Detection, processing and reinforcement of social cues: regulation by the oxytocin system.

Many social behaviours are evolutionarily conserved and are essential for the healthy development of an individual. The neuropeptide oxytocin (OXT) is crucial for the fine-tuned regulation of social interactions in mammals. The advent and application of state-of-the-art methodological approaches that allow the activity of neuronal circuits involving OXT to be monitored and functionally manipulated in laboratory mammals have deepened our understanding of the roles of OXT in these behaviours. In this Review, we discuss how OXT promotes the sensory detection and evaluation of social cues, the subsequent approach and display of social behaviour, and the rewarding consequences of social interactions in selected reproductive and non-reproductive social behaviours. Social stressors - such as social isolation, exposure to social defeat or social trauma, and partner loss - are often paralleled by maladaptations of the OXT system, and restoring OXT system functioning can reinstate socio-emotional allostasis. Thus, the OXT system acts as a dynamic mediator of appropriate behavioural adaptations to environmental challenges by enhancing and reinforcing social salience and buffering social stress.

Effects of oxytocin receptor blockade on dyadic social behavior in monogamous and non-monogamous Eulemur.

A prominent body of research spanning disciplines has been focused on the potential underlying role for oxytocin in the social signatures of monogamous mating bonds. Behavioral differences between monogamous and non-monogamous vole species, putatively mediated by oxytocinergic function, constitute a key source of support for this mechanism, but it is unclear to what extent this hormone-behavior linkage extends to the primate order. In a preregistered experiment, we test if oxytocin receptor blockade affects affiliative behavior in mixed-sex pairs of Eulemur, a genus of strepsirrhine primate containing both monogamous and non-monogamous species. Inconsistent with past studies in monogamous voles or monkeys, we do not find confirmatory evidence in Eulemur that monogamous pairs affiliate more than non-monogamous pairs, nor that oxytocin receptor blockade of one pair member selectively corresponds to reduced affiliative or scent-marking behavior in monogamous species. We do, however, find exploratory evidence of a pattern not previously investigated: simultaneously blocking oxytocin receptors in both members of a monogamous pair predicts lower rates of affiliative behavior relative to controls. Our study demonstrates the value of non-traditional animal models in challenging generalizations based on model organisms, and of methodological reform in providing a potential path forward for behavioral oxytocin research.

Oral Supplementation with L-Carnosine Attenuates Social Recognition Deficits in CD157KO Mice via Oxytocin Release.

The outcomes of supplementation with L-carnosine have been investigated in clinical trials in children with autism spectrum disorder (ASD). However, reports on the effects of L-carnosine in humans have been inconsistent, and the efficacy of L-carnosine supplementation for improving ASD symptoms has yet to be investigated in animal studies. Here, we examined the effects of oral supplementation with L-carnosine on social deficits in CD157KO mice, a murine model of ASD. Social deficits in CD157KO mice were assessed using a three-chamber social approach test. Oral supplementation with L-carnosine attenuated social behavioral deficits. The number of c-Fos-positive oxytocin neurons in the supraoptic nucleus and paraventricular nucleus was increased with L-carnosine supplementation in CD157KO mice after the three-chamber social approach test. We observed an increase in the number of c-Fos-positive neurons in the basolateral amygdala, a brain region involved in social behavior. Although the expression of oxytocin and oxytocin receptors in the hypothalamus was not altered by L-carnosine supplementation, the concentration of oxytocin in cerebrospinal fluid was increased in CD157KO mice by L-carnosine supplementation. These results suggest that L-carnosine supplementation restores social recognition impairments by augmenting the level of released oxytocin. Thus, we could imply the possibility of a safe nutritional intervention for at least some types of ASD in the human population.

Oxytocin and Fear Memory Extinction: Possible Implications for the Therapy of Fear Disorders?

