PDF hosted at the Radboud Repository of the Radboud University Nijmegen The following full text is a publisher's version. For additional information about this publication click this link. http://hdl.handle.net/2066/71267 Please be advised that this information was generated on 2021-09-26 and may be subject to change. Frank van Broekhoven Effects of progesterone and allopregnanolone on stress, attention, cognition and mood | Frank van Broekhoven ISBN 978-90-9023655-1 Copyright ©2008 Frank van Broekhoven. The copyright of articles that have already been published has been transferred to the respective journals. No part of this book may be reproduced, in any form, without prior written permission from the author. Niets uit deze uitgave mag worden verveelvoudigd en/of openbaar gemaakt in welke vorm dan ook, zonder voorafgaande schriftelijke toestemming van de auteur. Coverdesign and layout by: Communicatie Kant, Dinxperlo, The Netherlands Printed by: Up2data, Bocholt, Germany The financial support for the printing of this thesis by Eli Lilly Nederland BV, Janssen-Cilag BV, the Department of Psychiatry from the Radboud University Nijmegen Medical Centre, and Karakter, Child and Adolescent Psy- chiatry University Centre, Nijmegen, is gratefully acknowledged. Effects of progesterone and allopregnanolone on stress, attention, cognition and mood Een wetenschappelijke proeve op het gebied van de Medische Wetenschappen Proefschrift ter verkrijging van de graad van doctor aan de Radboud Universiteit Nijmegen op gezag van de rector magnificus prof. mr. S.C.J.J. Kortmann, volgens besluit van het College van Decanen in het openbaar te verdedigen op maandag 24 november 2008 om 15.30 uur precies door Frank van Broekhoven geboren op 8 december 1969 te Groenlo Promotores: prof. dr. J.K. Buitelaar prof. dr. T. Bäckström (Umeå Universiteit) Copromotor: dr. R.J. Verkes Manuscriptcommissie: Prof. dr. Y.A. Hekster Prof. dr. J.A. den Boer (Rijksuniversiteit Groningen) Prof. dr. J.A.M. Kremer Effects of progesterone and allopregnanolone on stress, attention, cognition and mood An academic assay in Medical Sciences Doctoral thesis to obtain the degree of doctor from Radboud University Nijmegen on the authority of the Rector Magnificus prof. dr. S.C.J.J. Kortmann, according to the decision of the Council of Deans to be defended in public on Monday, 24 November 2008 at 15.30 hours by Frank van Broekhoven born in Groenlo on 8 december 1969 Doctoral supervisors: prof. dr. J.K. Buitelaar prof. dr. T. Bäckström (Umeå University) Co-supervisor: dr. R.J. Verkes Doctoral Thesis Committee: Prof. dr. Y.A. Hekster Prof. dr. J.A. den Boer (University of Groningen) Prof. dr. J.A.M. Kremer Effects of progesterone and allopregnanolone on stress, attention, cognition and mood | Frank van Broekhoven Contents page chaPter 1 Introduction 9 chaPter 2 Pharmacological characteristics of progesterone and allopregnanolone, steroid nomenclature, and development of neuroactive steroids to drugs 21 chaPter 3 Allopregnanolone and serotonin 33 chaPter 4 Neurosteroids in depression: a review 39 chaPter 5 Effects of PhD examination stress on allopregnanolone and cortisol plasma levels and peripheral benzodiazepine receptor density 59 chaPter 6 Effects of allopregnanolone on sedation in men, and in women on oral contraceptives 67 chaPter 7 Oral progesterone decreases saccadic eye velocity and increases sedation in women 85 chaPter 8 Increased sensitivity to oral progesterone in the luteal phase in healthy women 103 chaPter 9 Progesterone selectively increases amygdala reactivity in women 117 chaPter 10 Discussion 133 chaPter 11 Summary 147 chaPter 12 References 153 samenvatting 181 Publications 187 DankwoorD 193 curriculum vitae 197 Effects of progesterone and allopregnanolone on stress, attention, cognition and mood | Frank van Broekhoven chaPter 1 | INTRODUCTION chaPter 1 | INTRODUCTION chaPter 1 | INTRODUCTION Neuroactive steroids are important for psychiatry. Being metabolites of sex and stress hormones, they are involved in the pathophysiology of menstrual cycle and stress linked psychiatric disorders like the Premenstrual Dysphoric Disorder (PMDD), depression and dementia. Neuroactive steroids influence the excitability of neurons by acting on membrane-bound neurotransmitter receptors. Changes in concentrations of neuroactive steroids or in sensitivity of receptors can cause psychiatric symptoms like negative mood, anxiety and cognitive disor- ders. Most data comes from animal research while human data is mostly limited to the assessment of levels of neuroactive steroids in plasma from psychiatric patients and healthy controls and from postmenopausal women during hormone replacement therapy. The latter model has the advantage that dose response studies have been