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Dissecting the Role of Oxytocin in the Formation and Loss of Social Relationships

Open AccessPublished:June 01, 2015DOI:https://doi.org/10.1016/j.biopsych.2015.05.013

      Abstract

      Current concepts of human sociality highlight a fundamental role of the hypothalamic peptide oxytocin (OXT) in the formation and maintenance of social relationships. However, emerging evidence indicates that OXT does not invariably facilitate social bonding but also produces nonprosocial effects that may have evolved to promote offspring survival. From a mechanistic perspective, we hypothesize that OXT modulates interoceptive signals and self-referential processing, which may result in various social outcomes depending on context- and person-dependent variables such as early-life adversity. Based on this theoretical framework, we discuss translational implications for clinical trials and identify open questions for future research. Specifically, we propose that disrupted OXT signaling due to the loss of affectionate bonds may contribute to emotional disequilibrium and confer elevated risk for the onset of stress-related disorders.

      Keywords

      A human ability to form and maintain interpersonal relationships, a product of evolutionary selective processes, is fundamental to mental health (
      • Insel T.R.
      • Young L.J.
      The neurobiology of attachment.
      ). For instance, social support by proximal others has been identified as a key resilience factor promoting successful coping with and adaptation to psychosocial stress (
      • Feder A.
      • Nestler E.J.
      • Charney D.S.
      Psychobiology and molecular genetics of resilience.
      ). However, the underlying neurobiological mechanisms are not precisely understood. Current perspectives on the neurochemistry of human sociality suggest a central role of the peptide oxytocin (OXT) and its receptor (OXTR), which is expressed both in the brain and the periphery (
      • Boccia M.L.
      • Petrusz P.
      • Suzuki K.
      • Marson L.
      • Pedersen C.A.
      Immunohistochemical localization of oxytocin receptors in human brain.
      ). As a peripherally acting hormone, OXT promotes parturition and lactation, whereas as a neuromodulator projected from the hypothalamus to brain areas implicated in social-emotional behavior, it helps create long-lasting social relationships ranging from infant-parent bonding in childhood to romantic relationships in adulthood. The loss of such affectionate bonds is associated with agonizing distress and elevated risk for the onset of multiple psychiatric disorders (
      • Keyes K.M.
      • Pratt C.
      • Galea S.
      • McLaughlin K.A.
      • Koenen K.C.
      • Shear M.K.
      The burden of loss: Unexpected death of a loved one and psychiatric disorders across the life course in a national study.
      ), suggesting that OXT signaling has a pivotal role in sustaining mental health.

      Oxytocin and Social Attachment in Nonhuman Species

      OXT has evolved over 700 million years and its homologs are present in various taxa from nonvertebrates to mammals (
      • Donaldson Z.R.
      • Young L.J.
      Oxytocin, vasopressin, and the neurogenetics of sociality.
      ), highlighting the ubiquitous role of the peptide in orchestrating social and reproductive behaviors. For example, genetically modified male nematodes (Caenorhabditis elegans) lacking an OXT-like molecule or the corresponding receptor perform poorly in mating (
      • Garrison J.L.
      • Macosko E.Z.
      • Bernstein S.
      • Pokala N.
      • Albrecht D.R.
      • Bargmann C.I.
      Oxytocin/vasopressin-related peptides have an ancient role in reproductive behavior.
      ). Further evidence supporting a key role of OXT-like peptides in pair-bond formation and offspring success comes from studies in monogamous zebra finches (Taeniopygia guttata) (
      • Klatt J.D.
      • Goodson J.L.
      Oxytocin-like receptors mediate pair bonding in a socially monogamous songbird.
      ) and teleost fish (Amatitlania nigrofasciata) (
      • Oldfield R.G.
      • Hofmann H.A.
      Neuropeptide regulation of social behavior in a monogamous cichlid fish.
      ). The crucial influence of OXT on pair bonding has been best studied in two closely related species of vole, i.e., the monogamous prairie vole (Microtus ochrogaster) and the polygamous montane vole (Microtus montanus) (
      • Young K.A.
      • Gobrogge K.L.
      • Liu Y.
      • Wang Z.
      The neurobiology of pair bonding: Insights from a socially monogamous rodent.
      ,
      • Young L.J.
      • Wang Z.
      The neurobiology of pair bonding.
      ). While the expression of OXT is similar among both species (
      • Wang Z.
      • Zhou L.
      • Hulihan T.J.
      • Insel T.R.
      Immunoreactivity of central vasopressin and oxytocin pathways in microtine rodents: A quantitative comparative study.
      ), brain distribution of the OXTR significantly differs between them, with high OXTR density in the prelimbic cortex and nucleus accumbens (NAcc) being crucial for the expression of monogamous behavior (
      • Shapiro L.E.
      • Insel T.R.
      Oxytocin receptor distribution reflects social organization in monogamous and polygamous voles.
      ,
      • Young L.J.
      • Lim M.M.
      • Gingrich B.
      • Insel T.R.
      Cellular mechanisms of social attachment.
      ). However, accumulating evidence suggests that species differences in social relationships are not restricted to the OXT system per se but extend to other signaling pathways, including dopamine (DA) and arginine-vasopressin (AVP), and their reciprocal interactions (
      • Aragona B.J.
      • Liu Y.
      • Yu Y.J.
      • Curtis J.T.
      • Detwiler J.M.
      • Insel T.R.
      • Wang Z.
      Nucleus accumbens dopamine differentially mediates the formation and maintenance of monogamous pair bonds.
      ,
      • Johnson Z.V.
      • Young L.J.
      Neurobiological mechanisms of social attachment and pair bonding.
      ). For example, heightened expression of AVP receptors (AVPRs) in the ventral forebrain of polygamous meadow voles (Microtus pennsylvanicus) elicits monogamous behavior (
      • Lim M.M.
      • Wang Z.
      • Olazabal D.E.
      • Ren X.
      • Terwilliger E.F.
      • Young L.J.
      Enhanced partner preference in a promiscuous species by manipulating the expression of a single gene.
      ). Current concepts hold that the AVP/OXT and DA systems closely interact in a site- and sex-specific manner to mediate partner preference formation, and similar cross-talk may also determine parenting styles (
      • Bosch O.J.
      • Neumann I.D.
      Both oxytocin and vasopressin are mediators of maternal care and aggression in rodents: From central release to sites of action.
      ). For instance, hypothalamic lesions block the initiation, but not the maintenance, of maternal behaviors in rats (
      • Insel T.R.
      • Harbaugh C.R.
      Lesions of the hypothalamic paraventricular nucleus disrupt the initiation of maternal behavior.
      ), suggesting that OXT may specifically facilitate the transition from avoidance of pups to caring for them (
      • Insel T.R.
      A neurobiological basis of social attachment.
      ,
      • Rilling J.K.
      • Young L.J.
      The biology of mammalian parenting and its effect on offspring social development.
      ). Recently, it was shown that OXT enables pup retrieval behavior in female mice by amplifying pup call responses in maternal auditory cortex (
      • Marlin B.J.
      • Mitre M.
      • D’Amour J.A.
      • Chao M.V.
      • Froemke R.C.
      Oxytocin enables maternal behaviour by balancing cortical inhibition.
      ). Furthermore, OXT has been implicated in maternal licking and grooming in rats (
      • Champagne F.
      • Diorio J.
      • Sharma S.
      • Meaney M.J.
      Naturally occurring variations in maternal behavior in the rat are associated with differences in estrogen-inducible central oxytocin receptors.
      ), social affiliation of dogs toward their owners (
      • Nagasawa M.
      • Mitsui S.
      • En S.
      • Ohtani N.
      • Ohta M.
      • Sakuma Y.
      • et al.
      Social evolution. Oxytocin-gaze positive loop and the coevolution of human-dog bonds.
      ), and grooming of nonbond partners in chimpanzees, thus providing a cross-species mechanism that enables long-term cooperative relationships between kin and nonkin mammals (
      • Crockford C.
      • Wittig R.M.
      • Langergraber K.
      • Ziegler T.E.
      • Zuberbuhler K.
      • Deschner T.
      Urinary oxytocin and social bonding in related and unrelated wild chimpanzees.
      ). Notably, the OXT system not only plays a pivotal role in the formation and maintenance of pair bonds but is also affected by their disruption. For example, social isolation through partner separation precipitates anxiety and depression-like behaviors in monogamous voles (
      • Grippo A.J.
      • Gerena D.
      • Huang J.
      • Kumar N.
      • Shah M.
      • Ughreja R.
      • Carter C.S.
      Social isolation induces behavioral and neuroendocrine disturbances relevant to depression in female and male prairie voles.
      ), which could be prevented by repeated subcutaneous injection of OXT (
      • Grippo A.J.
      • Pournajafi-Nazarloo H.
      • Sanzenbacher L.
      • Trahanas D.M.
      • McNeal N.
      • Clarke D.A.
      • et al.
      Peripheral oxytocin administration buffers autonomic but not behavioral responses to environmental stressors in isolated prairie voles.
      ). Furthermore, even short-term separation from their female partners induced profound grief reactions and heightened hypothalamic-pituitary-adrenal axis activity in male voles (
      • Bosch O.J.
      • Nair H.P.
      • Ahern T.H.
      • Neumann I.D.
      • Young L.J.
      The CRF system mediates increased passive stress-coping behavior following the loss of a bonded partner in a monogamous rodent.
      ), suggesting that in highly social species, decreases in OXT signaling due to partner loss rapidly translate into stress-related disorders such as anxiety and depression.

