Oxytocin and the Psyche. Summary of Data.

Effects of stimulation of C-tactile afferents or other influences on the oxytocin system. Effects of oxytocin on the sensitivity of the C-tactile system, on other physiological characteristics, on affective responses and affiliativeness - a person’s need to create warm, trusting, emotionally meaningful relationships with other people, and on character and social behavior.

(this collection of references integrates our own analysis of the literature and the results of several recent reviews of the oxytocin literature that are among the most popular in the scientific community and are listed in the references)

Oxytocin and Its Receptors. Basic Properties.

Oxytocin (OT) and the closely related peptide hormone vasopressin (VP) are among the oldest mammalian hormones and are considered central to human evolution ( Robinson et al., 2019 ).

1. Robinson K. J., Bosch O. J., Levkowitz G., Busch K. E., Jarman A. P., Ludwig M. (2019). Social creatures: model animal systems for studying the neuroendocrine mechanisms of social behaviour. J. Neuroendocrinol. 31:e12807. 10.1111/jne.12807

General information on the organization of the network of oxytocin influence in the body:

OT has a dual function, both as a hormone and as a neurotransmitter. Its hormonal effects are manifested through magnocellular neurons of the paraventricular nucleus and supraoptic nucleus, which project to the neurohypophysis, from which oxytocin is released into the bloodstream, where it mediates the classically known effects of OT on uterine contraction during childbirth and milk ejection during breastfeeding. However, magnocellular neurons are also supplied with axon collaterals that reach other regulatory parts of the brain, including the frontal cortex. the amygdala and anterior pituitary, where OT acts as a neurotransmitter. Parvocellular OT neurons originating from the paraventricular nucleus also contribute to the neurotransmitter function of OT through their projections to many different cortical, limbic, and brainstem regions (Uvnäs-Moberg, 2015). Under conditions of intense stimulation of OT secretion, when OT is released not only from the axons of OT-producing neurons but also from the cell body and dendrites, OT may also exert its effects by diffusion into nearby and even distant parts of the brain to which no OT neurons project but which contain OT receptors ( Ludwig and Leng, 2006 ).

OT production is not limited to the hypothalamus; it has also been found to occur in the uterus, ovaries, amniotic fluid, placenta, heart, blood vessels, gastrointestinal tract, testes, kidneys, and thymus, where it exerts local (paracrine) effects. ( Gimpl and Fahrenholz, 2001 ).

OT performs its functions by binding to identical oxytocin receptors (OTR) present both in the brain and in peripheral organs (uterus, mammary glands, kidneys, stomach, heart, blood vessels). In experiments, blocking uterine-type OT receptors with antagonists does not abolish all effects induced by OT, so additional, as yet unidentified OT receptors may evidently also exist. In addition, elongated OT preoxytocin molecules ( Amico and Hempel, 1990 ; Green et al., 2001 ), as well as OT degradation products, may also produce specific effects by binding to such unidentified OT receptors or by binding to opioid receptors and alpha-2-adrenoceptors ( Uvnäs-Moberg, 2015; Uvnäs Moberg et al., 2019 ).

The OT network, consisting of both OTergic neurons and OTR, is capable of undergoing dynamic changes, not least during early life, through a complex interaction between the caregiving environment (grooming, animals’ care of themselves and other individuals) and genetic susceptibility to this caregiving environment ( Toepfer et al., 2017 ).

1. Amico J. A., Hempel J. (1990). An oxytocin precursor intermediate circulates in the plasma of humans and rhesus monkeys administered estrogen. Neuroendocrinology 51 437–443. 10.1159/000125371 https://www.ncbi.nlm.nih.gov/pubmed/2111891

2. Gimpl G., Fahrenholz F. (2001). The oxytocin receptor system: Structure, function, and regulation. Physiol. Rev. 81 629–683. 10.1152/physrev.2001.81.2.629 https://www.ncbi.nlm.nih.gov/pubmed/11274341

3. Green L., Fein D., Modahl C., Feinstein C., Waterhouse L., Morris M. (2001). Oxytocin and autistic disorder: alterations in peptide forms. Biol. Psychiatry 50 609–613. 10.1016/s0006-3223(01)01139-8 https://www.ncbi.nlm.nih.gov/pubmed/11690596