Several psychiatric conditions such as phobias, generalized anxiety, and post-traumatic stress disorder (PTSD) are characterized by pathological fear and anxiety. The main therapeutic approach used in the management of these disorders is exposure-based therapy, which is conceptually based upon fear extinction with the formation of a new safe memory association, allowing the reduction in behavioral conditioned fear responses. Nevertheless, this approach is only partially resolutive, since many patients have difficulty following the demanding and long process, and relapses are frequently observed over time. One strategy to improve the efficacy of the cognitive therapy is the combination with pharmacological agents. Therefore, the identification of compounds able to strengthen the formation and persistence of the inhibitory associations is a key goal. Recently, growing interest has been aroused by the neuropeptide oxytocin (OXT), which has been shown to have anxiolytic effects. Furthermore, OXT receptors and binding sites have been found in the critical brain structures involved in fear extinction. In this review, the recent literature addressing the complex effects of OXT on fear extinction at preclinical and clinical levels is discussed. These studies suggest that the OXT roles in fear behavior are due to its local effects in several brain regions, most notably, distinct amygdaloid regions.

Oxytocin receptor induces mammary tumorigenesis through prolactin/p-STAT5 pathway.

Oxytocin receptor (OXTR) is involved in social behaviors, thermoregulation, and milk ejection, yet little is known about its role in breast cancer. To investigate the role of OXTR in mammary gland development and tumorigenesis, a transgenic mouse model of OXTR overexpression (++Oxtr) was used. Overexpression of OXTR-induced progressive mammary hyperplasia, unexpected milk production, and tumorigenesis in females. OXTR-induced mammary tumors showed ERBB2 upregulation and mixed histological subtypes with predomination of papillary and medullary carcinomas. OXTR overexpression led to an activation of prolactin (PRL)/p-STAT5 pathway and created a microenvironment that promotes mammary-specific tumorigenesis. PRL inhibitor bromocriptine (Br) could mitigate OXTR-driven mammary tumor growth. The study demonstrates Oxtr is an oncogene and a potential drug target for HER2-type breast cancer.

Experiences affect social behaviors via altering neuronal morphology and oxytocin system.

Life experiences, such as maternal deprivation (MD) and environment enrichment (EE), affect social behaviors in the adult. But, the underlying mechanism remains unclear. In the present study, we determined whether neonatal MD induces social deficits, whether postweaning EE restores the deficits, and their effects on neuron morphology and oxytocin (OT)-oxytocin receptor (OTR) system. We found that MD induced repetitive behavior and deficits in novel object recognition and sociability, and EE alleviated these deficits. MD decreased oxytocinergic neurons in the magnocellular hypothalamic paraventricular nucleus (mPVH), which was parallel to the increased OTR levels and dendritic branches of projection neurons in the basolateral amygdala (BLA). EE increased the OTR levels in the prelimbic cortex (PL) and the oxytocinergic neurons in the parvocellular PVH (vPVH), which were parallel to the increased dendritic branches of small pyramidal neurons in the PL and synaptic connections marked with synaptophysin and postsynaptic density protein 95 in the BLA and PL. Together, the results suggest that postweaning EE alleviates the social impairments induced by neonatal MD and OT-OTR system are experience-dependent and associated with social behaviors and neuron morphology.

Influence of Two Single-Nucleotide Polymorphisms of the Oxytocin Receptor Gene (OXTR) on Empathy: the Mediation Role of a Primary Emotion, CARE.

To feel other's pain would elicit empathy. Some theorists hypothesized that observing other's pain may activate the primary emotion of maternal care instinct, which may function as a precursor of empathy. The maternal care instinct and empathy share the same genetic background and neuroendocrine underpinnings. An extensive body of research has shown that maternal behaviors relate to the oxytocinergic system, which has a strong influence on empathy. These studies suggest that the maternal care instinct may mediate the effect of oxytocin receptor gene (OXTR) on empathy. To provide evidence for this mediation, we used the subscale of CARE in Affective Neuroscience Personality Scales (ANPS) to measure the maternal care instinct and tested two OXTR single-nucleotide polymorphisms (SNPs), rs53576 and rs13316193, in 880 high school participants (588 females, 292 males; Mage = 16.51 years old, SD = 0.65). Results showed that the genotype of rs13316193 was indirectly associated with empathy via CARE, suggesting a mediating role of CARE in the pathway from OXTR to empathy. These findings may contribute to an understanding of how empathy emerges when one witnesses another person in pain.

