Comparison of the distribution of oxytocin and vasopressin 1a receptors in rodents reveals conserved and derived patterns of nonapeptide evolution

Oxytocin (OT) and vasopressin (VP) are known modulators of social behaviour across rodents. Research has revealed the location of action of these nonapeptides through localization of their associated receptors, which include the oxytocin receptor (OTR) and the vasopressin 1a receptor (V1aR). As research into these complex systems has progressed, studies investigating how these systems modulate behaviour have remained relatively narrow in scope (ie, focused on how a single brain region shapes behaviour in only a handful of species). However, the brain regions that regulate social behaviour are part of interconnected neural networks for which coordinated activity enables behavioural variation. Thus, to better understand how nonapeptide systems have evolved under different selective pressures among rodent species, we conducted a meta‐analysis using a multivariate comparative method to examine the patterns of OTR and V1aR density expression in this taxon. Several brain regions were highly correlated based on their OTR and V1aR binding patterns across species, supporting the notion that the distribution of these receptors is highly conserved in rodents. However, our results also revealed that specific patterns of V1aR density differed from OTR density, and within‐genus variance for V1aR was low compared to between‐genus variance, suggesting that these systems have responded and evolved quite differently to selective pressures over evolutionary time. We propose that, in addition to examining single brain regions of interest, taking a broad comparative approach when studying the OT and VP systems is important for understanding how the systemic action of nonapeptides modulate social behaviour across species.     

Vasopressin and oxytocin receptor systems in the brain: Sex differences and sex-specific regulation of social behavior

The neuropeptides vasopressin (VP) and oxytocin (OT) and their receptors in the brain are involved in the regulation of various social behaviors and have emerged as drug targets for the treatment of social dysfunction in several sex-biased neuropsychiatric disorders. Sex differences in the VP and OT systems may therefore be implicated in sex-specific regulation of healthy as well as impaired social behaviors. We begin this review by highlighting the sex differences, or lack of sex differences, in VP and OT synthesis in the brain. We then discuss the evidence showing the presence or absence of sex differences in VP and OT receptors in rodents and humans, as well as showing new data of sexually dimorphic V1a receptor binding in the rat brain. Importantly, we find that there is lack of comprehensive analysis of sex differences in these systems in common laboratory species, and we find that, when sex differences are present, they are highly brain region- and species-specific. Interestingly, VP system parameters (VP and V1aR) are typically higher in males, while sex differences in the OT system are not always in the same direction, often showing higher OT expression in females, but higher OT receptor expression in males. Furthermore, VP and OT receptor systems show distinct and largely non-overlapping expression in the rodent brain, which may cause these receptors to have either complementary or opposing functional roles in the sex-specific regulation of social behavior. Though still in need of further research, we close by discussing how manipulations of the VP and OT systems have given important insights into the involvement of these neuropeptide systems in the sex-specific regulation of social behavior in rodents and humans.     

Neuropeptide diversity and the regulation of social behavior in New World primates

Oxytocin (OT) and vasopressin (AVP) are important hypothalamic neuropeptides that regulate peripheral physiology, and have emerged as important modulators of brain function, particularly in the social realm. OT structure and the genes that ultimately determine structure are highly conserved among diverse eutherian mammals, but recent discoveries have identified surprising variability in OT and peptide structure in New World monkeys (NWM), with five new OT variants identified to date. This review explores these new findings in light of comparative OT/AVP ligand evolution, documents coevolutionary changes in the oxytocin and vasopressin receptors (OTR and V1aR), and highlights the distribution of neuropeptidergic neurons and receptors in the primate brain. Finally, the behavioral consequences of OT and AVP in regulating NWM sociality are summarized, demonstrating important neuromodulatory effects of these compounds and OT ligand-specific influences in certain social domains.     