4. Ludwig M., Leng G. (2006). Dendritic peptide release and peptide-dependent behaviours. Nat. Rev. Neurosci. 7 126–136. 10.1038/nrn1845 https://www.ncbi.nlm.nih.gov/pubmed/16429122

5. Toepfer P., Heim C., Entringer S., Binder E., Wadhwa P., Buss C. (2017). Oxytocin pathways in the intergenerational transmission of maternal early life stress. Neurosci. Biobehav. Rev. 73 293–308. 10.1016/j.neubiorev.2016.12.026 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5272812/

6. Uvnäs Moberg K., Handlin L., Kendall-Tackett K., Petersson M. (2019). Oxytocin is a principal hormone that exerts part of its effects by active fragments. Med. Hypotheses 133:109394. 10.1016/j.mehy.2019.109394 https://www.ncbi.nlm.nih.gov/pubmed/31525634

7. Uvnäs-Moberg K. (2015). Oxytocin: The Biological Guide to Motherhood. London: Hale Publishing. https://scholar.google.com/scholar_lookup?title=Oxytocin:+The+Biological+Guide+to+Motherhood.&author=K.+Uvn%C3%A4s-Moberg&publication_year=2015&

Interaction of Oxytocin with Sex Hormones and Glucocorticoids

The number of oxytocin receptors and their binding properties are, of course, of fundamental importance to the effects of oxytocin. However, both sex steroids and glucocorticoids also play an important role here, because both have the ability to influence oxytocin receptor expression as well as the binding of oxytocin to receptors in the brain. Thus, oxytocin release is stimulated by the hormone estrogen.

1. Uvnäs-Moberg K, Handlin L, Petersson M. Self-soothing behaviors with particular reference to oxytocin release induced by non-noxious sensory stimulation. Front Psychol. 2015 Jan 12;5:1529. doi: 10.3389/fpsyg.2014.01529. PMID: 25628581; PMCID: PMC4290532.

Intranasal oxytocin also increases paternal gaze and affectionate touch toward their infants, but only in those whose plasma testosterone level also increases after oxytocin administration ( Weisman et al., 2014 ).

2. Ellingsen DM, Leknes S, Løseth G, Wessberg J, Olausson H. The Neurobiology Shaping Affective Touch: Expectation, Motivation, and Meaning in the Multisensory Context. Front Psychol. 2016 Jan 6;6:1986. doi: 10.3389/fpsyg.2015.01986. PMID: 26779092; PMCID: PMC4701942.

Not all effects mediated by oxytocin are blocked by antagonists directed at the principal uterine-type oxytocin receptor - for example, this applies to some of oxytocin’s anti-stress, growth-promoting, and restorative effects. The reason is that oxytocin is metabolized and broken down into several smaller cyclic and linear oxytocin fragments. Of these, it is specifically the C-terminal fragment that is associated with oxytocin’s calming, anti-stress, and growth-promoting effects ( Petersson et al., 1999c ; Petersson and Uvnäs-Moberg, 2004 ).

1. Petersson M., Lundeberg T., Uvnäs-Moberg K. (1999c). Short-term increase and long-term decrease of blood pressure in response to oxytocin-potentiating effect of female steroid hormones. J. Cardiovasc. Pharmacol. 33, 102–108. 10.1097/00005344-199901000-00015 [PubMed] [CrossRef] [Google Scholar]

2. Petersson M., Uvnäs-Moberg K. (2004). Prolyl-leucyl-glycinamide shares some effects with oxytocin but decreases oxytocin levels. Physiol. Behav. 83, 475–481. 10.1016/j.physbeh.2004.08.034 [PubMed] [CrossRef] [Google Scholar]

Plasma oxytocin levels (pg / ml, mean ± standard deviation) are significantly higher in women than in men (4,53 ± 1,18 versus 1,53 ± 1,19, p 0,001). It is possible that these differences may partly underlie sex differences related to behavior, attitudes, as well as susceptibility to the stress response, resilience, and social emotions.