Oxytocinergic regulation in pathogenesis of pelvic pain caused by adenomyosis.

OBJECTIVE: The aim of the study was to expand the understanding of pathogenesis of adenomyosis-associated pelvic pain. MATERIAL AND METHODS: We studied 30 (n = 30) biopsy samples obtained after hysterectomy in women with diffuse adenomyosis of grade II-III, accompanied by severe pain syndrome, who did not receive hormonal therapy. The morphologic comparison group comprised 30 (n = 30) biopsy samples obtained from women with adenomyosis, without pain syndrome, operated on for abnormal uterine bleeding, who also did not receive hormone therapy. RESULTS: The total density of immunological OTR labeling in the adenomyotic lesion foci was 73.7 ± 1.8%, and in the morphological control group it was 35.2 ± 1.4% (p <0.05), which indicates a significant effect of oxytocin as a ureterotonic peptide. Processes of local neurogenesis and growth of nerve fibers was established due to an increase in the expression of the nervous system growth factor NGF in the myometrium stroma, in comparison with biopsy samples of morphological control.Conclusion: Pelvic pain pathogenesis in women with diffuse adenomyosis compared with the painless form of the disease is an increase in the activity of ureterotonic factors of OTR oxytocin. Compared to the painless form of adenomyosis, the myometrial innervation apparatus of patients with pelvic pain is characterized by a significantly higher expression of nerve growth factor.

Cell proliferation and anti-oxidant effects of oxytocin and oxytocin receptors: role of extracellular signal-regulating kinase in astrocyte-like cells.

OBJECTIVES: Oxytocin (OXT) participates in various physiological functions ranging from reproduction to social and non-social behaviors. Recent studies indicate that OXT affects cell growth and metabolism. Here we characterized the growth stimulating and antioxidant actions of OXT and of OXT receptors (OXTR) in a glial cell-line (U-87MG). METHODS: We developed an OXTR-knockdown cell-line (U-87MG KD) to establish the receptor specificity of OXT's actions, and the impact of lacking OXTR on growth and survival in glial cells. The role Extracellular-Signal Regulated Kinases (ERK1/2) on glial cell protection against consequences of oxidative stress, and cell proliferation was investigated. RESULTS: In U-87MG cells, OXT stimulated cell proliferation and increased ERK1/2 phosphorylation. The specific ERK1/2 inhibitor, PD098059, produced marked inhibition of cell proliferation, and antagonized the stimulating effect of OXT on ERK1/2 phosphorylation and on cell proliferation. Slower growth rates and lower levels of phosphorylated ERK1/2 were observed in OXTR-knockdown cells and in U-87MG cells treated with an OXTR antagonist (L-371,257). In addition to increasing cell proliferation, OXT significantly blunted the rise in reactive oxygen species induced by H2O2, and antagonized the reductions in cell viability induced by H2O2 and camptothecin. The cell protective and antioxidant actions of OXT in U-87MG cells were not observed in the OXTR-knockdown cells. CONCLUSION: OXT stimulates the growth of astrocyte-like cells acting on OXTR via ERK1/2 phosphorylation. The protection against apoptosis and the antioxidant capacity of OXT may contribute to the observed increase in cell proliferation. Oxytocin and OXTR appear to be fundamental for cell growth and viability of glial cells.