      Oxytocin and Infant-Caregiver Attachment

      A plethora of studies in humans has focused on the potential validity of endogenous OXT concentrations as biomarkers for infant-caregiver attachment bonds and parenting styles. For instance, OXT plasma concentrations in the first trimester of pregnancy were shown to predict postpartum maternal attachment (
      • Feldman R.
      • Weller A.
      • Zagoory-Sharon O.
      • Levine A.
      Evidence for a neuroendocrinological foundation of human affiliation: Plasma oxytocin levels across pregnancy and the postpartum period predict mother-infant bonding.
      ). Moreover, OXT plasma concentrations appear to correlate with the time devoted to affectionate parenting (such as soft hugs, caresses, or baby talk) in mothers and with stimulatory parenting (i.e., tossing the baby in the air or encouraging exploration and laughter) in fathers (
      • Gordon I.
      • Zagoory-Sharon O.
      • Leckman J.F.
      • Feldman R.
      Oxytocin and the development of parenting in humans.
      ). Perhaps more informative than OXT concentrations at baseline is the rise in OXT levels during infant-caregiver interactions. The evidence suggests that the greater the amounts of OXT released in plasma during such interactions, the greater the mother’s readiness for social reciprocity and flexible adaptation to the child’s needs (
      • Strathearn L.
      • Iyengar U.
      • Fonagy P.
      • Kim S.
      Maternal oxytocin response during mother-infant interaction: Associations with adult temperament.
      ). Lower than normal cerebrospinal fluid (CSF) levels of OXT were measured in adult women with a history of childhood trauma and abuse (
      • Heim C.
      • Young L.J.
      • Newport D.J.
      • Mletzko T.
      • Miller A.H.
      • Nemeroff C.B.
      Lower CSF oxytocin concentrations in women with a history of childhood abuse.
      ), as well as in the urine of socially deprived children interacting with their mothers (
      • Wismer Fries A.B.
      • Ziegler T.E.
      • Kurian J.R.
      • Jacoris S.
      • Pollak S.D.
      Early experience in humans is associated with changes in neuropeptides critical for regulating social behavior.
      ) [but see also (
      • Young S.N.
      • Anderson G.N.
      Bioanalytical inaccuracy: A threat to the integrity and efficiency of research.
      )], indicating that early-life adversity has long-lasting impact on OXT signaling. However, the tempting idea that endogenous OXT concentrations specifically reflect and positively correlate with parenting contrasts with findings that OXT levels in urine tend to be higher in mothers interacting with unfamiliar children compared with their own children (
      • Bick J.
      • Dozier M.
      Mothers’ and children’s concentrations of oxytocin following close, physical interactions with biological and non-biological children.
      ) and increase as a function of relationship anxiety and parenting stress (
      • Feldman R.
      • Gordon I.
      • Zagoory-Sharon O.
      Maternal and paternal plasma, salivary, and urinary oxytocin and parent-infant synchrony: Considering stress and affiliation components of human bonding.
      ).
      A large body of evidence indicates a link between infant-caregiver attachment bonds and genetic variation in OXT pathways. For example, mothers with a silent G to A allele change in the OXTR gene (rs53576) show lower levels of sensitive parenting (
      • Bakermans-Kranenburg M.J.
      • van Ijzendoorn M.H.
      Oxytocin receptor (OXTR) and serotonin transporter (5-HTT) genes associated with observed parenting.
      ), and in a large twin sample, the same polymorphism was found to predict a mother’s warmth toward her children (
      • Klahr A.M.
      • Klump K.
      • Burt S.A.
      A constructive replication of the association between the oxytocin receptor genotype and parenting.
      ). Additionally, there is evidence for an association between the A allele of OXTR (rs2254298) and attachment security in non-Caucasian infants (
      • Chen F.S.
      • Barth M.E.
      • Johnson S.L.
      • Gotlib I.H.
      • Johnson S.C.
      Oxytocin receptor (OXTR) polymorphisms and attachment in human infants.
      ). Indirect evidence for the relevance of rs2254298 also comes from a community study of women exhibiting higher or lower depression scores postpartum (
      • Apter-Levy Y.
      • Feldman M.
      • Vakart A.
      • Ebstein R.P.
      • Feldman R.
      Impact of maternal depression across the first 6 years of life on the child’s mental health, social engagement, and empathy: The moderating role of oxytocin.
      ). Specifically, the rs2254298 GG homozygous genotype was overrepresented in depressed mothers and their families and was associated with lower OXT saliva concentrations. However, other studies have failed to establish a link between rs53576 or rs2254298 and attachment styles (
      • Mesquita A.R.
      • Soares I.
      • Roisman G.I.
      • Ijzendoorn M.
      • Bakermans-Kranenburg M.
      • Luijk M.
      • et al.
      Predicting children’s attachment behaviors from the interaction between oxytocin and glucocorticoid receptors polymorphisms.
      ,
      • Connelly J.J.
      • Golding J.
      • Gregory S.P.
      • Ring S.M.
      • Davis J.M.
      • Davey Smith G.
      • et al.
      Personality, behavior and environmental features associated with OXTR genetic variants in British mothers.
      ), and a recent study even identified a reverse association between genotype and positive parenting (i.e., that mothers with the GG genotype of rs53576 displayed lower levels of positive parenting) (
      • Michalska K.J.
      • Decety J.
      • Liu C.
      • Chen Q.
      • Martz M.E.
      • Jacob S.
      • et al.
      Genetic imaging of the association of oxytocin receptor gene (OXTR) polymorphisms with positive maternal parenting.
      ). It thus appears that genetic variation confers susceptibility for distinct attachment styles, but the extent to which a specific style is expressed in the behavioral phenotype is moderated by family environment (
      • Bradley B.
      • Davis T.A.
      • Wingo A.P.
      • Mercer K.B.
      • Ressler K.J.
      Family environment and adult resilience: Contributions of positive parenting and the oxytocin receptor gene.
      ,
      • Bradley B.
      • Westen D.
      • Mercer K.B.
      • Binder E.B.
      • Jovanovic T.
      • Crain D.
      • et al.
      Association between childhood maltreatment and adult emotional dysregulation in a low-income, urban, African American sample: Moderation by oxytocin receptor gene.
      ).
      Substantial evidence suggests that intranasal delivery of synthetic OXT (OXTIN) is a useful means to dissect the peptide’s contribution to infant-caregiver attachment. OXTIN causes an increase in CSF levels of OXT (
      • Striepens N.
      • Kendrick K.M.
      • Hanking V.
      • Landgraf R.
      • Wullner U.
      • Maier W.
      • Hurlemann R.
      Elevated cerebrospinal fluid and blood concentrations of oxytocin following its intranasal administration in humans.
      ), although we note that the exact transnasal route the peptide takes to reach the brain is still unclear and even a peripheral feedback mechanism enhancing endogenous release cannot be excluded. Recently, a single 24-IU dose of OXTIN was found to be sufficient for inducing a significant increase in perceived attachment security in male adults previously classified as insecure (
      • Buchheim A.
      • Heinrichs M.
      • George C.
      • Pokorny D.
      • Koops E.
      • Henningsen P.
      • et al.
      Oxytocin enhances the experience of attachment security.
      ). Furthermore, OXTIN made fathers less hostile and motivated them to foster exploration behavior in their children (
      • Naber F.
      • van Ijzendoorn M.H.
      • Deschamps P.
      • van Engeland H.
      • Bakermans-Kranenburg M.J.
      Intranasal oxytocin increases fathers’ observed responsiveness during play with their children: A double-blind within-subject experiment.
      ). Interestingly, OXTIN not only encouraged fathers to engage in stimulatory parenting but also increased the infant’s salivary OXT concentrations in addition to changes in respiratory sinus arrhythmia response, an index of emotional reactivity, and social-emotional behavior (
      • Weisman O.
      • Zagoory-Sharon O.
      • Feldman R.
      Oxytocin administration to parent enhances infant physiological and behavioral readiness for social engagement.
      ). Together, these results suggest that heightened OXT levels may enhance social interactions between fathers and their children, perhaps by establishing closer proximity between them (
      • Weisman O.
      • Delaherche E.
      • Rondeau M.
      • Chetouani M.
      • Cohen D.
      • Feldman R.
      Oxytocin shapes parental motion during father-infant interaction.
      ). Functional magnetic resonance imaging (fMRI) studies have sought to reveal the neural representations of parenting and its modulation by OXTIN. For instance, OXTIN in fathers was shown to alter globus pallidus responses to pictures of their own children (
      • Wittfoth-Schardt D.
      • Grunding J.
      • Wittfoth M.
      • Lanfermann H.
      • Heinrichs M.
      • Domes G.
      • et al.
      Oxytocin modulates neural reactivity to children’s faces as a function of social salience.
      ). OXTIN evoked greater responses in insula and inferior frontal gyrus, both of which are implicated in empathy (
      • Riem M.M.
      • Bakermans-Kranenburg M.J.
      • Pieper S.
      • Tops M.
      • Boksem M.A.
      • Vermeiren R.R.
      • et al.
      Oxytocin modulates amygdala, insula, and inferior frontal gyrus responses to infant crying: A randomized controlled trial.
      ) in women exposed to infant crying. OXTIN also reduced amygdala responses to infant laughter (
      • Riem M.M.
      • van IJzendoorn M.H.
      • Tops M.
      • Boksem M.A.
      • Rombouts S.A.
      • Bakermans-Kranenburg M.J.
      No laughing matter: Intranasal oxytocin administration changes functional brain connectivity during exposure to infant laughter.
      ). Notably, the effects of OXTIN appear to be influenced by the attachment representations people possess. Less anxiously attached individuals remembered their mother as more caring and close after OXTIN, but the opposite effect was observed for more anxiously attached individuals (
      • Bartz J.A.
      • Zaki J.
      • Ochsner K.N.
      • Bolger N.
      • Kolevzon A.
      • Ludwig N.
      • Lydon J.E.
      Effects of oxytocin on recollections of maternal care and closeness.
      ). In another study, OXTIN decreased handgrip force in reaction to infant crying in female subjects without a childhood history of harsh parenting experiences (
      • Bakermans-Kranenburg M.J.
      • van Ijzendoorn M.H.
      • Riem M.M.
      • Tops M.
      • Alink L.R.
      Oxytocin decreases handgrip force in reaction to infant crying in females without harsh parenting experiences.
      ). Together, these results challenge the popular notion that oxytocin has broad positive effects on social perception and instead suggest a strong dependency of OXT effects on person-dependent factors including early-life adversity.