Relationships among estrogen receptor, oxytocin and vasopressin gene expression and social interaction in male mice

The incidence of social disorders such as autism and schizophrenia is significantly higher in males, and the presentation more severe, than in females. This suggests the possible contribution of sex hormones to the development of these psychiatric disorders. There is also evidence that these disorders are highly heritable. To contribute toward our understanding of the mechanisms underlying social behaviors, particularly social interaction, we assessed the relationship of social interaction with gene expression for two neuropeptides, oxytocin (OT) and arginine vasopressin (AVP), using adult male mice. Social interaction was positively correlated with: oxytocin receptor (OTR) and vasopressin receptor (V1aR) mRNA expression in the medial amygdala; and OT and AVP mRNA expression in the paraventricular nucleus of the hypothalamus (PVN). When mice representing extremes of social interaction were compared, all of these mRNAs were more highly expressed in high social interaction mice than in low social interaction mice. OTR and V1aR mRNAs were highly correlated with estrogen receptor α (ERα) mRNA in the medial amygdala, and OT and AVP mRNAs with estrogen receptor β (ERβ) mRNA in the PVN, indicating that OT and AVP systems are tightly regulated by estrogen receptors. A significant difference in the level of ERα mRNA in the medial amygdala between high and low social interaction mice was also observed. These results support the hypothesis that variations of estrogen receptor levels are associated with differences in social interaction through the OT and AVP systems, by upregulating gene expression for those peptides and their receptors.     

Oxytocin and vasopressin agonists and antagonists as research tools and potential therapeutics

We recently reviewed the status of peptide and nonpeptide agonists and antagonists for the V(1a), V(1b) and V(2) receptors for arginine vasopressin (AVP) and the oxytocin receptor for oxytocin (OT). In the present review, we update the status of peptides and nonpeptides as: (i) research tools and (ii) therapeutic agents. We also present our recent findings on the design of fluorescent ligands for V(1b) receptor localisation and for OT receptor dimerisation. We note the exciting discoveries regarding two novel naturally occurring analogues of OT. Recent reports of a selective VP V(1a) agonist and a selective OT agonist point to the continued therapeutic potential of peptides in this field. To date, only two nonpeptides, the V(2) /V(1a) antagonist, conivaptan and the V(2) antagonist tolvaptan have received Food and Drug Administration approval for clinical use. The development of nonpeptide AVP V(1a), V(1b) and V(2) antagonists and OT agonists and antagonists has recently been abandoned by Merck, Sanofi and Pfizer. A promising OT antagonist, Retosiban, developed at Glaxo SmithKline is currently in a Phase II clinical trial for the prevention of premature labour. A number of the nonpeptide ligands that were not successful in clinical trials are proving to be valuable as research tools. Peptide agonists and antagonists continue to be very widely used as research tools in this field. In this regard, we present receptor data on some of the most widely used peptide and nonpeptide ligands, as a guide for their use, especially with regard to receptor selectivity and species differences.     

Histaminergic control of oxytocin release in the paraventricular nucleus during lactation in rats

The central neurotransmitters regulating both systemic and central release of oxytocin (OT) during lactation are not completely defined. Although central histaminergic systems have been implicated in systemic release of OT, the role of this neurotransmitter in suckling-induced intranuclear OT secretion has not been investigated. Therefore, microdialysis of the paraventricular nucleus (PVN) was used to determine if suckling stimulates histamine release within the PVN and if nursing-induced intranuclear OT release is reduced by local blockade of either H1 or H2 histamine receptors. Female Holtzman rats were implanted with microdialysis probes adjacent to the PVN on lactation days 8-12. The next day, the pups and dam were separated for 4 h, reunited, and again separated. Histamine concentrations in dialysates were measured before, during, and following suckling. In separate animals, a similar separation/reunion paradigm was used, but the dialysate OT concentration was measured during PVN perfusion with vehicle or an H1 or H2 receptor antagonist. Suckling increased dialysate concentrations of both histamine and OT in the PVN. Furthermore, local pharmacological blockade of either H1 or H2 receptors prevented the increase in OT release in the PVN during suckling. These data demonstrate that activation of histamine receptors in the PVN is necessary for intranuclear release of OT induced by suckling and extend previous findings demonstrating a similar relationship between central histamine and systemic release of OT.     

The social deficits of the oxytocin knockout mouse

Numerous studies have implicated oxytocin (OT) and oxytocin receptors in the central mediation of social cognition and social behavior. Much of our understanding of OT's central effects depends on pharmacological studies with OT agonists and antagonists. Recently, our knowledge of OT's effects has been extended by the development of oxytocin knockout (OTKO) mice. Mice with a null mutation of the OT gene manifest several interesting cognitive and behavioral changes, only some of which were predicted by pharmacological studies. Contrary to studies in rats, mice do not appear to require OT for normal sexual or maternal behavior, though OT is necessary for the milk ejection reflex during lactation. OTKO pups thrive if raised by a lactating female, but OTKO pups emit fewer ultrasonic vocalizations with maternal separation and OTKO adults are more aggressive than WT mice. Remarkably, OTKO mice fail to recognize familiar conspecifics after repeated social encounters, though olfactory and non-social memory functions appear to be intact. Central OT administration into the amygdala restores social recognition. The development of transgenic mice with specific deficits in social memory represents a promising approach to examine the cellular and neural systems of social cognition. These studies may provide valuable new perspectives on diseases characterized by social deficits, such as autism or reactive attachment disorder.     