Acciones óseas de las hormonas de la neurohipófisis / Bone actions of neuro hypophyseal hormones

La oxitocina (OXT) como la arginina-vasopresina (AVP) son dos hormonas primitivas secretadas por la hipófisis posterior. Sus receptores están mucho más ampliamente distribuidos en el organismo de lo que se pensaba originalmente, incluido el hueso. En los estudios preclínicos, la OXT ha mostrado ser anabólica para el hueso, promoviendo la osteogénesis sobre la adipogénesis y favoreciendo la actividad osteoblástica sobre la osteoclástica. Tanto los osteoblastos como los osteoclastos tienen receptores para la OXT, y los efectos de los estrógenos sobre la masa ósea en ratones está mediada por lo menos en parte por la OXT. El mecanismo preciso por el cual la activación de los receptores de oxitocina (OXTR) se traduce en un incremento de la formación ósea permanece poco claro. La AVP también podría afectar el esqueleto en forma directa. Dos de los receptores de la AVP, V1a y V2 están expresados en osteoblastos y osteoclastos. La inyección de AVP en ratones de tipo salvaje aumenta la formación osteoclastos que producen resorción y reduce los osteoblastos formadores de hueso. En forma opuesta, la exposición de precursores osteoblásticos a antagonistas de los receptores V1a o V2, incrementan la osteoblastogénesis, como también lo hace la deleción genética del receptor V1a. (AU)

Both oxytocin (OXT) and argininevasopressin (AVP) are primitive hormones secreted by the posterior pituitary gland. OXT receptors are much more widely distributed in the body than originally thought, including in bone. In preclinical studies, OXT has been shown to be anabolic for bone, promoting osteogenesis over adipogenesis and favoring osteoblastic over osteoclastic activity. Both osteoblasts and osteoclasts have receptors for OXT, and the effects of estrogen on bone mass in mice is mediated at least in part by OXT. The precise mechanism by which the activation of oxytocin receptors (OXTRs) results in an increase in bone formation remains unclear. AVP could also have direct actions on the skeleton. The two AVP receptors, V1a and V2, are expressed in osteoblasts and osteoclasts. Injection of AVP in wild-type mice increases the formation of osteoclasts increasing bone resorption, and reduces bone-forming osteoblasts. On the contrary, the exposure of osteoblastic precursors to V1a and V2 antagonists increase osteoblastogenesis, the same as the genetic deletion of the V1a receptor. (AU)

Oxytocin Ameliorates Impaired Behaviors of High Fat Diet-Induced Obese Mice.

Excessive intake of fat is a major risk factor for lifestyle-related diseases such as heart disease and also affects brain function such as object recognition memory, social recognition, anxiety behavior, and depression-like behavior. Although oxytocin (OXT) has been reported to improve object recognition, social recognition, anxiety behavior, and depression-like behavior in specific conditions, previous studies did not explore the impact of OXT in high-fat diet (HFD)-fed mice. Furthermore, it remains unclear whether intake of HFD affects OXT/oxytocin receptor (OXTR) in the brain. Here, we demonstrated that peripheral OXT administration improves not only social recognition but also object recognition and depressive-like behavior in HFD-fed mice. In contrast, peripheral OXT administration to HFD-fed male mice increased fear and anxiety-related behavior. In addition, we observed that intake of HFD decreased OXTR and c-fos mRNA expression in the hippocampus, specifically. Furthermore, peripheral OXT administration increased OXT mRNA expression in the hypothalamus. Altogether, these findings suggest that OXT has the potential to improve various recognition memory processes via peripheral administration but also has side effects that increase fear-related behavior in males.

The role of D2 dopamine receptors in oxytocin induced place preference and anxiolytic effect.