      Oxytocin and Romantic Attachment

      During the early stages of romantic relationships, OXT plasma concentrations are elevated in new lovers compared with singles (
      • Schneiderman I.
      • Zagoory-Sharon O.
      • Leckman J.F.
      • Feldman R.
      Oxytocin during the initial stages of romantic attachment: Relations to couples’ interactive reciprocity.
      ). OXT plasma levels are also increased in couples who exhibit higher interactive reciprocity and spend more time thinking of the partner and the relationship (
      • Schneiderman I.
      • Zagoory-Sharon O.
      • Leckman J.F.
      • Feldman R.
      Oxytocin during the initial stages of romantic attachment: Relations to couples’ interactive reciprocity.
      ). In an instructed couple conflict scenario, participants showed more empathy if their partners had higher OXT plasma levels (
      • Schneiderman I.
      • Kanat-Maymon Y.
      • Zagoory-Sharon O.
      • Feldman R.
      Mutual influences between partners’ hormones shape conflict dialog and relationship duration at the initiation of romantic love.
      ). In another study, OXT plasma levels were associated with more affectionate communication during a structured social support interaction task (
      • Gouin J.P.
      • Carter C.S.
      • Pournajafi-Nazarloo H.
      • Glaser R.
      • Malarkey W.B.
      • Loving T.J.
      • et al.
      Marital behavior, oxytocin, vasopressin, and wound healing.
      ). In women, the expression of nonverbal affiliation cues was positively correlated with OXT plasma release (
      • Gonzaga G.C.
      • Turner R.A.
      • Keltner D.
      • Campos B.
      • Altemus M.
      Romantic love and sexual desire in close relationships.
      ). In both sexes, greater self-reported levels of partner support and partner intimacy were related to higher OXT plasma concentrations (
      • Grewen K.M.
      • Girdler S.S.
      • Amico J.
      • Light K.C.
      Effects of partner support on resting oxytocin, cortisol, norepinephrine, and blood pressure before and after warm partner contact.
      ,
      • Light K.C.
      • Grewen K.M.
      • Amico J.A.
      More frequent partner hugs and higher oxytocin levels are linked to lower blood pressure and heart rate in premenopausal women.
      ). Early studies could not establish a relationship between interpersonal touch and OXT release (
      • Turner R.A.
      • Altemus M.
      • Enos T.
      • Cooper B.
      • McGuinness T.
      Preliminary research on plasma oxytocin in normal cycling women: Investigating emotion and interpersonal distress.
      ,
      • Wikstrom S.
      • Gunnarsson T.
      • Nordin C.
      Tactile stimulus and neurohormonal response: A pilot study.
      ,
      • Billhult A.
      • Lindholm C.
      • Gunnarsson R.
      • Stener-Victorin E.
      The effect of massage on cellular immunity, endocrine and psychological factors in women with breast cancer -- a randomized controlled clinical trial.
      ), but more recent studies have detected a rise in OXT plasma levels after light touch or a massage (
      • Rapaport M.H.
      • Schettler P.
      • Bresee C.
      A Preliminary study of the effects of a single session of Swedish massage on hypothalamic-pituitary-adrenal and immune function in normal individuals.
      ,
      • Morhenn V.B.
      • Park J.W.
      • Piper E.
      • Zak P.J.
      Monetary sacrifice among strangers is mediated by endogenous oxytocin release after physical contact.
      ,
      • Morhenn V.
      • Beavin L.E.
      • Zak P.J.
      Massage increases oxytocin and reduces adrenocorticotropin hormone in humans.
      ). The impact of sexual activity on endogenous OXT release is informed by numerous studies showing increased OXT plasma concentrations after orgasm in humans (
      • Ogawa S.
      • Kudo S.
      • Kitsunai Y.
      • Fukuchi S.
      Increase in oxytocin secretion at ejaculation in male.
      ,
      • Carmichael M.S.
      • Warburton V.L.
      • Dixen J.
      • Davidson J.M.
      Relationships among cardiovascular, muscular, and oxytocin responses during human sexual activity.
      ,
      • Murphy M.R.
      • Checkley S.A.
      • Seckl J.R.
      • Lightman S.L.
      Naloxone inhibits oxytocin release at orgasm in man.
      ,
      • Blaicher W.
      • Gruber D.
      • Bieglmayer C.
      • Blaicher A.M.
      • Knogler W.
      • Huber J.C.
      The role of oxytocin in relation to female sexual arousal.
      ) [but see also (
      • Kruger T.H.
      • Schiffer B.
      • Eikermann M.
      • Haake P.
      • Gizewski E.
      • Schedlowski M.
      Serial neurochemical measurement of cerebrospinal fluid during the human sexual response cycle.
      )].
      Moreover, there are also reports documenting a positive correlation between OXT plasma concentrations and attachment anxiety (
      • Marazziti D.
      • Dell’Osso B.
      • Baroni S.
      • Mungai F.
      • Catena M.
      • Rucci P.
      • et al.
      A relationship between oxytocin and anxiety of romantic attachment.
      ) and interpersonal distress (
      • Turner R.A.
      • Altemus M.
      • Enos T.
      • Cooper B.
      • McGuinness T.
      Preliminary research on plasma oxytocin in normal cycling women: Investigating emotion and interpersonal distress.
      ,
      • Taylor S.E.
      • Gonzaga G.C.
      • Klein L.C.
      • Hu P.
      • Greendale G.A.
      • Seeman T.E.
      Relation of oxytocin to psychological stress responses and hypothalamic-pituitary-adrenocortical axis activity in older women.
      ). As such, the tend and befriend model has been proposed (
      • Taylor S.E.
      Tend and befriend: Biobehavioral bases of affiliation under stress.
      ,
      • Tabak B.A.
      • McCullough M.E.
      • Szeto A.
      • Mendez A.J.
      • McCabe P.M.
      Oxytocin indexes relational distress following interpersonal harms in women.
      ), which states that gaps in positive social relationships are accompanied by elevations in OXT and that these increased OXT levels prompt affiliative efforts aimed at restoring positive social contact. Of note, the interpretation of peripheral OXT measurements is hampered by methodological issues (
      • McCullough M.E.
      • Churchland P.S.
      • Mendez A.J.
      Problems with measuring peripheral oxytocin: Can the data on oxytocin and human behavior be trusted?.
      ) and the absence of a strong linear relationship between peripheral and central OXT concentrations (
      • Kagerbauer S.M.
      • Martin J.
      • Schuster T.
      • Blobner M.
      • Kochs E.F.
      • Landgraf R.
      Plasma oxytocin and vasopressin do not predict neuropeptide concentrations in human cerebrospinal fluid.
      ). It is also still elusive whether peripheral or CSF measurements can reflect the subtle release of OXT from axons in a manner specific to a certain brain region (
      • Knobloch H.S.
      • Charlet A.
      • Hoffmann L.C.
      • Eliava M.
      • Khrulev S.
      • Cetin A.H.
      • et al.
      Evoked axonal oxytocin release in the central amygdala attenuates fear response.
      ). Associations between peripheral OXT levels and a specific type of social behavior may result from a positive feedback system such that one particular behavior elicits the release of endogenous OXT and vice versa. In addition, peripheral OXT may affect a diverse repertoire of social behaviors by modulating visceral target organs of the autonomic nervous system, many of which (e.g., the heart or digestive system) both locally synthesize OXT and express OXTRs (
      • Gimpl G.
      • Fahrenholz F.
      The oxytocin receptor system: Structure, function, and regulation.
      ).
      OXTR gene variations (rs7632287) have also been associated with traits reflecting pair bonding, such as the quality of interactions with their romantic partners in women (
      • Walum H.
      • Lichtenstein P.
      • Neiderhiser J.M.
      • Reiss D.
      • Ganiban J.M.
      • Spotts E.L.
      • et al.
      Variation in the oxytocin receptor gene is associated with pair-bonding and social behavior.
      ). Furthermore, a cumulative genetic risk for social dysfunctions was computed by summing up risk alleles on different polymorphisms, with high-risk individuals exhibiting difficulties in empathic communication in couple interactions (
      • Schneiderman I.
      • Kanat-Maymon Y.
      • Ebstein R.P.
      • Feldman R.
      Cumulative risk on the oxytocin receptor gene (OXTR) underpins empathic communication difficulties at the first stages of romantic love.
      ).
      Evidence for effects of OXTIN on behaviors related to pair bonding is scarce. It has been shown, for example, that the peptide enhances positive communication in relation to negative behavior during couple conflicts and reduces cortisol saliva levels after the conflict (
      • Ditzen B.
      • Schaer M.
      • Gabriel B.
      • Bodenmann G.
      • Ehlert U.
      • Heinrichs M.
      Intranasal oxytocin increases positive communication and reduces cortisol levels during couple conflict.
      ). In women, OXTIN also reduced salivary alpha-amylase, an index of sympathetic activity, whereas in men the peptide increased salivary alpha-amylase levels and emotional arousal during couple conflict (
      • Ditzen B.
      • Nater U.M.
      • Schaer M.
      • La Marca R.
      • Bodenmann G.
      • Ehlert U.
      • Heinrichs M.
      Sex-specific effects of intranasal oxytocin on autonomic nervous system and emotional responses to couple conflict.
      ). Interestingly, men under OXT were faster to detect the valence of positive stimuli conceptually associated with sexuality, bonding, and social relationships (
      • Unkelbach C.
      • Guastella A.J.
      • Forgas J.P.
      Oxytocin selectively facilitates recognition of positive sex and relationship words.
      ). Notably, OXTIN further augmented epinephrine plasma responses to sexual activity in men (
      • Burri A.
      • Heinrichs M.
      • Schedlowski M.
      • Kruger T.H.
      The acute effects of intranasal oxytocin administration on endocrine and sexual function in males.
      ) and increased the intensity of orgasm and contentment following sexual intercourse in heterosexual couples (
      • Behnia B.
      • Heinrichs M.
      • Bergmann W.
      • Jung S.
      • Germann J.
      • Schedlowski M.
      • et al.
      Differential effects of intranasal oxytocin on sexual experiences and partner interactions in couples.
      ). By contrast, an early study using a 32-IU dose of OXTIN failed to detect any behavioral or neural effects in 21 men who observed their female partner receiving painful stimulation (
      • Singer T.
      • Snozzi R.
      • Bird G.
      • Petrovic P.
      • Silani G.
      • Heinrichs M.
      • Dolan R.J.
      Effects of oxytocin and prosocial behavior on brain responses to direct and vicariously experienced pain.
      ).
      Few studies have sought to explore a role of OXTIN in partner preference. In one study, OXTIN stimulated subjects to seek out information about an old partner but had no effect on the participant’s choice for company (to work with or date) (
      • Liu J.C.
      • Guastella A.J.
      • Dadds M.R.
      Exploring the role of intra-nasal oxytocin on the partner preference effect in humans.
      ). In another study, OXTIN motivated pair-bonded, but not single, men to keep a larger social distance from an unknown female experimenter (Figure 1) and inhibited approach toward attractive women depicted in photos (
      • Scheele D.
      • Striepens N.
      • Güntürkün O.
      • Deutschlander S.
      • Maier W.
      • Kendrick K.M.
      • Hurlemann R.
      Oxytocin modulates social distance between males and females.
      ). Previous fMRI studies have revealed that viewing the face of a romantic partner while recalling experiences with them activates reward-associated regions such as the ventral tegmental area (VTA) and NAcc (
      • Bartels A.
      • Zeki S.
      The neural correlates of maternal and romantic love.
      ,
      • Acevedo B.P.
      • Aron A.
      • Fisher H.E.
      • Brown L.L.
      Neural correlates of long-term intense romantic love.
      ). In healthy pair-bonded men, OXTIN facilitated neural responses to the partner compared with unfamiliar women in the VTA and NAcc (Figure 2). On the behavioral level, these neural effects were paralleled by a more favorable attractiveness perception of the female partner (
      • Scheele D.
      • Wille A.
      • Kendrick K.M.
      • Stoffel-Wagner B.
      • Becker B.
      • Güntürkün O.
      • et al.
      Oxytocin enhances brain reward system responses in men viewing the face of their female partner.
      ). Interestingly, viewing pictures of a romantic partner also reduced self-reported thermal pain and greater analgesia was associated with increased activity in several reward-processing regions including the NAcc (
      • Younger J.
      • Aron A.
      • Parke S.
      • Chatterjee N.
      • Mackey S.
      Viewing pictures of a romantic partner reduces experimental pain: Involvement of neural reward systems.
      ). To our knowledge, no study so far has tested whether partner-induced analgesia is related to OXT-mediated pain inhibition (
      • Zunhammer M.
      • Geis S.
      • Busch V.
      • Greenlee M.W.
      • Eichhammer P.
      Effects of intranasal oxytocin on thermal pain in healthy men: A randomized functional magnetic resonance imaging study.
      ). Furthermore, by employing a mental imagery task, it has been shown that OXTIN diminishes subjects’ arousal judgments of and anterior cingulate cortex (ACC) responses to scenes describing sexual infidelity of the partner (
      • Preckel K.
      • Scheele D.
      • Eckstein M.
      • Maier W.
      • Hurlemann R.
      The influence of oxytocin on volitional and emotional ambivalence.
      ). Collectively, these data provide little support that OXT is involved in the formation of new pair bonds in humans but rather suggest that OXT may be more important for the maintenance of an already established pair bond. As such, this discrepancy compared with the role of OXT in prairie voles, where the peptide is necessary for the formation of new pair bonds (
      • Liu Y.
      • Wang Z.X.
      Nucleus accumbens oxytocin and dopamine interact to regulate pair bond formation in female prairie voles.
      ), may be related to methodological differences in the assessment of pair bonding in rodents and humans or indicate a species-specific function of OXT.
      Figure thumbnail gr1
      Figure 1Oxytocin effects on the social distance between women and men. Male participants were asked to choose the ideal (most comfortable) distance to an attractive female experimenter. In the first half of the trials, the experimenter moved either toward (far, i.e., start distance of 2 m) or away from the subject (close, start distance of 30 cm), whereas in the second half, the male volunteer was the one approaching or withdrawing. Oxytocin increased the ideal distance that pair-bonded men maintained in relation to the unknown attractive woman across all conditions.
      Figure thumbnail gr2
      Figure 2Oxytocin (OXT) effects on nucleus accumbens (NAcc) responses. The intranasal administration of OXT increased NAcc response to the female partner’s face compared with a matched, unfamiliar woman. Error bars indicate the standard error of the mean. L, left hemisphere; PLC, placebo; R, right hemisphere.
      It would stand to reason that OXT effects on pair bonding are mediated by DA, as the NAcc and VTA form two central hubs of the mesolimbic DA pathway. In a recent [11C]raclopride positron emission tomography study, DA release was measured during a face-attraction rating task after OXTIN administration (
      • Striepens N.
      • Matusch A.
      • Kendrick K.M.
      • Mihov Y.
      • Elmenhorst D.
      • Becker B.
      • et al.
      Oxytocin enhances attractiveness of unfamiliar female faces independent of the dopamine reward system.
      ). The authors could replicate the previous finding that OXT, in the absence of any partner stimuli, can enhance the perceived attractiveness of unfamiliar women (
      • Theodoridou A.
      • Rowe A.C.
      • Penton-Voak I.S.
      • Rogers P.J.
      Oxytocin and social perception: Oxytocin increases perceived facial trustworthiness and attractiveness.
      ), but this effect was not accompanied by an altered raclopride binding in the striatum. Instead, they observed increased binding in subregions of the right dorsomedial prefrontal gyrus and superior parietal gyrus under OXT. These data could mean that an OXT-DA interplay in the striatum is restricted to the domain of pair bonding or that OXT interacts with a different family of DA receptors or a completely different class of neurotransmitters. For instance, the rewarding properties of social interactions in mice require the coordinated activity of OXT and serotonin in the NAcc (
      • Dolen G.
      • Darvishzadeh A.
      • Huang K.W.
      • Malenka R.C.
      Social reward requires coordinated activity of nucleus accumbens oxytocin and serotonin.
      ) and a recent [18F]MPPF positron emission tomography study demonstrated that OXTIN modulates serotonergic signaling in humans (
      • Mottolese R.
      • Redoute J.
      • Costes N.
      • Le Bars D.
      • Sirigu A.
      Switching brain serotonin with oxytocin.
      ).
      As of yet, no study has examined the behavioral and neural effects of OXTIN on the processing of partner stimuli in women. In an fMRI study (
      • Rupp H.A.
      • James T.W.
      • Ketterson E.D.
      • Sengelaub D.R.
      • Ditzen B.
      • Heiman J.R.
      Lower sexual interest in postpartum women: Relationship to amygdala activation and intranasal oxytocin.
      ), OXTIN did not alter amygdala responses, but it did selectively increase arousal ratings of infant stimuli in nulliparous, but not postpartum, women. In all women, OXTIN administration resulted in greater VTA, but not NAcc, activation to infant and sexual images (
      • Gregory R.
      • Cheng H.
      • Rupp H.A.
      • Sengelaub D.R.
      • Heiman J.R.
      Oxytocin increases VTA activation to infant and sexual stimuli in nulliparous and postpartum women.
      ). A recent study also points to the importance of moderator variables for OXT effects on pair-bonding behavior (
      • DeWall C.N.
      • Gillath O.
      • Pressman S.D.
      • Black L.L.
      • Bartz J.A.
      • Moskovitz J.
      • et al.
      When the love hormone leads to violence: Oxytocin increases intimate partner violence inclinations among high trait aggressive people.
      ). For instance, OXTIN specifically increased the inclination for intimate partner violence in participants prone to physical aggression but not in participants with low aggressiveness traits. These data resonate well with the idea that OXT enhances an a priori existing predisposition, possibly by modulating self-referential processing and interoception.