Systemic oxytocin and vasopressin excite gastrointestinal motility through oxytocin receptor in rabbits

The aim of the present study was to investigate the effect of systemic oxytocin (OT) and vasopressin (VP) on the motility of stomach and duodenum. Two plastic balloons made of condom were inserted into stomach and duodenum to monitor the change of mean pressure. Intravenous injection of OT (0.1-0.8 microg kg(-1)) or VP (0.02-0.08 IU kg(-1)) dose-dependently increased the stomach and duodenum pressure. Pretreatment of atosiban (1 microg kg(-1)), the specific OT receptor (OTR) antagonist, attenuated the excitatory effect of OT or VP on the pressure of stomach and duodenum. Pretreatment of V1880 (1 microg kg(-1)), the specific V1 receptor blocker, did not influence this effect. So we conclude that both of OT and VP injected systemically increased the gastric and duodenum motility via OTR.     

Maternal Behaviour is Associated with Vasopressin Release in the Medial Preoptic Area and Bed Nucleus of the Stria Terminalis in the Rat

The neuropeptide arginine vasopressin was recently shown to be an important regulator of female social behaviour, including maternal care and aggression. A key brain site for vasopressin‐ as well as oxytocin‐mediated maternal care is the medial preoptic area (MPOA). Together with the adjacent bed nucleus of the stria terminalis (BNST), these brain regions are considered to form a ‘super‐region’ for maternal behaviour. In the present study, we investigated the vasopressin and oxytocin systems within the MPOA and the BNST during maternal care in lactating rats in more detail. Binding to V1a and oxytocin receptors in the BNST and to oxytocin receptors in the MPOA was increased in lactation. Furthermore, microdialysis revealed that vasopressin release significantly increased (MPOA) or tended to increase (BNST) during different phases of maternal care (i.e. with or without suckling stimulus). In support, manipulations of V1a receptors in the MPOA are known to alter maternal care. We now show that local injection of a selective V1a receptor antagonist bilaterally into the BNST did not affect maternal care, but reduced maternal aggression and tended to lower anxiety‐related behaviour. The release of oxytocin did not change in any of the brain regions during maternal care. The results obtained indicate that locally‐released vasopressin within the MPOA and the BNST is important for the maintenance of complex maternal behaviours, including maternal care and aggression, respectively.     

Mice Heterozygous for the Oxytocin Receptor Gene (Oxtr+/−) Show Impaired Social Behaviour but not Increased Aggression or Cognitive Inflexibility: Evidence of a Selective Haploinsufficiency Gene Effect

We characterised the behavioural phenotype of mice heterozygous (Oxtr^+/?) for the oxytocin receptor gene (Oxtr) and compared it with that of Oxtr null mice (Oxtr^?/?), which display autistic‐like behaviours, including impaired sociability and preference for social novelty, impaired cognitive flexibility, and increased aggression. Similar to Oxtr^?/? mice, the Oxtr^+/? showed impaired sociability and preference for social novelty but, unlike the null genotype, their cognitive flexibility and aggression were normal. By autoradiography, Oxtr^+/? mice were found to have approximately 50% fewer oxytocin receptors (OXTRs) in all of the examined brain regions. Thus, because a partial reduction in Oxtr gene expression is sufficient to compromise social behaviour, the Oxtr acts as a haploinsufficient gene. Furthermore, the inactivation of the Oxtr gene affects specific behaviours in a dose‐dependent manner: social behaviour is sensitive to even a partial reduction in Oxtr gene expression, whereas defects in aggression and cognitive flexibility require the complete inactivation of the Oxtr gene to emerge. We then investigated the rescue of the Oxtr^+/? social deficits by oxytocin (OT) and Thr⁴Gly⁷OT (TGOT) administered i.c.v. at different doses. TGOT was more potent than OT in rescuing sociability and social novelty in both genotypes. Furthermore, the TGOT doses that reverted impaired sociability and preference for social novelty in Oxtr^+/? were lower than those required in Oxtr^?/?, thus suggesting that the rescue effect is mediated by OXTR in Oxtr^+/? and by other receptors (presumably vasopressin V1a receptors) in Oxtr^?/?. In line with this, a low dose of the selective oxytocin antagonist desGlyDTyrOVT blocks the rescue effect of TGOT only in the Oxtr^+/? genotype, whereas the less selective antagonist SR49059 blocks rescue in both genotypes. In conclusion, the Oxtr^+/? mouse is a unique animal model for investigating how partial loss of the Oxtr gene impair social interactions, and for designing pharmacological rescue strategies.     

