebenwirkungen. Auf der Suche nach Alternativen stellen Substanzen, die das Translokator Protein (TSPO), auch bekannt als peripherer Benzodiazepinrezeptor, forcieren, vielversprechende Kandidaten dar. Ziel der vorliegenden Arbeit war es, die Effekte eines Benzodiazepins und eines TSPO Liganden, der ferner an GABAA Rezeptoren bindet, auf Stress- und angstassoziierte Parameter zu vergleichen. Im Rahmen einer randomisierten klinische Studie erhielten 60 gesunde männliche Probanden entweder täglich 1.5 mg Alprazolam, 150 mg Etifoxin oder Placebo über einen Zeitraum von fünf Tagen. Wir setzten den Trier Sozialen Stress Tests in Virtueller Realität, den NPU Threat Test, funktionelle Bildgebung während Ruhe und den Continuous Performance Test ein und erfassten Selbstberichte, physiologische Parameter, Speichel- und Blutmarker, objektive Leistungsparameter sowie Veränderungen der funktionellen Konnektivität im Gehirn. Während Alprazolam die Reaktion der HPA Achse auf akuten psychosozialen Stress reduziere, erhöhte Etifoxin die Expression von TSPO unabhängig von weiterer externer Stimulation. Es zeigten sich keine Effekte der Medikation auf subjektive oder physiologische Parameter der Stressreaktion. Weder Alprazolam noch Etifoxin beeinflussten den Angst- bezogenen Schreckreflex, während Etifoxin den Furcht-potenzierten Startle an Tag 1 der Behandlung reduzierte. Alprazolam erhöhte die funktionelle neuronale Konnektivität innerhalb und zwischen verschiedenen Ruhenetzwerken. In keiner der Gruppen zeigte sich eine merkliche Beeinträchtigung der Aufmerksamkeit und es waren keine schwerwiegenden unerwünschten Ereignisse oder Studienabbrüche zu verzeichnen. Mit Fokus auf unerwünschte Ereignisse in Zusammenhang mit Sedierung gab es mehr Berichte von Probanden, die Alprazolam erhalten hatten. Die vorliegende Arbeit ergab unterschiedliche Effekte der eingesetzten Substanzen auf molekulare, physiologische und neuronale Marker von Stress und Angst. Dabei scheint vor allem die Stärke, mit der das GABAerge System beeinflusst wird, eine entscheidende Rolle zu spielen, während die Beteiligung von TSPO eher spezifisch und abhängig vom jeweiligen pathologischen Zustand zu sein scheint. V CONTENT LIST OF FIGURES .................................................................................................................. IX LIST OF TABLES ................................................................................................................... XI ABBREVIATIONS ............................................................................................................... XIII CHAPTER 1: General introduction ........................................................................................... 1 1.1 Overview ................................................................................................................... 2 1.2 Stress ......................................................................................................................... 2 1.2.1 Overview of stress concepts ................................................................................. 2 1.2.2 Major physiological stress systems ...................................................................... 4 1.2.3 Chronic stress and disease: focus on anxiety disorders ........................................ 9 1.3 Anxiolytic therapy ................................................................................................... 10 1.3.1 Overview of established anxiolytics and related target systems ........................ 11 1.3.2 Central benzodiazepine receptor: GABAA receptor ..........................................
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