      A Self-Reference Model of Oxytocin

      Several theoretical frameworks have been proposed to explain the wide repertoire of social OXT effects (Table S1 in Supplement 1). On the one hand, OXT enhances the stress-and anxiety-buffering effect of social support from proximal others (
      • Heinrichs M.
      • Baumgartner T.
      • Kirschbaum C.
      • Ehlert U.
      Social support and oxytocin interact to suppress cortisol and subjective responses to psychosocial stress.
      ) and facilitates fear extinction by strengthening the control of regulatory prefrontal areas over amygdalar fear responses (
      • Eckstein M.
      • Becker B.
      • Scheele D.
      • Scholz C.
      • Preckel K.
      • Schlaepfer T.
      • et al.
      Oxytocin facilitates the extinction of conditioned fear in humans.
      ). On the other hand, in the absence of social support, OXT may increase the sensation of social stress, augment the impact of aversive information on defensive responses (i.e., the startle reflex), and induce a privileged recall of negative information by increasing neural responses in insular cortex (
      • Striepens N.
      • Scheele D.
      • Kendrick K.M.
      • Becker B.
      • Schafer L.
      • Schwalba K.
      • et al.
      Oxytocin facilitates protective responses to aversive social stimuli in males.
      ,
      • Eckstein M.
      • Scheele D.
      • Weber K.
      • Stoffel-Wagner B.
      • Maier W.
      • Hurlemann R.
      Oxytocin facilitates the sensation of social stress.
      ). In an attempt to reconcile this conflicting evidence, it has been proposed that OXT exerts a lower-level general effect on general states and dispositions (
      • Churchland P.S.
      • Winkielman P.
      Modulating social behavior with oxytocin: How does it work?.
      ) and that the outcome of OXT administration is constrained by features of situations and/or individuals (
      • Bartz J.A.
      • Zaki J.
      • Bolger N.
      • Ochsner K.N.
      Social effects of oxytocin in humans: Context and person matter.
      ). In fact, OXTIN effects are often moderated by the subject’s gender (
      • Preckel K.
      • Scheele D.
      • Kendrick K.M.
      • Maier W.
      • Hurlemann R.
      Oxytocin facilitates social approach behavior in women.
      ,
      • Scheele D.
      • Striepens N.
      • Kendrick K.M.
      • Schwering C.
      • Noelle J.
      • Wille A.
      • et al.
      Opposing effects of oxytocin on moral judgment in males and females.
      ) and context-dependent factors. One example for the latter is an fMRI study in which the subjective valence of interpersonal touch was experimentally manipulated (
      • Scheele D.
      • Kendrick K.M.
      • Khouri C.
      • Kretzer E.
      • Schlapfer T.E.
      • Stoffel-Wagner B.
      • et al.
      An oxytocin-induced facilitation of neural and emotional responses to social touch correlates inversely with autism traits.
      ). Specifically, OXTIN was found to augment behavioral pleasantness ratings only in a positively framed social context. On the neural level, OXTIN enhanced responses in a neural circuitry spanning the insula, precuneus, orbitofrontal cortex, and pregenual ACC. Interestingly, both the behavioral and neural effects were blunted in subjects with higher autistic-like traits. Modulatory influences of OXTIN on neural reactivity of the insula, precuneus, and ACC have been observed across various cognitive and emotional domains in fMRI studies (
      • Preckel K.
      • Scheele D.
      • Eckstein M.
      • Maier W.
      • Hurlemann R.
      The influence of oxytocin on volitional and emotional ambivalence.
      ,
      • Eckstein M.
      • Scheele D.
      • Weber K.
      • Stoffel-Wagner B.
      • Maier W.
      • Hurlemann R.
      Oxytocin facilitates the sensation of social stress.
      ,
      • Scheele D.
      • Striepens N.
      • Kendrick K.M.
      • Schwering C.
      • Noelle J.
      • Wille A.
      • et al.
      Opposing effects of oxytocin on moral judgment in males and females.
      ). Current concepts of human emotional awareness (
      • Craig A.D.
      How do you feel--now? The anterior insula and human awareness.
      ) highlight that the anterior insula cortex, which is often jointly activated with the ACC, contains representations that provide an emergent basis for subjective feelings from the body. The precuneus belongs to a widespread neurocircuitry of higher association cortical and subcortical areas and has been implicated in interoceptive awareness and consciousness (
      • Lou H.C.
      • Luber B.
      • Crupain M.
      • Keenan J.P.
      • Nowak M.
      • Kjaer T.W.
      • et al.
      Parietal cortex and representation of the mental Self.
      ). Thus, the observed pattern of results has been interpreted as indicating an OXT-induced self-referential processing bias that could explain the increased pleasantness in an already pleasant context and a diminished effect for participants with high autistic-like traits who experience social touch as less pleasant (
      • Voos A.C.
      • Pelphrey K.A.
      • Kaiser M.D.
      Autistic traits are associated with diminished neural response to affective touch.
      ). This view was recently extended by the hypothesis that OXT’s influence on self-referential processing and interoception is also context-dependent (
      • Quattrocki E.
      • Friston K.
      Autism, oxytocin and interoception.
      ). The authors predict that OXT augments interoceptive prediction errors through top-down modulation in the context of passive perception and that the peptide participates in interoceptive sensory attenuation in the context of self-generated action.
      The idea that OXT influences self-referential processing and interoception is further supported by a recent study that indicates that OXT sharpens self-other perceptual boundaries (
      • Colonnello V.
      • Chen F.S.
      • Panksepp J.
      • Heinrichs M.
      Oxytocin sharpens self-other perceptual boundary.
      ). In a video-morphing task, OXT-treated participants exhibited a significantly shorter latency when discriminating between self and other. In two other studies (
      • Cardoso C.
      • Ellenbogen M.A.
      • Linnen A.M.
      Acute intranasal oxytocin improves positive self-perceptions of personality.
      ,
      • Colonnello V.
      • Heinrichs M.
      Intranasal oxytocin enhances positive self-attribution in healthy men.
      ), OXTIN influenced participants’ self-perception assessed by personality questionnaires and an adjective-sorting task. Specifically, subjects under OXT reported higher ratings of extraversion and openness to experiences and stronger positive attitudes toward themselves. At first glance, an OXT-induced self-referential processing bias seems hard to reconcile with the above mentioned bonding-related OXT effects and the fact that OXT has also been found to enhance other-regarding tendencies such as mind reading and emotional empathy (
      • Domes G.
      • Heinrichs M.
      • Michel A.
      • Berger C.
      • Herpertz S.C.
      Oxytocin improves “mind-reading” in humans.
      ,
      • Hurlemann R.
      • Patin A.
      • Onur O.A.
      • Cohen M.X.
      • Baumgartner T.
      • Metzler S.
      • et al.
      Oxytocin enhances amygdala-dependent, socially reinforced learning and emotional empathy in humans.
      ). However, empathy and interoception are closely linked (
      • Ernst J.
      • Northoff G.
      • Boker H.
      • Seifritz E.
      • Grimm S.
      Interoceptive awareness enhances neural activity during empathy.
      ) and improved empathy may even be the by-product of sharpened interoceptive awareness. Furthermore, it is increasingly recognized that self-processing extends to incorporate significant others (
      • Aron A.
      • Fraley B.
      Relationship closeness as including other in the self: Cognitive underpinnings and measures.
      ,
      • Krienen F.M.
      • Tu P.C.
      • Buckner R.L.
      Clan mentality: Evidence that the medial prefrontal cortex responds to close others.
      ). By increasing self-referential processing in this way, OXT may be acting to promote in-group survival. Such a mechanism could help to explain why OXT promotes parochial altruism and ethnocentrism (
      • De Dreu C.K.
      • Greer L.L.
      • Handgraaf M.J.
      • Shalvi S.
      • Van Kleef G.A.
      • Baas M.
      • et al.
      The neuropeptide oxytocin regulates parochial altruism in intergroup conflict among humans.
      ,
      • De Dreu C.K.
      • Greer L.L.
      • Van Kleef G.A.
      • Shalvi S.
      • Handgraaf M.J.
      Oxytocin promotes human ethnocentrism.
      ) and it may also account for the surprising observation that a pharmacologic augmentation of a first individual psychotherapy session via OXT caused more rather than less anxiety over the course of the session in patients with depression (
      • Macdonald K.
      • Macdonald T.M.
      • Brune M.
      • Lamb K.
      • Wilson M.P.
      • Golshan S.
      • Feifel D.
      Oxytocin and psychotherapy: A pilot study of its physiological, behavioral and subjective effects in males with depression.
      ). Given this background, we conclude that one common denominator across diverse social OXT effects may be that the peptide induces a self-referential processing bias that can produce various social outcomes by enabling subjects to represent emotional experiences more consciously. Along these lines, the use of OXT as a pharmacologic augmentation of established treatments for psychiatric disorders not only contains the promise of an improved social functioning but may also aggravate an already distorted social perception. Clearly, future studies are warranted to selectively test the predictions of our preliminary model.