Naturally occurring differences in maternal care are associated with the expression of oxytocin and vasopressin (V1a) receptors: gender differences

Variations in maternal care have been associated with long-term changes in neurochemistry and behaviour in adult rats. Rats receiving high levels of licking and grooming as pups are less fearful and more maternal than rats receiving low levels of maternal licking and grooming. Central pathways for oxytocin and vasopressin have been implicated in the neurobiology of anxiety and social behaviours. We assessed whether variations in maternal care were associated with differences in oxytocin receptors (OTR) or vasopressin (V1a) receptors in the brains of adult offspring. In the central nucleus of the amygdala and bed nucleus of the stria terminalis, OTR binding was increased in adult females, but not adult males, that had received high levels of maternal licking and grooming as pups. Conversely, amygdala V1a receptor binding was increased in males, but not females, that had received high levels of maternal licking and grooming. These findings suggest that variations in maternal care may influence the expression of oxytocin and vasopressin receptors in a gender-specific manner.     

Neuroendocrinology of social information processing in rats and mice

We reviewed oxytocin (OT), arginine–vasopressin (AVP) and gonadal hormone involvement in various modes of social information processing in mice and rats. Gonadal hormones regulate OT and AVP mediation of social recognition and social learning. Estrogens foster OT-mediated social recognition and the recognition and avoidance of parasitized conspecifics via estrogen receptor (ER) alpha (ERα) and ERβ. Testosterone and its metabolites, including estrogens, regulate social recognition in males predominantly via the AVP V1a receptor. Both OT and AVP are involved in the social transmission of food preferences and ERα has inhibitory, while ERβ has enhancing, roles. OT also enhances mate copying by females. ERα mediates the sexual, and ERβ the recognition, aspects of the risk-taking enhancing effects of females on males. Thus, androgens and estrogens control social information processing by regulating OT and AVP. This control is finely tuned for different forms of social information processing.     

Comparison of the distribution of oxytocin and vasopressin in the rat brain

While immunohistochemistry has been used extensively to map both oxytocin (OT) and vasopressin (VP) pathways in the brain, little information is available concerning the quantitative distribution of these hormones--particularly oxytocin. We have isolated oxytocin from extrahypothalamic regions of the rat brain and shown it to behave identically with standard oxytocin in radioimmunoassay (RIA) and on high-performance liquid chromatography. Using sensitive RIA we have measured and compared levels of both oxytocin and vasopressin in the rat brain. Both hormones are widely distributed, with the largest amounts outside the hypothalamus being found in the locus coeruleus. Considerable quantities of both peptides (but particularly oxytocin) are found in mesencephalic, pontine and medullary nuclei. This distribution is similar to that of the catecholamines, and the possible interaction of oxytocin and vasopressin with catecholaminergic pathways in the central control of various functions is discussed.     

Tracking oxytocin functions in the rodent brain during the last 30 years: From push‐pull perfusion to chemogenetic silencing

A short overview is provided of the last 30 years of oxytocin (and vasopressin) research performed in our laboratories, starting with attempts to monitor the release of this nonapeptide in the rodent brain during physiological conditions such as suckling in the lactating animal. Using push‐pull perfusion and microdialysis approaches, release patterns in hypothalamic and limbic brain regions could be characterised to occur from intact neuronal structures, to be independent of peripheral secretion into blood, and to respond differentially to various stimuli, particularly those related to reproduction and stress. Parallel efforts focused on the functional impact of central oxytocin release, including neuroendocrine and behavioural effects mediated by nonapeptide receptor interactions and subsequent intraneuronal signalling cascades. The use of a variety of sophisticated behavioural paradigms to manipulate central oxytocin release, along with pharmacological, genetic and pharmacogenetic approaches, revealed multiple consequences on social behaviours, particularly social fear.     