1. Marazziti D, Baroni S, Mucci F, Piccinni A, Moroni I, Giannaccini G, Carmassi C, Massimetti E, Dell’Osso L. Sex-Related Differences in Plasma Oxytocin Levels in Humans. Clin Pract Epidemiol Ment Health. 2019 Mar 26;15:58-63. doi: 10.2174/1745017901915010058. PMID: 31015856; PMCID: PMC6446474.

Pharmacological Properties of Oxytocin

The half-life of oxytocin in the human circulation is 30 minutes ( De Groot et al., 1995 ). A similar half-life has been demonstrated in cerebrospinal fluid, but in different parts of the brain it may be even longer ( Jones and Robinson, 1982 ). The half-life of oxytocin fragments is unknown, but may be longer than that of the parent molecule. Only a very small amount of oxytocin in the circulation enters the brain across the blood-brain barrier (BBB; <1%), but BBB permeability may increase during stress and in association with certain types of disease. Oxytocin may also be transported across the BBB by certain carrier proteins ( Jones and Robinson, 1982 ).

1. Jones P. M., Robinson I. C. (1982). Differential clearance of neurophysin and neurohypophysial peptides from the cerebrospinal fluid in conscious guinea pigs. Neuroendocrinology 34, 297–302. 10.1159/000123316 [PubMed] [CrossRef] [Google Scholar] https://www.ncbi.nlm.nih.gov/pubmed/7070597

Foci (sites of action) of oxytocin in the brain:

Oxytocin may, for example, produce a sense of well-being by stimulating dopamine release in the nucleus accumbens (NA) ( Insel, 2003 ), increase social interaction and reduce anxiety through actions in the amygdala ( Amico et al., 2004 ), reduce stress responses through actions. in the hypothalamic-pituitary-adrenal axis (HPA axis) ( Petersson et al., 1999b ; Neumann, 2002 ) and by reducing the release of noradrenergic receptors in the locus coeruleus (LC) ( Petersson et al., 1998b ) and the nucleus of the solitary tract (NTS) ( Petersson et al., 2005a ). Oxytocin may also reduce pain sensitivity by increasing opioidergic activity in the periaqueductal gray (PAG) ( Lund et al., 2002).

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2. Amico J. A., Mantella R. C., Vollmer R. R., Li X. (2004). Anxiety and stress responses in female oxytocin deficient mice. J. Neuroendocrinol. 16, 319–324. 10.1111/j.0953-8194.2004.01161.x [PubMed] [CrossRef] [Google Scholar] https://www.ncbi.nlm.nih.gov/pubmed/15089969

3. Petersson M., Hulting A. L., Uvnäs-Moberg K. (1999b). Oxytocin causes a sustained decrease in plasma levels of corticosterone in rats. Neurosci. Lett. 264, 41–44 10.1016/S0304-3940(99)00159-7 [PubMed] [CrossRef] [Google Scholar] https://www.ncbi.nlm.nih.gov/pubmed/10320009

4. Neumann I. D. (2002). Involvement of the brain oxytocin system in stress coping: interactions with the hypothalamo-pituitary-adrenal axis. Prog. Brain Res. 139, 147–162 10.1016/S0079-6123(02)39014-9 [PubMed] [CrossRef] [Google Scholar] https://www.ncbi.nlm.nih.gov/pubmed/12436933

5. Petersson M., Uvnäs-Moberg K., Erhardt S., Engberg G. (1998b). Oxytocin increases locus coeruleus α2-adrenoreceptor responsiveness in rats. Neurosci. Lett. 255, 115–118 10.1016/S0304-3940(98)00729-0 [PubMed] [CrossRef] [Google Scholar] https://www.ncbi.nlm.nih.gov/pubmed/9835228

6. Petersson M., Diaz-Cabiale Z., Angel Narvaez J., Fuxe K., Uvnäs-Moberg K. (2005a). Oxytocin increases the density of high affinity α2-adrenoceptors within the hypothalamus, the amygdala and the nucleus of the solitary tract in ovariectomized rats. Brain Res. 1049, 234–239. 10.1016/j.brainres.2005.05.034 [PubMed] [CrossRef] [Google Scholar] https://www.ncbi.nlm.nih.gov/pubmed/15967417