      Translational Implications and New Avenues for Future Research

      Intact social relationships can bring the elation of profound joy and they are an important resilience factor that can help to buffer the deteriorating consequences of stress preponderance. However, throughout life, humans are confronted with the breakup of relationships, which can be the source of sorrow and despair. In fact, acute grief after a relationship breakup (
      • Najib A.
      • Lorberbaum J.P.
      • Kose S.
      • Bohning D.E.
      • George M.S.
      Regional brain activity in women grieving a romantic relationship breakup.
      ,
      • O’Connor M.F.
      • Wellisch D.K.
      • Stanton A.L.
      • Eisenberger N.I.
      • Irwin M.R.
      • Lieberman M.D.
      Craving love? Enduring grief activates brain’s reward center.
      ) or the loss of an unborn child (
      • Kersting A.
      • Ohrmann P.
      • Pedersen A.
      • Kroker K.
      • Samberg D.
      • Bauer J.
      • et al.
      Neural activation underlying acute grief in women after the loss of an unborn child.
      ) is related to intense responses of the physical pain network encompassing the ACC and insula. Grief is a major risk factor for clinical depression (
      • Cole M.G.
      • Dendukuri N.
      Risk factors for depression among elderly community subjects: A systematic review and meta-analysis.
      ), and in a substantial minority, the grief reaction does not abate but instead develops into complicated grief, which is associated with enduring functional impairments (
      • Prigerson H.G.
      • Frank E.
      • Kasl S.V.
      • Reynolds 3rd, C.F.
      • Anderson B.
      • Zubenko G.S.
      • et al.
      Complicated grief and bereavement-related depression as distinct disorders: Preliminary empirical validation in elderly bereaved spouses.
      ). Based on the strong overlap between human love and drug addiction, from initial encounter to withdrawal, it has been proposed that social attachment can be understood as a behavioral addiction, with OXT hijacking the brain reward system to promote bonding and affiliative behavior, and that treatments used to reduce drug cravings may also be effective in treating grief resulting from the loss of a loved one or a bad breakup (
      • Burkett J.P.
      • Young L.J.
      The behavioral, anatomical and pharmacological parallels between social attachment, love and addiction.
      ). In two recent studies, OXTIN was found to suppress stress-induced craving in cannabis-dependent individuals (
      • McRae-Clark A.L.
      • Baker N.L.
      • Maria M.M.
      • Brady K.T.
      Effect of oxytocin on craving and stress response in marijuana-dependent individuals: A pilot study.
      ) and to block alcohol withdrawal (
      • Pedersen C.A.
      • Smedley K.L.
      • Leserman J.
      • Jarskog L.F.
      • Rau S.W.
      • Kampov-Polevoi A.
      • et al.
      Intranasal oxytocin blocks alcohol withdrawal in human subjects.
      ). Against this background and given the strong body of evidence implicating OXT as a key modulator of human pair bonding reviewed above, future studies should probe OXT’s potential to ameliorate withdrawal symptoms after a relationship breakup.
      Another open question is related to the optimal treatment protocol. Considering the previous finding that OXT augments the antistress effects of social support (
      • Heinrichs M.
      • Baumgartner T.
      • Kirschbaum C.
      • Ehlert U.
      Social support and oxytocin interact to suppress cortisol and subjective responses to psychosocial stress.
      ), we expect that OXT should produce the most powerful effects as an adjunct to social interventions relying on the human attachment system. Previous clinical trials exploring the clinical potential of OXT have consistently shown that the OXT system is an enticing pharmacologic target for enhancing social cognition (
      • Shahrestani S.
      • Kemp A.H.
      • Guastella A.J.
      The impact of a single administration of intranasal oxytocin on the recognition of basic emotions in humans: A meta-analysis.
      ), but relatively few studies have focused on the bonding-related effects of OXT. A reduced capacity to form and maintain long-lasting social relationships is a hallmark of several conditions, including borderline personality disorder and autism and schizophrenia spectrum disorders; OXT could be a promising treatment option selectively targeting attachment dysfunctions. Based on our self-referential processing model, it also seems promising to combine OXTIN with nonpharmacologic treatments of autism spectrum disorder such as real-time fMRI neurofeedback aimed at restoring control over anterior insula activity (
      • Caria A.
      • de Falco S.
      Anterior insular cortex regulation in autism spectrum disorders.
      ).
      Furthermore, the effects of a single dose may deviate from that of a long-term OXT treatment, seeing as other antianxiety agents also produce anxiogenic effects after first-time dosage (
      • Birkett M.A.
      • Shinday N.M.
      • Kessler E.J.
      • Meyer J.S.
      • Ritchie S.
      • Rowlett J.K.
      Acute anxiogenic-like effects of selective serotonin reuptake inhibitors are attenuated by the benzodiazepine diazepam in BALB/c mice.
      ). In male voles, a long-term developmental treatment with low doses of OXTIN resulted in a deficit in partner preference behavior (
      • Bales K.L.
      • Perkeybile A.M.
      • Conley O.G.
      • Lee M.H.
      • Guoynes C.D.
      • Downing G.M.
      • et al.
      Chronic intranasal oxytocin causes long-term impairments in partner preference formation in male prairie voles.
      ), and in mice, chronic OXT treatment even induced an anxiogenic phenotype (
      • Huang H.
      • Michetti C.
      • Busnelli M.
      • Manago F.
      • Sannino S.
      • Scheggia D.
      • et al.
      Chronic and acute intranasal oxytocin produce divergent social effects in mice.
      ). In humans, OXTIN treatment over 10 days in elderly subjects produced no significant effects on mood or the cardiovascular indices but yielded positive changes in psychological well-being and physical functioning (
      • Barraza J.A.
      • Grewal N.S.
      • Ropacki S.
      • Perez P.
      • Gonzalez A.
      • Zak P.J.
      Effects of a 10-day oxytocin trial in older adults on health and well-being.
      ). Similarly, the optimal dose for an OXTIN-based intervention is still elusive. In voles, the propensity to display behaviors such as pair bonding is modulated in a dose-dependent manner (
      • Bales K.L.
      • van Westerhuyzen J.A.
      • Lewis-Reese A.D.
      • Grotte N.D.
      • Lanter J.A.
      • Carter C.S.
      Oxytocin has dose-dependent developmental effects on pair-bonding and alloparental care in female prairie voles.
      ), and in humans, 24-IU, but not 48-IU, of OXTIN attenuates cortisol levels in response to physical stress (
      • Cardoso C.
      • Ellenbogen M.A.
      • Orlando M.A.
      • Bacon S.L.
      • Joober R.
      Intranasal oxytocin attenuates the cortisol response to physical stress: A dose-response study.
      ). The selectivity of OXT for the OXTR relative to AVPRs is at least twentyfold (cf. Psychoactive Drug Screening Program Ki database), but AVPR cross-binding may occur and dominate resultant effects at higher doses. The majority of OXT studies in humans include a dose of 24-IU, but dose-response investigations are clearly necessary to establish individually tailored treatment regimens that consider additional factors such as gender, age, and weight.
      In conclusion, the OXT system plays an integral role for human parenting and pair bonding, but future clinical trials are warranted to elucidate specific conditions and treatment parameters under which an OXT-induced self-referential processing bias may lead to the most beneficial clinical outcome.

      Acknowledgments and Disclosures

      RH was supported by a Starting Independent Researcher Grant (NEMO–Neuromodulation of Emotion) jointly provided by the Ministry of Innovation, Science, Research & Technology of the German State of North Rhine-Westphalia and the University of Bonn.
      We thank J. Horowitz for her comments on an early draft of this manuscript and Alexandra Patin for proofreading the manuscript.
      The authors report no biomedical financial interests or potential conflicts of interest.