Neuropeptide oxytocin (OT) is involved in the regulation of social and non-social behaviour. The central nucleus of amygdala (CeA), part of the limbic system, plays an important role in learning, memory, anxiety and reinforcing mechanisms. CeA has been shown to be rich in OT receptors in rodents. Our previous findings indicated that OT in the rat CeA has a dose dependent rewarding and anxiolytic effect. The aim of our present study was to examine in the CeA the possible interaction of OT and D2 dopamine (DA) receptor antagonist Sulpiride on reinforcement in place preference test and on anxiety in elevated plus maze test. Wistar rats were microinjected bilaterally with 10 ng OT. In different group of animals 4 µg D2 DA receptor antagonist was applied. Other animals received D2 DA receptor antagonist 15 min before 10 ng OT treatment or vehicle solution into the CeA. Rats receiving 10 ng OT spent significantly longer time in the treatment quadrant during the test session in conditioned place preference test. Prior treatment with D2 DA receptor antagonist blocked the rewarding effects of OT. Antagonist in itself did not influence the time rats spent in the treatment quadrant. In elevated plus maze test, rats receiving 10 ng OT spent significantly longer time on the open arms. Prior treatment with D2 DA receptor antagonist blocked the effects of OT. Our results show that DA system plays a role in positive reinforcing and anxiolytic effects of OT because D2 DA receptor antagonist can block these actions.

Oxytocin Receptors Regulate Social Preference in Zebrafish.

With a strong tendency to socialise, the zebrafish is a useful model to study social behaviour, with implications for better treatments of social impairments, for instance in autism spectrum disorders. Although oxytocin is crucial for social behaviour in mammals, the importance of the fish orthologue - isotocin or zebrafish oxytocin (zOT) - for social behaviour in zebrafish is unclear. The aims of this study were firstly, to elucidate the receptor specificity of zOT and the related vasotocin or zebrafish vasopressin (zVP; the orthologue of mammalian vasopressin) and the nonpeptidergic oxytocin receptor antagonist L-368,899, and secondly to investigate if L-368,899 inhibits social preference in zebrafish. The potencies of ligands were evaluated for zOT/zVP family receptors in HEK293 cells. Adult and larval zebrafish were treated with L-368,899 or vehicle and subsequently assessed for social behaviour and anxiety (adults only). The antagonist L-368,899 specifically inhibited the two zOT receptors, but not the two zVP-1 receptors. The antagonist decreased social preference in adult and larval zebrafish. It did not affect anxiety in adults. These results indicate that endogenous zOT, and possibly zVP, is involved in social behaviour in zebrafish via either or both of the two zOT receptors, and show promise for future explorations of the anatomy and evolution of networks underlying social behaviour.

Social Stimuli Induce Activation of Oxytocin Neurons Within the Paraventricular Nucleus of the Hypothalamus to Promote Social Behavior in Male Mice.

Oxytocin (OT) is critical for the expression of social behavior across a wide array of species; however, the role of this system in the encoding of socially relevant information is not well understood. In the present study, we show that chemogenetic activation of OT neurons within the paraventricular nucleus of the hypothalamus (PVH) of male mice (OT-Ires-Cre) enhanced social investigation during a social choice test, while chemogenetic inhibition of these neurons abolished typical social preferences. These data suggest that activation of the OT system is necessary to direct behavior preferentially toward social stimuli. To determine whether the presence of a social stimulus is sufficient to induce activation of PVH-OT neurons, we performed the first definitive recording of OT neurons in awake mice using two-photon calcium imaging. These recordings demonstrate that social stimuli activate PVH-OT neurons and that these neurons differentially encode social and nonsocial stimuli, suggesting that PVH-OT neurons may act to convey social salience of environmental stimuli. Finally, an attenuation of social salience is associated with social disorders, such as autism. We therefore also examined possible OT system dysfunction in a mouse model of autism, Shank3b knock-out (KO) mice. Male Shank3b KO mice showed a marked reduction in PVH-OT neuron number and administration of an OT receptor agonist improved social deficits. Overall, these data suggest that the presence of a social stimulus induces activation of the PVH-OT neurons to promote adaptive social behavior responses.SIGNIFICANCE STATEMENT Although the oxytocin (OT) system is well known to regulate a diverse array of social behaviors, the mechanism in which OT acts to promote the appropriate social response is poorly understood. One hypothesis is that the presence of social conspecifics activates the OT system to generate an adaptive social response. Here, we selectively recorded from OT neurons in the paraventricular hypothalamic nucleus (PVH) to show that social stimulus exposure indeed induces activation of the OT system. We also show that activation of the OT system is necessary to promote social behavior and that mice with abnormal social behavior have reduced numbers of PVH-OT neurons. Finally, aberrant social behavior in these mice was rescued by administration of an OT receptor agonist.