performed in humans. Definitions Steroid hormones are synthesized in the gonads, adrenal glands and placenta. Some steroid hormones are also synthesised in the brain and are called neurosteroids (Baulieu, 1998). The synthesis of steroids within the brain was first discovered in 1981 when dehydroepiandrosterone-sulphate (DHEAS) was detected in the brain of rats in concentrations much more higher than in plasma and not being influenced by adrenalectomy or adreno- corticotropic hormone (ACTH) administration (i.e. by manipulation peripherally) (Corpechot et al., 1981). When steroid hormones or neurosteroids have effect on the central nervous system (CNS) they are called neuroactive steroids (Paul and Purdy, 1992). Steroid hormones are known to act through intracellular receptors that act as ligand-activated transcrip- tion factors in the regulation of gene expression (genomic way). Neuroactive steroids have effects through membrane-bound receptors such as ligand-gated ion channels (non-genomic way) (McEwen, 1991; Rupprecht, 2003). This a-genomic mechanism of action accounts for rapid steroid effects that occur within milliseconds to seconds. Although neuroactive steroids can act on many different membrane-bound receptors, neuroactive steroids that act on the GABA(A) receptor are among the best studied (Baulieu, 1998). These so called GABA- steroids are defined as 3alpha-hydroxy-5alpha/beta metabolites of endogenous steroid hormones (Rupprecht and Holsboer, 1999). The main endogenous steroid hormones that generate GABA-steroids are stress hormones (cortisol and desoxycorticosterone (DOC)), and sex hormones (progesterone and testosterone). Many of the CNS effects of stress and sex hormones are mediated via the 3alpha-hydroxy-5alpha/beta metabolites while these GABA-steroids themselves do not activate the classical hormonal nuclear receptors of their parent compounds (Backstrom et al., 2003). 11 Chapter 1 | INTRODUCTION GABA, GABA(A) receptor, and GABA-steroids Gamma-amino butyric acid (GABA) is the major inhibitory neurotransmitter in the CNS and activates the GABA(A) receptor. The transmembrane heteropentameric GABA(A) receptor is composed of five subunits that belong to different subunit classes (Rudolph et al., 2001). These subunits form an ion channel through which chloride ions can enter the cell. When chloride ions flow into the neuron the possibility to generate an action potential is inhibited. Opening and closing of the channel is regulated by substances that bind to the GABA(A) receptor such as GABA itself, benzodiazepines, alcohol and GABA-steroids. GABA-steroids enhance the GABA effect on the GABA(A) receptor in a similar way as barbiturates, benzodiazepines and alcohol and are therefore potent positive allosteric modulators of the GABA(A) receptor (Majewska et al., 1986). The concentrations of GABA-steroids in the brain change in parallel with the ovarian and adrenal production. Conditions in which high GABA-steroid production occurs are stress, the luteal phase of the menstrual cycle, preg- nancy, progestagen treatment (oral contraceptive use, hormonal replacement treatment), and steroid treatment. GABA-steroids and GABA(A) receptors interact with each other. The sensitivity of GABA(A) receptors to GABA- steroids depends on the subunit composition of the receptor, with receptors containing the delta-subunit being the most sensitive (Spigelman et al., 2003), and on the phosphorylation state of the receptor (Lambert et al., 2001). Subunit composition differs between brain regions (Gee et al., 1988; Lambert et al., 2001). Vice versa, GABA-steroids influence the subunit composition of the GABA(A) receptor (Follesa et al., 2004); withdrawal of GABA-steroids increase alpha 4 subunit resulting in decreased sensitivity to GABA-steroids (Smith et al., 1998) while exposure to GABA-steroids increase alpha 1 and 2 subunits (Birzniece et al., 2006; Guerra-Araiza et al., 2008). Thus, the interaction between GABA-steroids and GABA(A) receptors is complex. GABA-steroids can induce CNS disorders (Backstrom et al., 2003). These disorders can be divided into menstrual cycle linked disorders (for example negative mood during hormone replacement therapy, PMDD, and catamenial epilepsy, which is a form of epilepsy characterised by increased frequency of epileptic seizures) and acute and chronic stress disorders (for example depression). In addition, GABA-steroids induce symptoms like cognitive disturbances (impaired memory and learning (Johansson et al., 2002)), increased appetite (Chen et al., 1996), and increased risk of substance abuse (Finn et al., 1997). They also induce negative mood symp- toms and aggressiveness (Backstrom et al., 2003; Miczek et al., 2003). Long-term treatment with precursors to GABA-steroids increases