      Appendix A. Supplementary Materials

      References

        • Insel T.R.
        • Young L.J.
        The neurobiology of attachment.
        Nat Rev Neurosci. 2001; 2: 129-136
        • Feder A.
        • Nestler E.J.
        • Charney D.S.
        Psychobiology and molecular genetics of resilience.
        Nat Rev Neurosci. 2009; 10: 446-457
        • Boccia M.L.
        • Petrusz P.
        • Suzuki K.
        • Marson L.
        • Pedersen C.A.
        Immunohistochemical localization of oxytocin receptors in human brain.
        Neuroscience. 2013; 253: 155-164
        • Keyes K.M.
        • Pratt C.
        • Galea S.
        • McLaughlin K.A.
        • Koenen K.C.
        • Shear M.K.
        The burden of loss: Unexpected death of a loved one and psychiatric disorders across the life course in a national study.
        Am J Psychiatry. 2014; 171: 864-871
        • Donaldson Z.R.
        • Young L.J.
        Oxytocin, vasopressin, and the neurogenetics of sociality.
        Science. 2008; 322: 900-904
        • Garrison J.L.
        • Macosko E.Z.
        • Bernstein S.
        • Pokala N.
        • Albrecht D.R.
        • Bargmann C.I.
        Oxytocin/vasopressin-related peptides have an ancient role in reproductive behavior.
        Science. 2012; 338: 540-543
        • Klatt J.D.
        • Goodson J.L.
        Oxytocin-like receptors mediate pair bonding in a socially monogamous songbird.
        Proc Biol Sci. 2013; 280: 20122396
        • Oldfield R.G.
        • Hofmann H.A.
        Neuropeptide regulation of social behavior in a monogamous cichlid fish.
        Physiol Behav. 2011; 102: 296-303
        • Young K.A.
        • Gobrogge K.L.
        • Liu Y.
        • Wang Z.
        The neurobiology of pair bonding: Insights from a socially monogamous rodent.
        Front Neuroendocrinol. 2011; 32: 53-69
        • Young L.J.
        • Wang Z.
        The neurobiology of pair bonding.
        Nat Neurosci. 2004; 7: 1048-1054
        • Wang Z.
        • Zhou L.
        • Hulihan T.J.
        • Insel T.R.
        Immunoreactivity of central vasopressin and oxytocin pathways in microtine rodents: A quantitative comparative study.
        J Comp Neurol. 1996; 366: 726-737
        • Shapiro L.E.
        • Insel T.R.
        Oxytocin receptor distribution reflects social organization in monogamous and polygamous voles.
        Ann N Y Acad Sci. 1992; 652: 448-451
        • Young L.J.
        • Lim M.M.
        • Gingrich B.
        • Insel T.R.
        Cellular mechanisms of social attachment.
        Horm Behav. 2001; 40: 133-138
        • Aragona B.J.
        • Liu Y.
        • Yu Y.J.
        • Curtis J.T.
        • Detwiler J.M.
        • Insel T.R.
        • Wang Z.
        Nucleus accumbens dopamine differentially mediates the formation and maintenance of monogamous pair bonds.
        Nat Neurosci. 2006; 9: 133-139
        • Johnson Z.V.
        • Young L.J.
        Neurobiological mechanisms of social attachment and pair bonding.
        Curr Opin Behav Sci. 2015; 3: 38-44
        • Lim M.M.
        • Wang Z.
        • Olazabal D.E.
        • Ren X.
        • Terwilliger E.F.
        • Young L.J.
        Enhanced partner preference in a promiscuous species by manipulating the expression of a single gene.
        Nature. 2004; 429: 754-757
        • Bosch O.J.
        • Neumann I.D.
        Both oxytocin and vasopressin are mediators of maternal care and aggression in rodents: From central release to sites of action.
        Horm Behav. 2012; 61: 293-303
        • Insel T.R.
        • Harbaugh C.R.
        Lesions of the hypothalamic paraventricular nucleus disrupt the initiation of maternal behavior.
        Physiol Behav. 1989; 45: 1033-1041
        • Insel T.R.
        A neurobiological basis of social attachment.
        Am J Psychiatry. 1997; 154: 726-735
        • Rilling J.K.
        • Young L.J.
        The biology of mammalian parenting and its effect on offspring social development.
        Science. 2014; 345: 771-776
        • Marlin B.J.
        • Mitre M.
        • D’Amour J.A.
        • Chao M.V.
        • Froemke R.C.
        Oxytocin enables maternal behaviour by balancing cortical inhibition.
        Nature. 2015; 520: 499-504
        • Champagne F.
        • Diorio J.
        • Sharma S.
        • Meaney M.J.
        Naturally occurring variations in maternal behavior in the rat are associated with differences in estrogen-inducible central oxytocin receptors.
        Proc Natl Acad Sci U S A. 2001; 98: 12736-12741
        • Nagasawa M.
        • Mitsui S.
        • En S.
        • Ohtani N.
        • Ohta M.
        • Sakuma Y.
        • et al.
        Social evolution. Oxytocin-gaze positive loop and the coevolution of human-dog bonds.
        Science. 2015; 348: 333-336
        • Crockford C.
        • Wittig R.M.
        • Langergraber K.
        • Ziegler T.E.
        • Zuberbuhler K.
        • Deschner T.
        Urinary oxytocin and social bonding in related and unrelated wild chimpanzees.
        Proc Biol Sci. 2013; 280: 20122765
        • Grippo A.J.
        • Gerena D.
        • Huang J.
        • Kumar N.
        • Shah M.
        • Ughreja R.
        • Carter C.S.
        Social isolation induces behavioral and neuroendocrine disturbances relevant to depression in female and male prairie voles.
        Psychoneuroendocrinology. 2007; 32: 966-980
        • Grippo A.J.
        • Pournajafi-Nazarloo H.
        • Sanzenbacher L.
        • Trahanas D.M.
        • McNeal N.
        • Clarke D.A.
        • et al.
        Peripheral oxytocin administration buffers autonomic but not behavioral responses to environmental stressors in isolated prairie voles.
        Stress. 2012; 15: 149-161
        • Bosch O.J.
        • Nair H.P.
        • Ahern T.H.
        • Neumann I.D.
        • Young L.J.
        The CRF system mediates increased passive stress-coping behavior following the loss of a bonded partner in a monogamous rodent.
        Neuropsychopharmacology. 2009; 34: 1406-1415
        • Feldman R.
        • Weller A.
        • Zagoory-Sharon O.
        • Levine A.
        Evidence for a neuroendocrinological foundation of human affiliation: Plasma oxytocin levels across pregnancy and the postpartum period predict mother-infant bonding.
        Psychol Sci. 2007; 18: 965-970
        • Gordon I.
        • Zagoory-Sharon O.
        • Leckman J.F.
        • Feldman R.
        Oxytocin and the development of parenting in humans.
        Biol Psychiatry. 2010; 68: 377-382
        • Strathearn L.
        • Iyengar U.
        • Fonagy P.
        • Kim S.
        Maternal oxytocin response during mother-infant interaction: Associations with adult temperament.
        Horm Behav. 2012; 61: 429-435
        • Heim C.
        • Young L.J.
        • Newport D.J.
        • Mletzko T.
        • Miller A.H.
        • Nemeroff C.B.
        Lower CSF oxytocin concentrations in women with a history of childhood abuse.
        Mol Psychiatry. 2009; 14: 954-958
        • Wismer Fries A.B.
        • Ziegler T.E.
        • Kurian J.R.
        • Jacoris S.
        • Pollak S.D.
        Early experience in humans is associated with changes in neuropeptides critical for regulating social behavior.
        Proc Natl Acad Sci U S A. 2005; 102: 17237-17240
        • Young S.N.
        • Anderson G.N.
        Bioanalytical inaccuracy: A threat to the integrity and efficiency of research.
        J Psychiatry Neurosci. 2010; 35: 3-6
        • Bick J.
        • Dozier M.
        Mothers’ and children’s concentrations of oxytocin following close, physical interactions with biological and non-biological children.
        Dev Psychobiol. 2010; 52: 100-107
        • Feldman R.
        • Gordon I.
        • Zagoory-Sharon O.
        Maternal and paternal plasma, salivary, and urinary oxytocin and parent-infant synchrony: Considering stress and affiliation components of human bonding.
        Dev Sci. 2011; 14: 752-761
        • Bakermans-Kranenburg M.J.
        • van Ijzendoorn M.H.
        Oxytocin receptor (OXTR) and serotonin transporter (5-HTT) genes associated with observed parenting.
        Soc Cogn Affect Neurosci. 2008; 3: 128-134
        • Klahr A.M.
        • Klump K.
        • Burt S.A.
        A constructive replication of the association between the oxytocin receptor genotype and parenting.
        J Fam Psychol. 2014; 29: 91-99
        • Chen F.S.
        • Barth M.E.
        • Johnson S.L.
        • Gotlib I.H.
        • Johnson S.C.
        Oxytocin receptor (OXTR) polymorphisms and attachment in human infants.
        Front Psychol. 2011; 2: 200
        • Apter-Levy Y.
        • Feldman M.
        • Vakart A.
        • Ebstein R.P.
        • Feldman R.
        Impact of maternal depression across the first 6 years of life on the child’s mental health, social engagement, and empathy: The moderating role of oxytocin.
        Am J Psychiatry. 2013; 170: 1161-1168
        • Mesquita A.R.
        • Soares I.
        • Roisman G.I.
        • Ijzendoorn M.
        • Bakermans-Kranenburg M.
        • Luijk M.
        • et al.
        Predicting children’s attachment behaviors from the interaction between oxytocin and glucocorticoid receptors polymorphisms.
        Psychiatry Res. 2013; 210: 1322-1323
        • Connelly J.J.
        • Golding J.
        • Gregory S.P.
        • Ring S.M.
        • Davis J.M.
        • Davey Smith G.
        • et al.
        Personality, behavior and environmental features associated with OXTR genetic variants in British mothers.
        PloS One. 2014; 9: e90465
        • Michalska K.J.
        • Decety J.
        • Liu C.
        • Chen Q.
        • Martz M.E.
        • Jacob S.
        • et al.
        Genetic imaging of the association of oxytocin receptor gene (OXTR) polymorphisms with positive maternal parenting.
        Front Behav Neurosci. 2014; 8: 21
        • Bradley B.
        • Davis T.A.
        • Wingo A.P.
        • Mercer K.B.
        • Ressler K.J.
        Family environment and adult resilience: Contributions of positive parenting and the oxytocin receptor gene.
        Eur J Psychotraumatol. 2013; 4
        • Bradley B.
        • Westen D.
        • Mercer K.B.
        • Binder E.B.
        • Jovanovic T.
        • Crain D.
        • et al.
        Association between childhood maltreatment and adult emotional dysregulation in a low-income, urban, African American sample: Moderation by oxytocin receptor gene.
        Dev Psychopathol. 2011; 23: 439-452
        • Striepens N.
        • Kendrick K.M.
        • Hanking V.
        • Landgraf R.
        • Wullner U.
        • Maier W.
        • Hurlemann R.
        Elevated cerebrospinal fluid and blood concentrations of oxytocin following its intranasal administration in humans.
        Sci Rep. 2013; 3: 3440
        • Buchheim A.
        • Heinrichs M.
        • George C.
        • Pokorny D.
        • Koops E.
        • Henningsen P.
        • et al.
        Oxytocin enhances the experience of attachment security.
        Psychoneuroendocrinology. 2009; 34: 1417-1422
        • Naber F.
        • van Ijzendoorn M.H.
        • Deschamps P.
        • van Engeland H.
        • Bakermans-Kranenburg M.J.
        Intranasal oxytocin increases fathers’ observed responsiveness during play with their children: A double-blind within-subject experiment.
        Psychoneuroendocrinology. 2010; 35: 1583-1586
        • Weisman O.
        • Zagoory-Sharon O.
        • Feldman R.
        Oxytocin administration to parent enhances infant physiological and behavioral readiness for social engagement.
        Biol Psychiatry. 2012; 72: 982-989
        • Weisman O.
        • Delaherche E.
        • Rondeau M.
        • Chetouani M.
        • Cohen D.
        • Feldman R.