Nonapeptides mediate trade-offs in parental care strategy.

Parental care represents a suite of distinct behaviors performed by parents to maximize fitness. Dynamic shifts in parental care behaviors, such as between nest defense and direct provisioning of the offspring, are required in response to environmental variation. However, the neural mechanisms which mediate such behavioral shifts remain a mystery. The anemonefish, Amphiprion ocellaris, represents an experimentally valuable model in social neuroscience which is conducive to manipulating the environment while simultaneously measuring parental care. The goal of this study was to determine the extent to which arginine vasotocin (AVT) and isotocin (IT) signaling are necessary for males to shift between direct egg care and aggressive nest defense in the presence of intruders, Domino damselfish (Dascyllus trimaculatus). The IT receptor antagonist desGly-NH2-d(CH2)5[D-Tyr2,Thr4]OVT, significantly reduced direct egg care, while at the same time increased levels of aggressive nest defense relative to vehicle. Conversely, blockade of AVT using the antagonist d(CH2)5[Tyr(Me)2]AVP, reduced aggression and tended to increase egg care. Results demonstrate that male anemonefish alter their parental strategy in response to allospecific intruders, and that IT and AVT signaling oppositely regulate parental care displays of aggression versus egg care.

The blockade of oxytocin receptors in the paraventricular thalamus reduces maternal crouching behavior over pups in lactating mice.

Oxytocin (OT) systems contribute to the elicitation of stereotypic maternal behaviors. OT peptide-expressing neurons are predominantly localized in the hypothalamus, whereas OT receptor (OTR)-expressing neurons are widely distributed throughout the brain. Among those OTR-expressing regions, the paraventricular thalamus (PVT) consists of heterogeneous neuropeptide-responsive neurons critical for appetitive motivation, food intake control, and social behaviors; however, the precise distribution of OTR-expressing neurons within the PVT and whether these neurons are involved in maternal behaviors in mice are unknown. The distribution of OTR-expressing neurons was examined in an OTR-Venus transgenic line expressing a fluorescent protein controlled by the OTR promoter. The number of Venus expressing neurons was higher in the posterior PVT (pPVT) than in the anterior PVT (aPVT). When OTR-Venus dams were exposed to pups, the number of double-labelled neurons expressing both OTR-Venus and a marker of neuronal activity (c-Fos) was increased in the pPVT compared to non-exposed dams, while the aPVT remained unchanged. To investigate whether OT signaling in the pPVT is essential for maternal behaviors, an OT antagonist (OTA) was transiently or chronically infused into the pPVT of lactating dams during the postpartum period. Although the transient OTR blockade did not affect maternal behaviors, a chronic OTR blockade specifically reduced the duration of crouching behavior over pups. Taken together, these findings suggest that OTR-expressing neurons in the pPVT are involved in maternal crouching behavior.

The role of oxytocin on self-serving lying.

INTRODUCTION: The effects of intranasal administration of the neuropeptide oxytocin on social cognition and behavior are highly specific. Potentially situational and personal variables influence these effects. The aim of the present study was to investigate effects of oxytocin administration on self-serving lying, including situational effects. METHODS: A total of 161 adult males participated in a randomized double-blind placebo-controlled between-subject intranasal oxytocin administration (24 international units) study. Self-serving lying was assessed using three subsequent rounds of the die-in-a-cup paradigm, in which different degrees of lying can be implemented by the participants that can be determined on group level. RESULTS: Oxytocin administration seemed to promote self-serving lying, particularly in the third (last) round and only to a certain degree (not to the maximum possible). CONCLUSIONS: Our findings demonstrate that oxytocin administration can promote self-serving lying when given repeated opportunities to lie. Moreover, exploratory results presented in the Supplementary Material indicate that the sensitivity to the effects of intranasal oxytocin in this domain might be moderated by individual differences in the oxytocin receptor gene.