7. Lund I., Ge Y., Yu L. C., Uvnäs-Moberg K., Wang J., Yu C., et al. (2002). Repeated massage-like stimulation induces long-term effects on nociception: contribution of oxytocinergic mechanisms. Eur. J. Neurosci. 16, 330–338. 10.1046/j.1460-9568.2002.02087.x [PubMed] [CrossRef] [Google Scholar] https://www.ncbi.nlm.nih.gov/pubmed/12169113

What Oxytocin Is Released (Discharged into the Bloodstream) in Response To:

Oxytocin is released in response to activation of sensory nerves ( Stock and Uvnäs-Moberg, 1988 ) not only during childbirth and breastfeeding, but also in response to skin-to-skin contact between mother and infant ( Matthiesen et al., 2001 ), during sexual intercourse in both sexes ( Carmichael et al., 1987 ), may be released in connection with positive, warm interaction between people ( Light et al., 2005 ) and interaction between people and animals (in particular, dogs; Odendaal and Meintjes, 2003 ; Miller et al., 2009 ; Handlin et al., 2011 ), may be released in response to several types of massage ( Uvnäs-Moberg, 2004 ) and even in response to suckling (Lupoli et al., 2001 ) and food intake ( Ohlsson et al., 2002 ).

1. Stock S., Uvnäs-Moberg K. (1988). Increased plasma levels of oxytocin in response to afferent electrical stimulation of the sciatic and vagal nerves and in response to touch and pinch in anaesthetized rats. Acta Physiol. Scand. 132, 29–34. 10.1111/j.1748-1716.1988.tb08294.x [PubMed] [CrossRef] [Google Scholar] https://www.ncbi.nlm.nih.gov/pubmed/3223304

2. Matthiesen A. S., Ransjo-Arvidson A. B., Nissen E., Uvnäs-Moberg K. (2001). Postpartum maternal oxytocin release by newborns: effects of infant hand massage and sucking. Birth 28, 13–19. 10.1046/j.1523-536x.2001.00013.x [PubMed] [CrossRef] [Google Scholar] https://www.ncbi.nlm.nih.gov/pubmed/11264623

3. Light K. C., Grewen K. M., Amico J. A. (2005). More frequent partner hugs and higher oxytocin levels are linked to lower blood pressure and heart rate in premenopausal women. Biol. Psychol. 69, 5–21. 10.1016/j.biopsycho.2004.11.002 [PubMed] [CrossRef] [Google Scholar] https://www.ncbi.nlm.nih.gov/pubmed/15740822

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5. Miller S. C., Kennedy C., Devoe D., Hickey M., Nelson T., Kogan L. (2009). An Examination of changes in oxytocin levels in men and women before and after interaction with a bonded dog. Anthrozoös 22, 31–42 10.2752/175303708X390455 [CrossRef] [Google Scholar] https://dx.doi.org/10.2752%2F175303708X390455

6. Handlin L., Hydbring-Sandberg E., Nilsson A., Ejdebäck M., Jansson A., Uvnäs-Moberg K. (2011). Short-term interaction between dogs and their owners—effects on oxytocin, cortisol, insulin and heart rate—an exploratory study. Anthrozoos 24, 301–315 10.2752/175303711X13045914865385 [CrossRef] [Google Scholar] https://dx.doi.org/10.2752%2F175303711X13045914865385

7. Uvnäs-Moberg K. (2004). “Massage, relaxation and well-being: a possible role for oxytocin as an integrative principle?,” in Touch and Massage in Early Child Development, ed. Field T. (Calverton, NY: Johnson & Johnson Pediatric Institute; ). [Google Scholar] https://scholar.google.com/scholar_lookup?title=Touch+and+Massage+in+Early+Child+Development&author=K.+Uvn%C3%A4s-Moberg&publication_year=2004&

8. Lupoli B., Johansson B., Uvnäs-Moberg K., Svennersten-Sjaunja K. (2001). Effect of suckling on the release of oxytocin, prolactin, cortisol, gastrin, cholecystokinin, somatostatin and insulin in dairy cows and their calves. J. Dairy Res. 68, 175–187. 10.1017/S0022029901004721 [PubMed] [CrossRef] [Google Scholar] https://www.ncbi.nlm.nih.gov/pubmed/11504382

