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Maternal Separation Interferes with Developmental Changes in Brain Vasopressin and Oxytocin Receptor Binding in Male Rats

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Maternal Separation Interferes with Developmental Changes in Brain Vasopressin and Oxytocin Receptor Binding in Male Rats Effects of central neuropeptides on social preference and social recognition in male rats DISSERTATION ZUR ERLANGUNG DES DOKTORGRADES DER NATURWISSENSCHAFTEN (DR. RER. NAT.) DER FAKULTÄT DER BIOLOGIE UND VORKLINISCHEN MEDIZIN DER UNIVERSITÄT REGENSBURG vorgelegt von Michael Lukas aus Roth im Jahr 2011 Das Promotionsgesuch wurde eingereicht am: 09.08.2011 Die Arbeit wurde angeleitet von: Prof. Dr. Inga. D. Neumann Unterschrift: Content Chapter 1: General Introduction ................................................................................................................. 4 Chapter 2: The neuropeptide oxytocin facilitates pro-social behavior and prevents social avoidance in rats and mice ........................................................................................................................... 24 Chapter 3: Early life stress impairs social recognition due to a blunted response of vasopressin release within the septum of adult male rats ...................................................................................... 52 Chapter 4: Maternal separation interferes with developmental changes in brain vasopressin and oxytocin receptor binding in male rats ................................................................................... 79 Chapter 5: Nasal application of neuropeptide S prolongs object, but not social memory, and reduces general anxiety ...................................................................................................................... 105 Chapter 6: General Discussion ................................................................................................................ 134 Summary in German .............................................................................................................. 161 References ............................................................................................................................. 166 Abbreviations ........................................................................................................................ 190 Acknowledgements ............................................................................................................... 192 CV and publications ............................................................................................................... 195 Chapter 1 General Introduction Content 1. Neuropeptides ....................................................................................................................... 6 1.1. OT and AVP ..................................................................................................................... 7 1.2 NPS ................................................................................................................................... 9 2. Involvement of OT, AVP and NPS in emotionality ................................................................ 9 3. Involvement of OT, AVP and NPS in social behaviors ......................................................... 11 3.1 Involvement of OT, AVP, and NPS in rodent social behaviors ....................................... 11 3.2 Neuropeptides and human social behavior .................................................................. 12 3.3 Social behaviors and psychiatric disorders .................................................................... 14 4. Role of OT, AVP and NPS in social preference and social recognition ................................ 15 4.1 Involvement of neuropeptides in social preference ..................................................... 15 4.2 Involvement of neuropeptides in social recognition ..................................................... 17 5. Rodent models of social stress ............................................................................................ 19 5.1 Social defeat .................................................................................................................. 20 5.2 Maternal separation ...................................................................................................... 20 6. Aim of present thesis ........................................................................................................... 21 7. Outline of the present thesis ............................................................................................... 22 Chapter 1 – General Introduction 6 1. Neuropeptides Since first mentioned by David de Wied in the 1970s, the definition of the term neuropeptide underwent several transformations. Therefore, an universal description of the term neuropeptide is hard to find. However, an example for a very clear definition, among many others, was given by Carsten Wotjak (2008): Neuropeptides are endogenous peptidergic neuromessengers, which are synthesized by and released from nerve cells and involved in nervous system functions. Throughout neuronal messengers, neuropeptides display effects via a variety of different routes of action (for review see Landgraf and Neumann, 2004; Wotjak et al., 2008). Some may be released as neurohormones in the periphery, but all of them act in the central nervous system (CNS) in the form of neurotransmitters released synaptically at axon terminals or as neuromodulators released from other structures of the neuronal surface, i.e. dendrites and soma (Pow and Morris, 1989). The effects of synaptic release are spatially restricted to the synaptic cleft and directly influence the neuronal activity of the target neurons, e.g. via activation of ion channels at the post-synapse. In contrast, during so called volume transmission high amounts of neuropeptides are released in the areas of their production that spread throughout the CNS to trigger indirect modulatory effects on neurotransmitter action at several target neurons via intracellular signal transduction mechanisms (Agnati et al., 1995; Zoli et al., 1999). The high affinity of neuropeptides to their receptors, which are mainly G protein-coupled receptors, and their inactivation via extracellular degradation or internalization of the receptor-ligand complex speak for a pronounced action of neuropeptides as neuromodulators (Landgraf and Neumann, 2004). Chapter 1 – General Introduction 7 This thesis focuses on the behavioral relevance of the neuropeptides arginine-vasopressin (AVP), oxytocin (OT) and the recently discovered neuropeptide S (NPS). 1.1. OT and AVP OT and AVP belong to the arginine vasotocin family (Acher et al., 1972) and consist of nine amino acids differing in only two positions. Two cystein residues form a disulfide bridge creating the circular structure of the nonapeptides (Du Vigneaud et al., 1953). Neuropeptides of this family are ubiquitous within vertebrates and evolutionary highly conserved, both in structure and functions (Hoyle, 1999). OT and AVP are mainly synthesized in a well-defined arrangement of magnocellular neurons located within the supraoptic (SON) and paraventricular nuclei (PVN) of the hypothalamus at the base of the brain. Via axonal projections, OT and AVP reach the neurohypophysis, where they are released into the blood stream in response to appropriate stimuli. In the context of their release into the blood stream, OT has been originally reported as a hormonal key regulator of female reproductive functions in all mammalian species. Thus, OT accelerates the delivery process as it promotes uterine contractions and is essential for the milk ejection during lactation (Freund-Mercier and Richard, 1984; Higuchi et al., 1985). The originally described physiological functions of AVP are the regulation of water resorption in the distal tubulus of the kidney and the constriction of vascular smooth muscle cells (Goldsmith, 1987). However, starting with the fundamental discoveries of David DeWied and Cort Pedersen (De Wied, 1965; Pedersen and Prange, 1979), both OT and AVP emerged as neuromodulators of the brain regulating a broad variety of behaviors. Chapter 1 – General Introduction 8 In the context of their multiple behavioral effects, neuronal release of OT and AVP within the brain is of significant interest. OT and AVP release was shown to occur from dendrites or perikarya of magnocellular neurons described within the hypothalamus (Ludwig and Leng, 2006), i.e. PVN, SON and superchiasmatic nucleus (only AVP), but also from axonal or collateral projections of parvo- or magnocellular neurons targeting, for example, regions of the limbic brain, like the amygdala and the lateral septum (Buijs et al., 1983). Additionally, AVP release within the brain occurs from distinct extra-hypothalamic brain regions synthesizing AVP, namely the bed nucleus of stria terminalis and the medial amygdala (De Vries and Buijs, 1983). AVP cells from the medial amygdala project to the lateral septum and to the ventral hippocampus (Caffe et al., 1987). The bed nucleus of stria terminalis projects to several limbic, prefrontal and hindbrain regions, including the lateral septum, the ventral septal area, the vertical diagonal band of broca, the lateral habenular nucleus, the olfactory tubercle, and the locus coeruleus (van Leeuwen and Caffe, 1983). The behavioral effects of OT and AVP release in these target regions are mediated by their respective receptors, the OT receptor (OTR), the AVP 1a receptor (V1aR), and the V1bR. These receptors form a phylogenetic group of 7-transmembrane domain G protein-coupled receptors. Owing to its higher and more wide-spread occurrence centrally compared to the V1bR, the V1aR is thought to be the predominant AVP receptor in the brain (Tribollet
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