Physiol Rev 98: 1805–1908, 2018 Published June 13, 2018; doi:10.1152/physrev.00031.2017 THE OXYTOCIN RECEPTOR: FROM INTRACELLULAR SIGNALING TO BEHAVIOR Benjamin Jurek and Inga D. Neumann Department of Behavioural and Molecular Neurobiology, Institute of Zoology, University of Regensburg, Regensburg, Germany Jurek B, Neumann ID. The Oxytocin Receptor: From Intracellular Signaling to Behav- ior. Physiol Rev 98: 1805–1908, 2018. Published June 13, 2018; doi:10.1152/ physrev.00031.2017.—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, Land 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 reproduc- tion, 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 G i or G q 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. I. INTRODUCTION AND HISTORY OF... 1805 historical perspective to gain a better understanding of pres- II. EVOLUTION OF THE BRAIN OXT/AVP ... 1808 ent developments of OXT research from basic studies into a III. THE ANATOMY OF THE OXT SYSTEM 1809 translational approach. IV. REGULATION OF OXT SYNTHESIS, ... 1817 V. REGULATION OF OXTR EXPRESSION ... 1830 The closely related nonapeptides OXT and arginine vaso- VI. OXTR-COUPLED SIGNALING IN ... 1835 pressin (AVP), which are synthesized within neurons of the VII. OXTR-MEDIATED CELLULAR EFFECTS 1844 hypothalamus, substantially form the hypothalamo-neuro- VIII. OXTR-MEDIATED REGULATION OF ... 1845 hypophysial system (HNS) in mammals. Due to its specific IX. LEARNING AND MEMORY 1864 anatomy and physiology, this system has become a text- X. FOOD INTAKE AND SATIETY 1867 book example that has been studied for more than 100 yr. XI. OXT AND ADDICTION 1869 Harold Gainer has described the HNS as “a veritable ‘Ro- XII. OXTR SNPs AND ASSOCIATED ... 1871 setta Stone’ for neuroendocrinology and neuroscience” XIII. CONCERNS AND UNSOLVED ... 1874 (364, 651). Indeed, we know far more about the OXT and AVP systems than about any other neuropeptide or neu- I. INTRODUCTION AND HISTORY OF roendocrine system, as many seminal findings on neuro- OXYTOCIN AND VASOPRESSIN physiological or neuroendocrine regulation have been re- RESEARCH vealed using the HNS. The scientific interest in the oxytocin (OXT) system has We can trace back the roots of OXT and AVP research to been boosted by the discovery of a plethora of behavioral the work of G. Oliver and E. A. Schäfer, who revealed first and physiological effects in animals and humans alike in the physiological effects of the pituitary gland and its extracts in last 30 yr. These studies are rooted in more than 100 yr of 1895. Specifically, they were the first to show vasopressor neuropeptide research, which we will briefly summarize in a effects, which were characterized by W. Howell as effects of 0031-9333/18 Copyright © 2018 the American Physiological Society 1805 Downloaded from www.physiology.org/journal/physrev by ${individualUser.givenNames} ${individualUser.surname} (132.199.072.184) on June 19, 2018. Copyright © 2018 American Physiological Society. All rights reserved. JUREK AND NEUMANN the posterior (infundibular) portion of the pituitary a few roendocrinology” not only because of his pioneering work years later (456). These observations were based on impor- on the hypothalamo-adenohypophysial system, but also be- tant anatomical contributions by S. Ramon y Cajal, who cause he furthered our physiological understanding of the described a neuronal pathway from the supraoptic nucleus posterior pituitary. He could show that electrical stimula- (SON) of the hypothalamus to the posterior pituitary in tion of the neuronal supraoptic-hypophysial tract elevates 1894. Shortly thereafter, in 1906, the English researcher Sir the intramammary pressure and results in the ejection of Henry H. Dale found—rather incidentally and reported as a milk from a cannulated duct in anesthetized lactating rab- side note—that a pituitary extract applied to an early preg- bits. Based on this finding and on earlier experiments dem- nant uterus of a cat has uterine-contracting properties onstrating that blood from milked cows could trigger milk (227). The proposed pituitary principle has later been ejection in the isolated udder (306), he hypothesized that ´ named oxytocin from the Greek words o’␰U␵, oxys, and the posterior pituitary contains a neurosecretory, i.e., re- ´ ␶O␬␱␵, tokos, meaning “quick birth.” These very first dis- leasable factor, which stimulates the observed milk letdown coveries on physiological effects of posterior pituitary hor- (213, 214). These early ideas of a neurosecretory origin of mones opened the way for its therapeutic use in obstetrics. posterior pituitary hormones (613), of OXT and AVP syn- The clinical use of OXT started with the first case descrip- thesis in magnocellular neurons of the hypothalamus and tions of infundibular extracts (also called extracts of the their transport via axonal connections within the pituitary infundibular body including the pituitary stalk and the pos- stalk to the posterior pituitary (neurohypophysis), are still ѧ terior pituitary at this time) “ to produce contractions of valid until today. the uterus in many serious obstetric complications” in 1909 by the Canadian W. Blair Bell (71). However, true neuropeptide chemistry only started in 1953 with the first successful sequencing of OXT after its isola- The third major hormonal function of pituitary extracts tion from lyophilized posterior lobes of beef pituitary was discovered by Ott and Scott in 1909 and by Schäfer and glands by Vincent du Vigneaud (288, 290). Subsequently, Mackenzie in 1911, who described its ability to trigger milk he and—independently—Roger Acher succeeded in synthe- ejection from the mammary gland (791, 914). sizing OXT (and later AVP) (5, 289). It is less well known that du Vigneaud’s work on OXT was a result of his origi- It is of interest to note that it was only in 1928 that O. nal interest in insulin, which he described at no less an Kamm used dialysis membranes to separate the vasopressor occasion than the Nobel Lecture on the 12th of December and the oxytocic principles of pituitary extracts (pituitrin) in 1955 that OXT was a result of a “trail of sulfa research.” (505). Shortly after, the development of synthetic agonists and The demonstration of cytoplasmic vesicles in specialized antagonists of OXT and AVP (666, 668) was an essential glandule-like giant cells in the hypothalamus (later called step into studies on the OXT receptor (OXTR) pharmacol- magnocellular neurons) of teleost fish by the German-born ogy, and the true starting point of a plethora of studies on researcher Ernst Scharrer and his wife Berta in the 1930s neuronal, behavioral, and physiological effects of these further paved the way for the definition of neurosecretion nonapeptides. Indeed, new vistas into OXT and AVP re- (915, 916) (FIGURE 1). However, it is the British physiolo- gist Geoffrey Harris, who is often called the “father of neu- search were opened with the demonstration of effects of synthetic OXT and AVP and their analogs on various as- pects of behavior, which will be discussed in detail later. OXT-related publications on PubMed Here, in this brief historical overview, only the pioneering 1000 work of David de Wied and his colleagues (93, 248), who revealed memory effects of synthetic AVP and OXT, and by 800 Cort Pedersen in the 1970s (809) reporting that synthetic OXT induces maternal behavior in rats, will be outlined. 600 Notably, the first demonstration of a nonapeptide effect on behavior in any species appeared in 1955 (1090): admin- 400 istration of vasotocin—the bony fish homolog of AVP—in the form of a pituitary extract induced a “spawning reflex” 200 in the killifish (Fundulus heteroclitus) similar to that ob- served during normal spawning activity. 0 In the 1980s, the first immunohistochemical demonstration of neurophysin—and later more specifically of OXT- and 1930 1940 1950 1960 1970 1980 1990 2000 2010 2016 AVP-containing pathways within the brain (963, 964, FIGURE 1. Number of OXT-related research articles per year 969)—substantiated these behavioral findings. These path- listed in PubMed from 1930 to 2016. ways were described to mainly originate in the hypothala- 1806 Physiol Rev • VOL 98 • JULY 2018 • www.prv.org Downloaded from www.physiology.org/journal/physrev by ${individualUser.givenNames} ${individualUser.surname} (132.199.072.184) on June 19, 2018. Copyright © 2018 American Physiological Society. All rights reserved. THE OXYTOCIN RECEPTOR mus and to project to extra-hypothalamic target regions, peptide release within distinct brain regions.