9. Ohlsson B., Forsling M. L., Rehfeld J. F., Sjolund K. (2002). Cholecystokinin stimulation leads to increased oxytocin secretion in women. Eur. J. Surg. 168, 114–118. 10.1080/11024150252884340 [PubMed] [CrossRef] [Google Scholar] https://www.ncbi.nlm.nih.gov/pubmed/12113268

Oxytocin release may be stimulated by hormones such as estrogen. In addition, oxytocin may be released in response to various types of sensory stimulation. Oxytocin may be released in response to stressful as well as positive and pleasant mental stimuli and in response to painful and non-noxious (pleasant) somatosensory stimulation ( Stock and Uvnäs-Moberg, 1988 ; Uvnäs-Moberg, 1998 ; Neumann, 2002 ; Uvnäs-Moberg and Petersson, 2005 ). When oxytocin is released in response to pain and stressful stimuli, it may play a role in certain types of stress and thus may also act to attenuate stress responses ( Neumann, 2002).).

1. Stock S., Uvnäs-Moberg K. (1988). Increased plasma levels of oxytocin in response to afferent electrical stimulation of the sciatic and vagal nerves and in response to touch and pinch in anaesthetized rats. Acta Physiol. Scand. 132, 29–34. 10.1111/j.1748-1716.1988.tb08294.x [PubMed] [CrossRef] [Google Scholar] https://www.ncbi.nlm.nih.gov/pubmed/3223304

2. Uvnäs-Moberg K. (1998). Oxytocin may mediate the benefits of positive social interaction and emotions. Psychoneuroendocrinology 23, 819–835 10.1016/S0306-4530(98)00056-0 [PubMed] [CrossRef] [Google Scholar] https://www.ncbi.nlm.nih.gov/pubmed/9924739

3. Neumann I. D. (2002). Involvement of the brain oxytocin system in stress coping: interactions with the hypothalamo-pituitary-adrenal axis. Prog. Brain Res. 139, 147–162 10.1016/S0079-6123(02)39014-9 [PubMed] [CrossRef] [Google Scholar] https://www.ncbi.nlm.nih.gov/pubmed/12436933

4. Uvnäs-Moberg K., Petersson M. (2005). [Oxytocin, a mediator of anti-stress, well-being, social interaction, growth and healing]. Z. Psychosom. Med. Psychother. 51, 57–80. [PubMed] [Google Scholar] https://www.ncbi.nlm.nih.gov/pubmed/15834840

Oxytocin released in response to non-noxious sensory stimulation may be critically involved in many types of self-soothing behavior, because this is associated with oxytocin effects related to a sense of well-being and, in particular, reduced stress levels.

1. Uvnäs-Moberg Kerstin, Handlin Linda, Petersson Maria. Self-soothing behaviors with particular reference to oxytocin release induced by non-noxious sensory stimulation. Frontiers in Psychology. V.5 (2015) P.1529 https://www.frontiersin.org/article/10.3389/fpsyg.2014.01529 DOI=10.3389/fpsyg.2014.01529

OT Release in Response to Stimulation of the C-Tactile Affective System by Slow Stroking or Warm Pulsating Skin Contact (Holding Against One’s Body, Embracing)

Slow, pressure-free skin stimulation directly aimed at optimal activation of C-tactile afferents reduces physiological arousal, carries positive affective valence, and under healthy conditions suppresses responses to painful stimuli. These effects are similar to those reported after endogenous release and exogenous administration of oxytocin. Taken together, this suggests that C-tactile afferent stimulation may mediate oxytocin release during affiliative tactile interactions.

1. Walker SC, Trotter PD, Swaney WT, Marshall A, Mcglone FP. C-tactile afferents: Cutaneous mediators of oxytocin release during affiliative tactile interactions? Neuropeptides. 2017 Aug;64:27-38. doi: 10.1016/j.npep.2017.01.001. Epub 2017 Jan 19. PMID: 28162847.

