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University of Groningen Oxytocin: the Neurochemical Mediator of Social Life Calcagnoli, Federica

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University of Groningen Oxytocin: the Neurochemical Mediator of Social Life Calcagnoli, Federica University of Groningen Oxytocin: the neurochemical mediator of social life Calcagnoli, Federica IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2014 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Calcagnoli, F. (2014). Oxytocin: the neurochemical mediator of social life: A pharmaco-behavioral and neurobiological study in male rats. [S.n.]. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license. More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne- amendment. Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 08-10-2021 OXYTOCIN: THE NEUROCHEMICAL MEDIATOR OF SOCIAL LIFE A pharmaco-behavioral and neurobiological study in male rats Federica Calcagnoli The research reported in this thesis was carried out at the Department of Behavioral Physiology, University of Groningen, The Netherlands. The data presented in chapter five have been obtained in collaboration with the Department of Behavioral and Molecular Neuroscience, University of Regensburg, Germany. All studies were approved by the Animal Ethics Committee on Care and Use of Laboratory Animals of the University of Groningen and were conducted in agreement with Dutch laws (Wet op de Dierproeven 1996) and European regulations (Guideline 86/609/EEC). The research was financially supported by an Ubbo Emmius scholarship from the Faculty of Medical Science of the University Medical Center Groningen, The Netherlands. The printing of this thesis was financially supported by the Graduate School of Science and the Faculty of Mathematics and Natural Sciences, University of Groningen. Lay-out and printing: Off Page, Amsterdam Cover image: Card III of the Rorschach test printed in Rorschach’s Rorschach Test – Psychodiagnostic plates ISBN: 978-90-367-7262-4 Copyright © Federica Calcagnoli. No parts of this book may be reproduced or transmitted in any form or by any means without prior written permission of the author. OXYTOCIN: THE NEUROCHEMICAL MEDIATOR OF SOCIAL LIFE A pharmaco-behavioral and neurobiological study in male rats PhD thesis to obtain the degree of PhD at the University of Groningen on the authority of the Rector Magnificus Prof. E. Sterken and in accordance with the decision by the College of Deans. This thesis will be defended in public on Monday 13 October 2014 at 14.30 hours by Federica Calcagnoli born on 15 February 1986 in Macerata, Italy Supervisor Prof. J.M. Koolhaas Co-supervisors Dr. S.F. de Boer Dr. M. Althaus Assessment committee Prof. A.G.G. Groothuis Prof. I.D. Neumann Prof. G. van Dijk TABLE OF CONTENTS Chapter 1 Introduction and synthesis 11 Chapter 2 Anti-aggressive activity of central oxytocin in male rats 61 Chapter 3 Chronic enhancement of brain oxytocin levels causes 85 enduring anti-aggressive and pro-social explorative effects in male rats Chapter 4 Oxytocin microinjected into the central amygdaloid 103 nuclei exerts anti-aggressive effects in male rats Chapter 5 Local oxytocin expression and oxytocin receptor binding 125 in the male rat brain is associated with aggressiveness Chapter 6 Acute and repeated intranasal oxytocin administration 147 exerts anti-aggressive and pro-affiliative effects in male rats Nederlandse samenvatting 171 English summary 177 Riassunto in italiano 181 Acknowledgments 185 Publications 189 Curriculum vitae 191 List of abbreViations AH anterior hypothalamus ALT attack latency time AN accessory nucleus AVP vasopressin AVPR vasopressin receptor BNST bed nucleus of the stria terminalis CeA central amygdala CSF cerebrospinal fluid DA dopamine DR dorsal raphe D1 (2 or 3)- dopamine receptor type 1 (2 or 3) E2 estradiol 5-HIAA five-hydroxyindoleacetic acid 5-HT five-hydroxy-tryptamine (serotonin) 5-HT1A (1B) five-hydroxy-tryptamine receptor type 1A (1B) GABA gamma (γ) aminobutyric acid GABAA gamma (γ) aminobutyric acid receptor type A GPCR G protein-coupled receptor HAB high anxiety-related behavior ICV intracerebroventricular IGR intergenic region IU international unit LAB low anxiety-related behavior LS lateral septum mRNA messenger RNA (ribonucleic acid) NAcc nucleus accumbens NP neurophysin I OXT oxytocin OXTR oxytocin receptor PP partner preference PVN paraventricular