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The many facets of the oxytocin (OXT) system of the brain and periphery elicited nearly 25,000 publications since 1930 (see FIGURE 1 , as listed in PubMed), which revealed central roles for OXT and its receptor (OXTR) in reproduction, and social and emotional behaviors in animal and human studies focusing on mental and physical health and disease. In this review, we discuss the mechanisms of OXT expression and release, expression and binding of the OXTR in brain and periphery, OXTR-coupled signaling cascades, and their involvement in behavioral outcomes to assemble a comprehensive picture of the central and peripheral OXT system. Traditionally known for its role in milk let-down and uterine contraction during labor, OXT also has implications in physiological, and also behavioral, aspects of reproduction, such as sexual and maternal behaviors and pair bonding, but also anxiety, trust, sociability, food intake, or even drug abuse. The many facets of OXT are, on a molecular basis, brought about by a single receptor. The OXTR, a 7-transmembrane G protein-coupled receptor capable of binding to either Gα or Gα proteins, activates a set of signaling cascades, such as the MAPK, PKC, PLC, or CaMK pathways, which converge on transcription factors like CREB or MEF-2. The cellular response to OXT includes regulation of neurite outgrowth, cellular viability, and increased survival. OXTergic projections in the brain represent anxiety and stress-regulating circuits connecting the paraventricular nucleus of the hypothalamus, amygdala, bed nucleus of the stria terminalis, or the medial prefrontal cortex. Which OXT-induced patterns finally alter the behavior of an animal or a human being is still poorly understood, and studying those OXTR-coupled signaling cascades is one initial step toward a better understanding of the molecular background of those behavioral effects.

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The neuropeptide oxytocin (OXT) is currently attracting considerable attention as a result of the discovery of the amazing behavioural functions it regulates, especially in the context of social interactions. A broad variety of behaviours, including maternal care and aggression, pair bonding, sexual behaviour, and social memory and support, as well as anxiety-related behaviour and stress coping, are modulated by brain OXT. These discoveries make this neuromodulator ⁄ neurotransmitter system of the brain a promising target for psychotherapeutic intervention and treatment of numerous psychiatric illnesses, for example, anxiety disorders, social phobia, autism and postpartum depression.Together with the related nonapeptide arginine vasopressin (AVP), OXT is an essential part of the hypothalamo-neurohypophysial system. Since the original description of this system in fish by the German biologist Ernst Scharrer in 1928 (1), this welldefined arrangement of magnocellular neurones at the base of the brain has been one of the most valuable model systems in neuroendocrinology and neuroscience. Outstanding discoveries have been made through studying the OXT and AVP systems. These include the very first characterisation of a neuropeptide by DuVigneaud and, independently, by Acher in the 1950s, important insights into the bursting pacemaker activity of neurosecretory neurones (2), the discovery of neuropeptidergic pathways within the brain (3), novel views of neuronal-glial interactive plasticity (4, 5), and the development of neuropeptide receptor antagonists (6). Furthermore, the OXT system served as a suitable model arrangement for discovering important molecular and cellular mechanisms of neuropeptide synthesis, precursor processing, and cellular trafficking (7,8), as well as the stimuli and neuronal mechanisms of intracerebral neuropeptide release within distinct brain regions (9-11). These important findings have, in parallel, raised the question of the behavioural consequences of local OXT release and subsequent OXT receptor-mediated actions within brain target regions (12, 13). Journal of NeuroendocrinologyCorrespondence to: Inga D. Neumann, Department of Behavioural and Molecular Neuroendocrinology, University of Regensburg, 93053 Regensburg, Germany (e-mail: inga.neumann@ biologie.uni-regensburg.de).In addition to various reproductive stimuli, the neuropeptide oxytocin (OXT) is released both from the neurohypophysial terminal into the blood stream and within distinct brain regions in response to stressful or social stimuli. Brain OXT receptor-mediated actions were shown to be significantly involved in the regulation of a variety of behaviours. Here, complementary methodological approaches are discussed which were utilised to reveal, for example, anxiolytic and anti-stress effects of OXT, both in females and in males, effects that were localised within the central amygdala and the hypothalamic paraventricular nucleus. Also, in male rats, activation of the brain OXT system is essential for the regulation of sexual be...

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The oxytocinergic system is critically involved in the regulation of maternal behavior, which includes maternal aggression. Because aggression has been linked to anxiety, we investigated the maternal aggression and the role of brain oxytocin in lactating Wistar rats selectively bred for high anxiety-related behavior (HAB) or low anxiety-related behavior (LAB) during the 10 min maternal defense test. HAB dams displayed more maternal aggression against a virgin intruder compared with LAB dams, resulting in more defensive behavior and higher anxiety of HAB-defeated virgins. The different levels of aggression were accompanied by opposite oxytocin release patterns within the paraventricular nucleus (PVN; HAB, increase; LAB, decrease). ]OVT) into the PVN or CeA reduced maternal aggression of HAB dams, whereas infusion of synthetic oxytocin into the PVN tended to increase aggression toward the intruder in LAB dams. There were no significant differences in oxytocin receptor mRNA expression or oxytocin receptor binding between lactating HAB and LAB dams. Therefore, differences in intracerebral release patterns of oxytocin, rather than differences at the level of oxytocin receptors, are critical for the regulation of maternal aggressive behavior.

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