Regulation of social behaviors by p-Stat3 via oxytocin and its receptor in the nucleus accumbens of male Brandt's voles (Lasiopodomys brandtii).

Social behavior plays a significant role in the formation of social structure and population regulation in both animals and humans. Oxytocin (OXT) and its receptor (OXTR) are well known for regulating social behaviors, but their upstream regulating factors are rarely investigated. We hypothesized that the phosphorylation of the signal transducer and activator of transcription 3 (p-Stat3) may regulate social and aggressive behaviors via the OXT system in the nucleus accumbens (NAc). To test this hypothesis, OXT, p-Stat3 inhibitor, OXTR antagonist, and OXT plus p-Stat3 inhibitor were infused, respectively, into the NAc in the brain of male Brandt's voles (Lasiopodomys brandtii) - a social rodent species in grassland of Inner Mongolia, China. Our data showed that blockage of p-Stat3-Tyr705 signaling pathway in the NAc not only increased aggressive behavior but also impaired social recognition of male Brandt's voles via its effects on the expression of local OXT and OXTR. These results have illustrated a novel signaling pathway of p-Stat3-Tyr705 in regulating social behaviors via the OXT system.

Oxytocin is a principal hormone that exerts part of its effects by active fragments.

Oxytocin is a nonapeptide consisting of a cyclic six amino-acid structure and a tail of three amino acids. It was originally known for its ability to induce milk ejection and to stimulate uterine contractions. More recently, oxytocin has been shown to stimulate social behaviors, and exert pain-relieving, anti-stress/anti-inflammatory and restorative effects. We hypothesize that oxytocin is a principal hormone that, in part, exerts its effects after degradation to active fragments with more specific effect profiles. Experimental findings on rats show that administered oxytocin exerts biphasic effects. For example, after an initial increase in pain threshold, a second more long-lasting increase follows. Blood pressure and cortisol levels initially increase and then reverse into a long-lasting decrease in blood pressure and cortisol. Whereas the initial effects are, the second-phase effects are not blocked by an oxytocin antagonist, but by an opioid mu-antagonist and by an alpha 2-adrenoreceptor antagonist, respectively, suggesting that other receptors are involved. Repeated administration of oxytocin induces multiple anti-stress effects, which are mediated by alpha 2-adrenoreceptors. Repeated administration of linear oxytocin and linear oxytocin fragments with a retained C-terminal reduce spontaneous motor activity, a sedative or anti-stress effect, suggesting that alpha 2-adrenoreceptors have been activated. In contrast, linear mid-fragments stimulate motor activity. Low-intensity stimulation of cutaneous nerves in rats, as well as breastfeeding and skin-to-skin contact between mothers and babies, trigger immediate anti-stress effects. Some of these effects are likely caused by open ring/linear C-terminal fragments activating alpha 2-adrenoreceptors. Oxytocin fragments may be pre-formed and released in the brain or created by metabolic conversion of the principal hormone oxytocin in the central nervous system. Oxytocin and its fragments may also be released from peripheral sites, such as peripheral nerves, the gastrointestinal tract, and blood vessels in response to decreased sympathetic or increased parasympathetic nervous tone. Smaller fragments of oxytocin produced in the periphery may easily pass the blood-brain barrier to induce effects in the brain. In conclusion, oxytocin is linked to many different, sometimes opposite effects. The intact cyclic molecule may act to initiate social interaction and associated psychophysiological effects, whereas linear oxytocin and C-terminal fragments may induce relaxation and anti-stress effects following social interaction. In this way, the principal hormone oxytocin and its fragments may take part in a behavioral sequence, ranging from approach and interaction to calm and relaxation. Linear fragments, with an exposed cysteine-residue, may exert anti-inflammatory and antioxidant effects and thereby contribute to the health-promoting effects of oxytocin.