Social functions of individual vasopressin–oxytocin cell groups in vertebrates: What do we really know?

Vasopressin–oxytocin (VP–OT) nonapeptides modulate numerous social and stress-related behaviors, yet these peptides are made in multiple nuclei and brain regions (e.g., >20 in some mammals), and VP–OT cells in these areas often exhibit overlapping axonal projections. Furthermore, the magnocellular cell groups release peptide volumetrically from dendrites and soma, which gives rise to paracrine modulation in distal brain areas. Nonapeptide receptors also tend to be promiscuous. Hence, behavioral effects that are mediated by any given receptor type (e.g., the OT receptor) in a target brain region cannot be conclusively attributed to either VP or OT, nor to a specific cell group. We here review what is actually known about the social behavior functions of nonapeptide cell groups, with a focus on aggression, affiliation, bonding, social stress, and parental behavior, and discuss recent studies that demonstrate a diversity of sex-specific contributions of VP–OT cell groups to gregariousness and pair bonding.     

Differential effects of oxytocin on mouse hippocampal oscillations in vitro

The hypothalamic neuropeptide oxytocin (OT) controls childbirth and lactation, is involved in social behaviors, plays a role in various psychiatric disorders, and has effects on learning and memory. Although behavioral effects of OT have been extensively studied, much less is known about its effects on neuronal and network activity patterns. Here, we investigate the effect of OT on two major patterns of hippocampal network activity in mouse hippocampal slices. We studied different in vitro models of gamma‐frequency oscillations and sharp wave‐ripple complexes (SPW‐R), two patterns implicated in spatial memory formation and memory consolidation respectively. Strikingly, we found a profound difference of OT on these distinct, mutually exclusive activity patterns. While gamma oscillations where not affected by the activation of hippocampal OT receptors, SPW‐R were potently and rapidly suppressed. Interestingly, the temporal precision of oscillation‐coupled spikes was enhanced at the same time. Thus, OT exerts strongly different modulatory effects on different network patterns, most likely by inhibition of different sets of inhibitory interneurons. The observed dichotomy between gamma and SPW‐R oscillations may have profound effects on the behavioral and cognitive effects of OT which are relevant to cognitive processes and to psychiatric diseases.     

The nonpeptide oxytocin receptor agonist WAY 267,464: receptor-binding profile, prosocial effects and distribution of c-Fos expression in adolescent rats

Previous research suggests that the nonpeptide oxytocin receptor (OTR) agonist WAY 267,464 may only partly mimic the effects of oxytocin in rodents. The present study further explored these differences and related them to OTR and vasopressin 1a receptor (V(1a) R) pharmacology and regional patterns of c-Fos expression. Binding data for WAY 267,464 and oxytocin were obtained by displacement binding assays on cellular membranes, while functional receptor data were generated by luciferase reporter assays. For behavioural testing, adolescent rats were tested in a social preference paradigm, the elevated plus-maze (EPM) and for locomotor activity changes following WAY 267,464 (10 and 100 mg/kg, i.p.) or oxytocin (0.1 and 1 mg/kg, i.p.). The higher doses were also examined for their effects on regional c-Fos expression. Results showed that WAY 267,464 had higher affinity (K(i) ) at the V(1a) R than the OTR (113 versus 978 nm). However, it had no functional response at the V(1a) R and only a weak functional effect (EC(50) ) at the OTR (881 nm). This suggests WAY 267,464 is an OTR agonist with weak affinity and a possible V(1a) R antagonist. Oxytocin showed high binding at the OTR (1.0 nm) and V(1a) R (503 nm), with a functional EC(50) of 9.0 and 59.7 nm, respectively, indicating it is a potent OTR agonist and full V(1a) R agonist. WAY 267,464 (100 mg/kg), but not oxytocin, significantly increased the proportion of time spent with a live rat, over a dummy rat, in the social preference test. Neither compound affected EPM behaviour, whereas the higher doses of WAY 267,464 and oxytocin suppressed locomotor activity. WAY 267,464 and oxytocin produced similar c-Fos expression in the paraventricular hypothalamic nucleus, central amygdala, lateral parabrachial nucleus and nucleus of the solitary tract, suggesting a commonality of action at the OTR with the differential doses employed. However, WAY 267,464 caused greater c-Fos expression in the medial amygdala and the supraoptic nucleus than oxytocin, and lesser effects in the locus coeruleus. Overall, our results confirm the differential effects of WAY 267,464 and oxytocin and suggest that this may reflect contrasting actions of WAY 267,464 and oxytocin at the V(1a) R. Antagonism of the V(1a) R by WAY 267,464 could underlie some of the prosocial effects of this drug either through a direct action or through disinhibition of oxytocin circuitry that is subject to vasopressin inhibitory influences.     