nucleus RI resident-intruder SON supraoptic nucleus SP signal protein V1A (1B or 2) vasopressin receptor type 1A (1B or 2) VMH ventromedial hypothalamus VTA ventral tegmental area WTG wild-type Groningen “Men ought to know that from the brain, and from the brain only, arise our pleasures, joys, laughter, and jests, as well as our sorrows, pains, griefs and tears” Hippocrates, “The sacred disease” 1 INTRODUCTION AND SYNTHESIS Federica Calcagnoli OXYTOCIN AS A NEUROPEPTIDE Not long ago, oxytocin (OXT) was largely thought to be confined to its hormonal role in 1 female reproduction. Its name, originally derived from the Greek words “quick birth”, referred in fact, to its uterotonic activity (Dale, 1906) and facilitating action on milk- ejection (Ott and Scott, 1910). The groundbreaking discovery that changed the prevailing view of an exclusively peripheral neuroendocrine action of OXT was the induction of maternal behavior in virgin rats after its intracerebroventricular (icv) administration (Pedersen and Prange, 1979). Subsequently, the role of OXT in mate social recognition and pair bonding in prairie voles (Carter, 1998; Williams et al., 1994), and social recognition in mice (Ferguson et al., 2000) were reported. Hence, its role in social behavior became target of a large number of research projects. Over the past decades, among many species, including humans, the central neuropeptidergic action of OXT has been demonstrated in a wide variety of social behaviors as summarized in Figure 1. Figure 1. Summary of the social signals stimulating oxytocin release and of the behavioral and physiological oxytocin-induced effects (Nagasawa et al., 2012). OXT is composed of nine amino acids (Cys–Tyr–Ile–Gln–Asn–Cys–Pro–Leu–Gly-NH2) with a disulfide bridge between the cysteines 1 and 6. This results in a peptide constituted of a rigid N-terminal cyclic 6-residue ring structure and a flexible COOH-terminal alfa- amidated three-residue tail (Figure 2) (Gimpl and Fahrenholz, 2001; Lee et al., 2009a; Tom and Assinder, 2010). OXT is the first peptide hormone to have its structure determined (Du Vigneaud et al., 1953) and to be chemically synthesized in a biologically active form (Du Vigneaud et al., 1954). The structure of the gene was elucidated in 1984 (Ivell and Richter, 1984), and the sequence of the OXT receptor (OXTR) gene was reported in 1992 (Kimura et al., 1992). The structure of OXT is very similar to another nonapeptide, entitled vasopressin 13 (AVP), which differs from OXT by only two amino acids in position 3 and 8 (Figure 2). OXT and AVP are both ancient neuropeptides which are evolutionary well conserved across phyla, and they have been found in species ranging from invertebrates to mammals (Caldwell and Young, 2006; Donaldson and Young, 2008). In all placental mammals examined to date, the amino acid sequence of OXT is identical, suggesting a strong selective pressure to withstand sequence variation (Lee et al., 2011). In the mouse, rat and human genomes, the OXT gene is located in the same chromosome as AVP, separated by an intergenic region (IGR) and in opposite transcriptional direction (Figure 2). Both genes are composed of three exons (shown as small solid arrows in Figure 2) separated by two introns. Figure 2. Schematic diagram of the oxytocin and vasopressin genes (large arrows), preprohormones (boxes), and neuropeptides (bottom) (Caldwell et al., 2008). Oxytocin and its receptor in the brain In mammals, OXT is primarily synthetized and expressed in the magnocellular neurons of the paraventricular (PVN), supraoptic (SON) and accessory (AN) nuclei of the hypothalamus (Gimpl and Fahrenholz, 2001; Landgraf and Neumann, 2004; Lee et al., 2009a; Sofroniew, 1983; Swanson and Sawchenko, 1983). Lower amounts of OXT are generated in parvocellular neurons of the PVN and, depending on species, the bed nucleus of the stria terminalis (BNST), medial preoptic area, as well as the lateral amygdala for release within the brain (Young and Gainer, 2003). OXT is synthesized as preprohormone and assembled in ribosomes at the level of the soma. The OXT precursor is then subsequently processed in neurosecretory vesicles and undergoes several post-translational processes such as phosphorylation, glycosylation or acetylation, which lead to the three final products: OXT, neurophysin I (NP) and a signal protein (SP) (Figure 2, left side) (Caldwell et al.,
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