        Oxytocin shapes parental motion during father-infant interaction.
        Biol Lett. 2013; 9: 20130828
        • Wittfoth-Schardt D.
        • Grunding J.
        • Wittfoth M.
        • Lanfermann H.
        • Heinrichs M.
        • Domes G.
        • et al.
        Oxytocin modulates neural reactivity to children’s faces as a function of social salience.
        Neuropsychopharmacology. 2012; 37: 1799-1807
        • Riem M.M.
        • Bakermans-Kranenburg M.J.
        • Pieper S.
        • Tops M.
        • Boksem M.A.
        • Vermeiren R.R.
        • et al.
        Oxytocin modulates amygdala, insula, and inferior frontal gyrus responses to infant crying: A randomized controlled trial.
        Biol Psychiatry. 2011; 70: 291-297
        • Riem M.M.
        • van IJzendoorn M.H.
        • Tops M.
        • Boksem M.A.
        • Rombouts S.A.
        • Bakermans-Kranenburg M.J.
        No laughing matter: Intranasal oxytocin administration changes functional brain connectivity during exposure to infant laughter.
        Neuropsychopharmacology. 2012; 37: 1257-1266
        • Bartz J.A.
        • Zaki J.
        • Ochsner K.N.
        • Bolger N.
        • Kolevzon A.
        • Ludwig N.
        • Lydon J.E.
        Effects of oxytocin on recollections of maternal care and closeness.
        Proc Natl Acad Sci U S A. 2010; 107: 21371-21375
        • Bakermans-Kranenburg M.J.
        • van Ijzendoorn M.H.
        • Riem M.M.
        • Tops M.
        • Alink L.R.
        Oxytocin decreases handgrip force in reaction to infant crying in females without harsh parenting experiences.
        Soc Cogn Affect Neurosci. 2012; 7: 951-957
        • Schneiderman I.
        • Zagoory-Sharon O.
        • Leckman J.F.
        • Feldman R.
        Oxytocin during the initial stages of romantic attachment: Relations to couples’ interactive reciprocity.
        Psychoneuroendocrinology. 2012; 37: 1277-1285
        • Schneiderman I.
        • Kanat-Maymon Y.
        • Zagoory-Sharon O.
        • Feldman R.
        Mutual influences between partners’ hormones shape conflict dialog and relationship duration at the initiation of romantic love.
        Soc Neurosci. 2014; 9: 337-351
        • Gouin J.P.
        • Carter C.S.
        • Pournajafi-Nazarloo H.
        • Glaser R.
        • Malarkey W.B.
        • Loving T.J.
        • et al.
        Marital behavior, oxytocin, vasopressin, and wound healing.
        Psychoneuroendocrinology. 2010; 35: 1082-1090
        • Gonzaga G.C.
        • Turner R.A.
        • Keltner D.
        • Campos B.
        • Altemus M.
        Romantic love and sexual desire in close relationships.
        Emotion. 2006; 6: 163-179
        • Grewen K.M.
        • Girdler S.S.
        • Amico J.
        • Light K.C.
        Effects of partner support on resting oxytocin, cortisol, norepinephrine, and blood pressure before and after warm partner contact.
        Psychosom Med. 2005; 67: 531-538
        • Light K.C.
        • Grewen K.M.
        • Amico J.A.
        More frequent partner hugs and higher oxytocin levels are linked to lower blood pressure and heart rate in premenopausal women.
        Biol Psychol. 2005; 69: 5-21
        • Turner R.A.
        • Altemus M.
        • Enos T.
        • Cooper B.
        • McGuinness T.
        Preliminary research on plasma oxytocin in normal cycling women: Investigating emotion and interpersonal distress.
        Psychiatry. 1999; 62: 97-113
        • Wikstrom S.
        • Gunnarsson T.
        • Nordin C.
        Tactile stimulus and neurohormonal response: A pilot study.
        Int J Neurosci. 2003; 113: 787-793
        • Billhult A.
        • Lindholm C.
        • Gunnarsson R.
        • Stener-Victorin E.
        The effect of massage on cellular immunity, endocrine and psychological factors in women with breast cancer -- a randomized controlled clinical trial.
        Auton Neurosci. 2008; 140: 88-95
        • Rapaport M.H.
        • Schettler P.
        • Bresee C.
        A Preliminary study of the effects of a single session of Swedish massage on hypothalamic-pituitary-adrenal and immune function in normal individuals.
        J Altern Complement Med. 2010; 16: 1079-1088
        • Morhenn V.B.
        • Park J.W.
        • Piper E.
        • Zak P.J.
        Monetary sacrifice among strangers is mediated by endogenous oxytocin release after physical contact.
        Evol Hum Behav. 2008; 29: 375-383
        • Morhenn V.
        • Beavin L.E.
        • Zak P.J.
        Massage increases oxytocin and reduces adrenocorticotropin hormone in humans.
        Altern Ther Health Med. 2012; 18: 11-18
        • Ogawa S.
        • Kudo S.
        • Kitsunai Y.
        • Fukuchi S.
        Increase in oxytocin secretion at ejaculation in male.
        Clin Endocrinol (Oxf). 1980; 13: 95-97
        • Carmichael M.S.
        • Warburton V.L.
        • Dixen J.
        • Davidson J.M.
        Relationships among cardiovascular, muscular, and oxytocin responses during human sexual activity.
        Arch Sex Behav. 1994; 23: 59-79
        • Murphy M.R.
        • Checkley S.A.
        • Seckl J.R.
        • Lightman S.L.
        Naloxone inhibits oxytocin release at orgasm in man.
        J Clin Endocrinol Metab. 1990; 71: 1056-1058
        • Blaicher W.
        • Gruber D.
        • Bieglmayer C.
        • Blaicher A.M.
        • Knogler W.
        • Huber J.C.
        The role of oxytocin in relation to female sexual arousal.
        Gynecol Obstet Invest. 1999; 47: 125-126
        • Kruger T.H.
        • Schiffer B.
        • Eikermann M.
        • Haake P.
        • Gizewski E.
        • Schedlowski M.
        Serial neurochemical measurement of cerebrospinal fluid during the human sexual response cycle.
        Eur J Neurosci. 2006; 24: 3445-3452
        • Marazziti D.
        • Dell’Osso B.
        • Baroni S.
        • Mungai F.
        • Catena M.
        • Rucci P.
        • et al.
        A relationship between oxytocin and anxiety of romantic attachment.
        Clin Pract Epidemiol Ment Health. 2006; 2: 28
        • Taylor S.E.
        • Gonzaga G.C.
        • Klein L.C.
        • Hu P.
        • Greendale G.A.
        • Seeman T.E.
        Relation of oxytocin to psychological stress responses and hypothalamic-pituitary-adrenocortical axis activity in older women.
        Psychosom Med. 2006; 68: 238-245
        • Taylor S.E.
        Tend and befriend: Biobehavioral bases of affiliation under stress.
        Curr Dir Psychol Sci. 2006; 15: 273-277
        • Tabak B.A.
        • McCullough M.E.
        • Szeto A.
        • Mendez A.J.
        • McCabe P.M.
        Oxytocin indexes relational distress following interpersonal harms in women.
        Psychoneuroendocrinology. 2011; 36: 115-122
        • McCullough M.E.
        • Churchland P.S.
        • Mendez A.J.
        Problems with measuring peripheral oxytocin: Can the data on oxytocin and human behavior be trusted?.
        Neurosci Biobehav Rev. 2013; 37: 1485-1492
        • Kagerbauer S.M.
        • Martin J.
        • Schuster T.
        • Blobner M.
        • Kochs E.F.
        • Landgraf R.
        Plasma oxytocin and vasopressin do not predict neuropeptide concentrations in human cerebrospinal fluid.
        J Neuroendocrinol. 2013; 25: 668-673
        • Knobloch H.S.
        • Charlet A.
        • Hoffmann L.C.
        • Eliava M.
        • Khrulev S.
        • Cetin A.H.
        • et al.
        Evoked axonal oxytocin release in the central amygdala attenuates fear response.
        Neuron. 2012; 73: 553-566
        • Gimpl G.
        • Fahrenholz F.
        The oxytocin receptor system: Structure, function, and regulation.
        Physiol Rev. 2001; 81: 629-683
        • Walum H.
        • Lichtenstein P.
        • Neiderhiser J.M.
        • Reiss D.
        • Ganiban J.M.
        • Spotts E.L.
        • et al.
        Variation in the oxytocin receptor gene is associated with pair-bonding and social behavior.
        Biol Psychiatry. 2012; 71: 419-426
        • Schneiderman I.
        • Kanat-Maymon Y.
        • Ebstein R.P.
        • Feldman R.
        Cumulative risk on the oxytocin receptor gene (OXTR) underpins empathic communication difficulties at the first stages of romantic love.
        Soc Cogn Affect Neurosci. 2013; 9: 1524-1529
        • Ditzen B.
        • Schaer M.
        • Gabriel B.
        • Bodenmann G.
        • Ehlert U.
        • Heinrichs M.
        Intranasal oxytocin increases positive communication and reduces cortisol levels during couple conflict.
        Biol Psychiatry. 2009; 65: 728-731
        • Ditzen B.
        • Nater U.M.
        • Schaer M.
        • La Marca R.
        • Bodenmann G.
        • Ehlert U.
        • Heinrichs M.
        Sex-specific effects of intranasal oxytocin on autonomic nervous system and emotional responses to couple conflict.
        Soc Cogn Affect Neurosci. 2012; 8: 897-902
        • Unkelbach C.
        • Guastella A.J.
        • Forgas J.P.
        Oxytocin selectively facilitates recognition of positive sex and relationship words.
        Psychol Sci. 2008; 19: 1092-1094
        • Burri A.
        • Heinrichs M.
        • Schedlowski M.
        • Kruger T.H.
        The acute effects of intranasal oxytocin administration on endocrine and sexual function in males.
        Psychoneuroendocrinology. 2008; 33: 591-600
        • Behnia B.
        • Heinrichs M.
        • Bergmann W.
        • Jung S.
        • Germann J.
        • Schedlowski M.
        • et al.
        Differential effects of intranasal oxytocin on sexual experiences and partner interactions in couples.
        Horm Behav. 2014; 65: 308-318
        • Singer T.
        • Snozzi R.
        • Bird G.
        • Petrovic P.
        • Silani G.
        • Heinrichs M.
        • Dolan R.J.
        Effects of oxytocin and prosocial behavior on brain responses to direct and vicariously experienced pain.
        Emotion. 2008; 8: 781-791
        • Liu J.C.
        • Guastella A.J.
        • Dadds M.R.
        Exploring the role of intra-nasal oxytocin on the partner preference effect in humans.
        Psychoneuroendocrinology. 2013; 38: 587-591
        • Scheele D.
        • Striepens N.
        • Güntürkün O.
        • Deutschlander S.
        • Maier W.
        • Kendrick K.M.
        • Hurlemann R.
        Oxytocin modulates social distance between males and females.
        J Neurosci. 2012; 32: 16074-16079
        • Bartels A.
        • Zeki S.
        The neural correlates of maternal and romantic love.
        Neuroimage. 2004; 21: 1155-1166
        • Acevedo B.P.
        • Aron A.
        • Fisher H.E.
        • Brown L.L.
        Neural correlates of long-term intense romantic love.
        Soc Cogn Affect Neurosci. 2012; 7: 145-159
        • Scheele D.
        • Wille A.
        • Kendrick K.M.
        • Stoffel-Wagner B.
        • Becker B.
        • Güntürkün O.
        • et al.
        Oxytocin enhances brain reward system responses in men viewing the face of their female partner.
        Proc Natl Acad Sci U S A. 2013; 110: 20308-20313
        • Younger J.
        • Aron A.
        • Parke S.
        • Chatterjee N.
        • Mackey S.
        Viewing pictures of a romantic partner reduces experimental pain: Involvement of neural reward systems.
        PloS One. 2010; 5: e13309
        • Zunhammer M.
        • Geis S.
        • Busch V.
        • Greenlee M.W.
        • Eichhammer P.
        Effects of intranasal oxytocin on thermal pain in healthy men: A randomized functional magnetic resonance imaging study.
        Psychosom Med. 2015; 77: 156-166
        • Preckel K.
        • Scheele D.
        • Eckstein M.
        • Maier W.
        • Hurlemann R.
        The influence of oxytocin on volitional and emotional ambivalence.