Gonadal Steroids have Paradoxical Effects on Brain Oxytocin Receptors

Specific brain receptors for oxytocin have been described in several mammalian species. The distribution of these receptors differs greatly across species and in the rat, receptor binding in specific brain regions appears to depend upon gonadal steroids. This study used in vitro receptor autoradiography to examine the effects of testosterone on oxytocin receptor binding in the mouse forebrain. Three groups of male mice were compared: castrates treated with blank capsules, castrates treated with testosterone filled capsules, and intact males. Irrespective of steroid treatment, the distribution of oxytocin receptors in mouse forebrain differed markedly from patterns previously described in the rat. In addition to these species differences in receptor distribution, testosterone had effects in the mouse which differed from the induction of receptors previously reported in the rat. In the mouse ventromedial nucleus of the hypothalamus, binding in the untreated castrate males was approximately double that observed in either the intact or the testosterone-treated castrates. In other regions of the mouse brain, such as the intermediate zone of the lateral septum, binding to oxytocin receptors was increased with testosterone treatment. These results suggest that the brain oxytocin receptor varies across species not only in its distribution but also in its regional regulation by gonadal steroids. These apparently paradoxical changes in oxytocin receptor binding may result from either direct or indirect effects of gonadal steroids in mouse brain.     

Neurohypophyseal peptides as regulators of growth and development

In addition to their classical hormonal role, the neurohypophyseal peptides vasopressin (AVP) and oxytocin (OT) are also implicated as regulators of growth and development. Mitogenic actions of AVP are particularly well characterized and may underly the potential role of AVP as an autocrine regulator of tumor growth. Effects of AVP and OT on neural development are suggested by numerous studies, but definitive physiological evidence is lacking. Current studies on the molecular characterization of AVP and OT receptors, and on transgenic animals will provide insights into the developmental actions of neurohypophyseal peptides.     

Oxytocin and oxytocin receptors in cancer cells and proliferation

The hypothalamic nonapeptide oxytocin plays a crucial role in many reproductive and behavioural functions. However, in recent years, an additional new role for oxytocin has been identified in neoplastic pathology. In tumours, oxytocin acts as a growth regulator, through the activation of a specific G-coupled transmembrane receptor, the oxytocin receptor. In vitro, oxytocin inhibits proliferation of neoplastic cells of either epithelial (mammary and endometrial), nervous or bone origin, all expressing oxytocin receptor. Furthermore, an oxytocin growth-inhibiting effect was also tested and confirmed in vivo in mouse and rat mammary carcinomas. In neoplastic cells derived from two additional oxytocin target tissues, trophoblast and endothelium, oxytocin was found to promote cell proliferation, an effect opposite to that previously described in all other neoplastic oxytocin-responsive cells. The signal transduction pathways coupled to the biological effects of oxytocin are different in oxytocin growth-inhibited or growth-stimulated cells, and may depend on the membrane localization of the oxytocin receptor itself. The inhibitory effect of oxytocin is apparently mediated by activation of the cAMP-protein kinase A pathway, a nonconventional oxytocin signalling pathway, whereas the mitogenic effect is coupled to the increase of intracellular [Ca(2+)] and tyrosine phosphorylation, 'classical' oxytocin transducers. Moreover, the oxytocin receptor localization in lipid rafts enriched in caveolin-1 turns the inhibition of cell growth into a proliferative response, eliciting different epidermal growth factor receptor/mitogen-activated protein kinase activation patterns. This unexpected role of oxytocin (and oxytocin analogues) in regulating cell proliferation, as well as the widespread expression of oxytocin receptors in neoplastic tissues of different origin, opens up new perspectives on the biological role of the oxytocin-oxytocin receptor system in cancer.