Some of the earliest indications of oxytocin release in response to stimulation of sensory nerves arising in the skin come from a rodent study conducted by the pioneer of oxytocin research, Kerstin Uvnäs-Moberg. When anesthetized adult rats underwent electrical stimulation of the sciatic or vagus nerves or received gentle stroking of the back (what is now interpreted as activation of the cutaneous affective C-tactile afferent system), plasma OT levels increased by 30–184% or 181%, respectively ( Stock and Uvnäs-Moberg, 1988 ). Applying vibration, warm temperature, or electroacupuncture to anesthetized male rats similarly increased OT levels in plasma and cerebrospinal fluid ( Uvnäs-Moberg et al., 1993 ). In humans, hand-massage movements applied by newborns to the mother’s breast increase maternal plasma oxytocin levels (Matthiesen et al., 2001 ). Likewise, 15 minutes of moderate-pressure Swedish massage significantly increased plasma oxytocin levels in both men and women ( Morhenn et al., 2012 ).

Stimulation of C-tactile afferents by stroking (in animals – in the form of allogrooming) leads to the release of oxytocin in the body and is therefore accompanied by the same pleasant and relaxing sensations and physiological effects that are characteristic of exogenous oxytocin administration. More generally, the effects of affectionate-touch-like stimulation have been shown to mirror those reported after endogenous release or exogenous administration of oxytocin (increased social motivation, reduced subsequent physiological and behavioral reactivity to stressors, etc.) and are probably partly mediated by C-tactile afferents, Walker et al. (2017) write in their review. The authors conclude that C-tactile afferents should play the role, in humans and animals, of cutaneous mediators of oxytocin release during affiliative tactile interactions. The same conclusion – that tactile stimulation through CT-fiber afferents is a cutaneous mediator of release of the hypothalamic neuropeptide oxytocin (OT) during social tactile interactions - is also presented by Uvnäs-Moberg et al. (2015).

Tang et al. (2020) clarified the mechanism of oxytocin activation during stimulation of the C-tactile system. They directly demonstrated activation of parvocellular oxytocin neurons during social interaction between female rats accompanied by their mutual social touch. According to the authors, social touch facilitates communication between females specifically through the resulting activation of parvocellular oxytocin neurons. The authors write that the activity of OT neurons during real social interactions remains poorly studied. Most OT neurons are magnocellular neurons that simultaneously project to pituitary and forebrain regions involved in social behavior. Their present study (2020) showed that a much smaller population of OT neurons, the parvocellular neurons, which project not to the pituitary but to synapses on large magnocellular neurons, are preferentially and primarily activated by somatosensory stimuli. This activation is then transmitted to the larger population of magnocellular OT neurons, which consequently show a coordinated increase in their activity during social interactions between virgin female rats. Selective activation of these parvocellular neurons promotes social motivation, whereas their inhibition reduces social interactions. Thus, parvocellular OT neurons receive specific inputs for controlling social behavior by coordinating the responses of a much larger population of magnocellular OT neurons.

Social contact reduces the stress response in social animals. Mice are known to engage in allogrooming toward distressed conspecifics, thereby reducing their stress response. However, the precise neural mechanisms underlying allogrooming behavior remain unclear. Matsumoto et al. (2021) demonstrated activation of oxytocin-receptor-expressing neurons during allogrooming. For this purpose, expression of the c-Fos protein, a marker of neuronal activation, was examined. Following allogrooming behavior, the percentage of oxytocin-receptor-expressing neurons that expressed c-Fos protein was significantly increased in the anterior olfactory nucleus, cingulate cortex, insular cortex, lateral septum, and medial amygdala of female mice, suggesting that oxytocin-receptor-expressing neurons in these regions were activated during allogrooming behavior toward distressed conspecifics. The duration of allogrooming correlated with the percentage of oxytocin-receptor-expressing neurons expressing c-Fos protein in the anterior olfactory nucleus, insular cortex, lateral septum, and medial amygdala. In oxytocin-receptor-deficient mice, allogrooming behavior toward socially defeated cage mates was markedly reduced in female mice but not in male mice, indicating the importance of the oxytocin receptor for allogrooming behavior toward distressed conspecifics specifically in female mice.