        Soc Cogn Affect Neurosci. 2015; 10: 987-993
        • Liu Y.
        • Wang Z.X.
        Nucleus accumbens oxytocin and dopamine interact to regulate pair bond formation in female prairie voles.
        Neuroscience. 2003; 121: 537-544
        • Striepens N.
        • Matusch A.
        • Kendrick K.M.
        • Mihov Y.
        • Elmenhorst D.
        • Becker B.
        • et al.
        Oxytocin enhances attractiveness of unfamiliar female faces independent of the dopamine reward system.
        Psychoneuroendocrinology. 2014; 39: 74-87
        • Theodoridou A.
        • Rowe A.C.
        • Penton-Voak I.S.
        • Rogers P.J.
        Oxytocin and social perception: Oxytocin increases perceived facial trustworthiness and attractiveness.
        Horm Behav. 2009; 56: 128-132
        • Dolen G.
        • Darvishzadeh A.
        • Huang K.W.
        • Malenka R.C.
        Social reward requires coordinated activity of nucleus accumbens oxytocin and serotonin.
        Nature. 2013; 501: 179-184
        • Mottolese R.
        • Redoute J.
        • Costes N.
        • Le Bars D.
        • Sirigu A.
        Switching brain serotonin with oxytocin.
        Proc Natl Acad Sci U S A. 2014; 111: 8637-8642
        • Rupp H.A.
        • James T.W.
        • Ketterson E.D.
        • Sengelaub D.R.
        • Ditzen B.
        • Heiman J.R.
        Lower sexual interest in postpartum women: Relationship to amygdala activation and intranasal oxytocin.
        Horm Behav. 2013; 63: 114-121
        • Gregory R.
        • Cheng H.
        • Rupp H.A.
        • Sengelaub D.R.
        • Heiman J.R.
        Oxytocin increases VTA activation to infant and sexual stimuli in nulliparous and postpartum women.
        Horm Behav. 2015; 69C: 82-88
        • DeWall C.N.
        • Gillath O.
        • Pressman S.D.
        • Black L.L.
        • Bartz J.A.
        • Moskovitz J.
        • et al.
        When the love hormone leads to violence: Oxytocin increases intimate partner violence inclinations among high trait aggressive people.
        Soc Psychol Persononal Sci. 2014; 5: 691-697
        • Heinrichs M.
        • Baumgartner T.
        • Kirschbaum C.
        • Ehlert U.
        Social support and oxytocin interact to suppress cortisol and subjective responses to psychosocial stress.
        Biol Psychiatry. 2003; 54: 1389-1398
        • Eckstein M.
        • Becker B.
        • Scheele D.
        • Scholz C.
        • Preckel K.
        • Schlaepfer T.
        • et al.
        Oxytocin facilitates the extinction of conditioned fear in humans.
        Biol Psychiatry. 2014; 78: 194-202
        • Striepens N.
        • Scheele D.
        • Kendrick K.M.
        • Becker B.
        • Schafer L.
        • Schwalba K.
        • et al.
        Oxytocin facilitates protective responses to aversive social stimuli in males.
        Proc Natl Acad Sci U S A. 2012; 109: 18144-18149
        • Eckstein M.
        • Scheele D.
        • Weber K.
        • Stoffel-Wagner B.
        • Maier W.
        • Hurlemann R.
        Oxytocin facilitates the sensation of social stress.
        Hum Brain Mapp. 2014; 35: 4741-4750
        • Churchland P.S.
        • Winkielman P.
        Modulating social behavior with oxytocin: How does it work?.
        What does it mean? Horm Behav. 2012; 61: 392-399
        • Bartz J.A.
        • Zaki J.
        • Bolger N.
        • Ochsner K.N.
        Social effects of oxytocin in humans: Context and person matter.
        Trends Cogn Sci. 2011; 15: 301-309
        • Preckel K.
        • Scheele D.
        • Kendrick K.M.
        • Maier W.
        • Hurlemann R.
        Oxytocin facilitates social approach behavior in women.
        Front Behav Neurosci. 2014; 8: 191
        • Scheele D.
        • Striepens N.
        • Kendrick K.M.
        • Schwering C.
        • Noelle J.
        • Wille A.
        • et al.
        Opposing effects of oxytocin on moral judgment in males and females.
        Hum Brain Mapp. 2014; 35: 6067-6076
        • Scheele D.
        • Kendrick K.M.
        • Khouri C.
        • Kretzer E.
        • Schlapfer T.E.
        • Stoffel-Wagner B.
        • et al.
        An oxytocin-induced facilitation of neural and emotional responses to social touch correlates inversely with autism traits.
        Neuropsychopharmacology. 2014; 39: 2078-2085
        • Craig A.D.
        How do you feel--now? The anterior insula and human awareness.
        Nat Rev Neurosci. 2009; 10: 59-70
        • Lou H.C.
        • Luber B.
        • Crupain M.
        • Keenan J.P.
        • Nowak M.
        • Kjaer T.W.
        • et al.
        Parietal cortex and representation of the mental Self.
        Proc Natl Acad Sci U S A. 2004; 101: 6827-6832
        • Voos A.C.
        • Pelphrey K.A.
        • Kaiser M.D.
        Autistic traits are associated with diminished neural response to affective touch.
        Soc Cogn Affect Neurosci. 2013; 8: 378-386
        • Quattrocki E.
        • Friston K.
        Autism, oxytocin and interoception.
        Neurosci Biobehav Rev. 2014; 47: 410-430
        • Colonnello V.
        • Chen F.S.
        • Panksepp J.
        • Heinrichs M.
        Oxytocin sharpens self-other perceptual boundary.
        Psychoneuroendocrinology. 2013; 38: 2996-3002
        • Cardoso C.
        • Ellenbogen M.A.
        • Linnen A.M.
        Acute intranasal oxytocin improves positive self-perceptions of personality.
        Psychopharmacology (Berl). 2012; 220: 741-749
        • Colonnello V.
        • Heinrichs M.
        Intranasal oxytocin enhances positive self-attribution in healthy men.
        J Psychosom Res. 2014; 77: 415-419
        • Domes G.
        • Heinrichs M.
        • Michel A.
        • Berger C.
        • Herpertz S.C.
        Oxytocin improves “mind-reading” in humans.
        Biol Psychiatry. 2007; 61: 731-733
        • Hurlemann R.
        • Patin A.
        • Onur O.A.
        • Cohen M.X.
        • Baumgartner T.
        • Metzler S.
        • et al.
        Oxytocin enhances amygdala-dependent, socially reinforced learning and emotional empathy in humans.
        J Neurosci. 2010; 30: 4999-5007
        • Ernst J.
        • Northoff G.
        • Boker H.
        • Seifritz E.
        • Grimm S.
        Interoceptive awareness enhances neural activity during empathy.
        Hum Brain Mapp. 2013; 34: 1615-1624
        • Aron A.
        • Fraley B.
        Relationship closeness as including other in the self: Cognitive underpinnings and measures.
        Soc Cogn. 1999; 17: 140-160
        • Krienen F.M.
        • Tu P.C.
        • Buckner R.L.
        Clan mentality: Evidence that the medial prefrontal cortex responds to close others.
        J Neurosci. 2010; 30: 13906-13915
        • De Dreu C.K.
        • Greer L.L.
        • Handgraaf M.J.
        • Shalvi S.
        • Van Kleef G.A.
        • Baas M.
        • et al.
        The neuropeptide oxytocin regulates parochial altruism in intergroup conflict among humans.
        Science. 2010; 328: 1408-1411
        • De Dreu C.K.
        • Greer L.L.
        • Van Kleef G.A.
        • Shalvi S.
        • Handgraaf M.J.
        Oxytocin promotes human ethnocentrism.
        Proc Natl Acad Sci U S A. 2011; 108: 1262-1266
        • Macdonald K.
        • Macdonald T.M.
        • Brune M.
        • Lamb K.
        • Wilson M.P.
        • Golshan S.
        • Feifel D.
        Oxytocin and psychotherapy: A pilot study of its physiological, behavioral and subjective effects in males with depression.
        Psychoneuroendocrinology. 2013; 38: 2831-2843
        • Najib A.
        • Lorberbaum J.P.
        • Kose S.
        • Bohning D.E.
        • George M.S.
        Regional brain activity in women grieving a romantic relationship breakup.
        Am J Psychiatry. 2004; 161: 2245-2256
        • O’Connor M.F.
        • Wellisch D.K.
        • Stanton A.L.
        • Eisenberger N.I.
        • Irwin M.R.
        • Lieberman M.D.
        Craving love? Enduring grief activates brain’s reward center.
        Neuroimage. 2008; 42: 969-972
        • Kersting A.
        • Ohrmann P.
        • Pedersen A.
        • Kroker K.
        • Samberg D.
        • Bauer J.
        • et al.
        Neural activation underlying acute grief in women after the loss of an unborn child.
        Am J Psychiatry. 2009; 166: 1402-1410
        • Cole M.G.
        • Dendukuri N.
        Risk factors for depression among elderly community subjects: A systematic review and meta-analysis.
        Am J Psychiatry. 2003; 160: 1147-1156
        • Prigerson H.G.
        • Frank E.
        • Kasl S.V.
        • Reynolds 3rd, C.F.
        • Anderson B.
        • Zubenko G.S.
        • et al.
        Complicated grief and bereavement-related depression as distinct disorders: Preliminary empirical validation in elderly bereaved spouses.
        Am J Psychiatry. 1995; 152: 22-30
        • Burkett J.P.
        • Young L.J.
        The behavioral, anatomical and pharmacological parallels between social attachment, love and addiction.
        Psychopharmacology (Berl). 2012; 224: 1-26
        • McRae-Clark A.L.
        • Baker N.L.
        • Maria M.M.
        • Brady K.T.
        Effect of oxytocin on craving and stress response in marijuana-dependent individuals: A pilot study.
        Psychopharmacology (Berl). 2013; 228: 623-631
        • Pedersen C.A.
        • Smedley K.L.
        • Leserman J.
        • Jarskog L.F.
        • Rau S.W.
        • Kampov-Polevoi A.
        • et al.
        Intranasal oxytocin blocks alcohol withdrawal in human subjects.
        Alcohol Clin Exp Res. 2013; 37: 484-489
        • Shahrestani S.
        • Kemp A.H.
        • Guastella A.J.
        The impact of a single administration of intranasal oxytocin on the recognition of basic emotions in humans: A meta-analysis.
        Neuropsychopharmacology. 2013; 38: 1929-1936
        • Caria A.
        • de Falco S.
        Anterior insular cortex regulation in autism spectrum disorders.
        Front Behav Neurosci. 2015; 9: 38
        • Birkett M.A.
        • Shinday N.M.
        • Kessler E.J.
        • Meyer J.S.
        • Ritchie S.
        • Rowlett J.K.
        Acute anxiogenic-like effects of selective serotonin reuptake inhibitors are attenuated by the benzodiazepine diazepam in BALB/c mice.
        Pharmacol Biochem Behav. 2011; 98: 544-551
        • Bales K.L.
        • Perkeybile A.M.
        • Conley O.G.
        • Lee M.H.
        • Guoynes C.D.
        • Downing G.M.
        • et al.
        Chronic intranasal oxytocin causes long-term impairments in partner preference formation in male prairie voles.
        Biol Psychiatry. 2013; 74: 180-188
        • Huang H.
        • Michetti C.
        • Busnelli M.
        • Manago F.
        • Sannino S.
        • Scheggia D.
        • et al.
        Chronic and acute intranasal oxytocin produce divergent social effects in mice.
        Neuropsychopharmacology. 2014; 39: 1102-1114
        • Barraza J.A.
        • Grewal N.S.
        • Ropacki S.
        • Perez P.
        • Gonzalez A.
        • Zak P.J.
        Effects of a 10-day oxytocin trial in older adults on health and well-being.
        Exp Clin Psychopharmacol. 2013; 21: 85-92
        • Bales K.L.
        • van Westerhuyzen J.A.
        • Lewis-Reese A.D.
        • Grotte N.D.
        • Lanter J.A.
        • Carter C.S.
        Oxytocin has dose-dependent developmental effects on pair-bonding and alloparental care in female prairie voles.
        Horm Behav. 2007; 52: 274-279
        • Cardoso C.
        • Ellenbogen M.A.
        • Orlando M.A.
        • Bacon S.L.
        • Joober R.
        Intranasal oxytocin attenuates the cortisol response to physical stress: A dose-response study.
        Psychoneuroendocrinology. 2013; 38: 399-407