Tactile stimulation, including stroking, social grooming, and social affective touch, has been found to promote OT release and thereby increase OT concentrations in blood, saliva, or urine across different species ( Mitsui et al., 2011 ; Schneiderman et al., 2012 ; Crockford et al., 2013; Uvnäs-Moberg et al., 2015 ; Vittner et al., 2018 ). In particular, plasma OT levels in rats rose sharply when their backs or abdomens were gently stroked ( Stock and Uvnäs-Moberg, 1988 ; Uvnäs-Moberg and Petersson, 2010 ). In humans, blood OT concentrations in postpartum mothers increase to some extent in response to skin-to-skin contact that includes several types of touching / stroking (also massage, or movement of the hand on the mother’s breast) during mother-infant interaction when radioimmunoassay (RIA) is used ( Matthiesen et al., 2001 ; Uvnäs-Moberg et al., 2015 , 2020 ). Uvnäs-Moberg et al. (2020) also suggest that skin-to-skin contact stimulates activity of the oxytocinergic system and thereby reduces stress and facilitates functions associated with restoration and the growth of socially interactive relationships. “Warm touch” between couples and gentle touch during the early stage of romantic relationships, at a certain frequency, may also increase plasma OT concentrations (see Light et al., 2005 ; Holt-Lunstad et al., 2008 ; Schneiderman et al., 2012 ) . In addition, a number of studies have reported reduced basal OT concentrations in autism spectrum disorder, which is characterized by problems in social interaction and communication as well as altered tolerance (in the form of intolerance) of social touch ( Kanner, 1943).), and basal OT concentrations are negatively correlated with the severity of autism symptoms in both clinical and healthy populations ( Parker et al., 2014 ; Taurines et al., 2014 ; Zhang et al., 2016 ).

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6. Walker SC, Trotter PD, Swaney WT, Marshall A, Mcglone FP. C-tactile afferents: Cutaneous mediators of oxytocin release during affiliative tactile interactions? Neuropeptides. 2017 Aug;64:27-38. doi: 10.1016/j.npep.2017.01.001. Epub 2017 Jan 19. PMID: 28162847.

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14. Parker K. J., Garner J. P., Libove R. A., Hyde S. A., Hornbeak K. B., Carson D. S., et al. (2014). Plasma oxytocin concentrations and OXTR polymorphisms predict social impairments in children with and without autism spectrum disorder. Proc. Natl. Acad. Sci. U.S.A. 111 12258–12263. 10.1073/pnas.1402236111

15. Schneiderman I., Zagoory-Sharon O., Leckman J. F., Feldman R. (2012). Oxytocin during the initial stages of romantic attachment: relations to couples’ interactive reciprocity. Psychoneuroendocrinology 37 1277–1285. 10.1016/j.psyneuen.2011.12.021

16. Taurines R., Schwenck C., Lyttwin B., Schecklmann M., Jans T., Reefschläger L., et al. (2014). Oxytocin plasma concentrations in children and adolescents with autism spectrum disorder: correlation with autistic symptomatology. Atten. Defic. Hyperact. Disord. 6 231–239. 10.1007/s12402-014-0145-y

17. Uvnäs-Moberg K., Handlin L., Petersson M. (2015). Self-soothing behaviors with particular reference to oxytocin release induced by non-noxious sensory stimulation. Front. Psychol. 5:1529. 10.3389/fpsyg.2014.01529 Uvnäs-Moberg K., Handlin L., Petersson M. (2020). Neuroendocrine mechanisms involved in the physiological effects caused by skin-to-skin contact–With a particular focus on the oxytocinergic system. Infant. Behav. Dev. 61:101482 10.1016/j.infbeh.2020.101482

18. Vittner D., McGrath J., Robinson J., Lawhon G., Cusson R., Eisenfeld L., et al. (2018). Increase in oxytocin from skin-to-skin contact enhances development of parent–infant relationship. Biol. Res. Nurs. 20 54–62. 10.1177/1099800417735633

19. Zhang H.-F., Dai Y.-C., Wu J., Jia M.-X., Zhang J.-S., Shou X.-J., et al. (2016). Plasma oxytocin and arginine-vasopressin levels in children with autism spectrum disorder in China: associations with symptoms. Neurosci. Bull. 32 423–432. 10.1007/s12264-016-0046-5 [PMC free article]

Overall findings on touch-induced peripheral oxytocin release in humans are inconsistent. While some studies have found peripheral oxytocin release in response to touch ( Light et al., 2000 ; Odendaal and Meintjes, 2003 ; Light et al., 2005 ; Holt-Lunstad et al., 2008 ), others found no effect ( Turner et al., 1999; Heinrichs et al., 2001 ; Wikstrom et al., 2003 ; Grewen et al., 2005 ; Ditzen et al., 2007 ). Moreover, methodological limitations, such as the lack of useful oxytocin antagonists for testing in humans and the current inability to assess oxytocin release in the human brain, constrain research on the functional neurobiology of oxytocin in humans.

1. Light K. C., Smith T. E., Johns J. M., Brownley K. A., Hofheimer J. A., Amico J. A. (2000). Oxytocin responsivity in mothers of infants: a preliminary study of relationships with blood pressure during laboratory stress and normal ambulatory activity. Health Psychol. 19 560–567. 10.1037/0278-6133.19.6.560 https://www.ncbi.nlm.nih.gov/pubmed/11129359

2. Odendaal J. S., Meintjes R. A. (2003). Neurophysiological correlates of affiliative behaviour between humans and dogs. Vet. J. 165 296–301. 10.1016/S1090-0233(02)00237-X https://www.ncbi.nlm.nih.gov/pubmed/12672376

3. Light K. C., Grewen K. M., Amico J. A. (2005). More frequent partner hugs and higher oxytocin levels are linked to lower blood pressure and heart rate in premenopausal women. Biol. Psychol. 69 5–21. 10.1016/j.biopsycho.2004.11.002 https://www.ncbi.nlm.nih.gov/pubmed/15740822

4. Holt-Lunstad J., Birmingham W. A., Light K. C. (2008). Influence of a “warm touch” support enhancement intervention among married couples on ambulatory blood pressure, oxytocin, alpha amylase, and cortisol. Psychosom. Med. 70 976–985. 10.1097/PSY.0b013e318187aef7 https://www.ncbi.nlm.nih.gov/pubmed/18842740

5. Turner R. A., Altemus M., Enos T., Cooper B., McGuinness T. (1999). Preliminary research on plasma oxytocin in normal cycling women: investigating emotion and interpersonal distress. Psychiatry 62 97–113. https://www.ncbi.nlm.nih.gov/pubmed/10420425

6. Heinrichs M., Meinlschmidt G., Neumann I., Wagner S., Kirschbaum C., Ehlert U., et al. (2001). Effects of suckling on hypothalamic-pituitary-adrenal axis responses to psychosocial stress in postpartum lactating women. J. Clin. Endocrinol. Metab. 86 4798–4804. 10.1210/jcem.86.10.7919 https://www.ncbi.nlm.nih.gov/pubmed/11600543

7. Wikstrom S., Gunnarsson T., Nordin C. (2003). Tactile stimulus and neurohormonal response: a pilot study. Int. J. Neurosci. 113 787–793. 10.1080/00207450390200954 https://www.ncbi.nlm.nih.gov/pubmed/12775343

8. Grewen K. M., Girdler S. S., Amico J., Light K. C. (2005). Effects of partner support on resting oxytocin, cortisol, norepinephrine, and blood pressure before and after warm partner contact. Psychosom. Med. 67 531–538. 10.1097/01.psy.0000170341.88395.47 https://www.ncbi.nlm.nih.gov/pubmed/16046364

9. Ditzen B., Neumann I. D., Bodenmann G., von Dawans B., Turner R. A., Ehlert U., et al. (2007). Effects of different kinds of couple interaction on cortisol and heart rate responses to stress in women. Psychoneuroendocrinology 32 565–574. 10.1016/j.psyneuen.2007.03.011 https://www.ncbi.nlm.nih.gov/pubmed/17499441

Physiological Effects of Non-Noxious (Pleasant) Sensory Tactile Stimulation and Its Resulting Oxytocin Response

Non-noxious (pleasant, non-painful) sensory stimulation directed at somatosensory nerves in rodents in conscious or unconscious states acts through differentiated brain pathways, respectively, to reduce sympathetic nervous system activity as well as to increase parasympathetic nervous system activity. These physiological changes produce a range of effects, such as enhanced gastrointestinal function ( Holst et al., 2005 ), increased sociability ( Wei et al., 2013 ), an increased pain threshold ( Agren et al., 1995 ). , as well as substantial anti-stress effects (reduced blood pressure and cortisol levels) ( Araki et al., 1984 ; Lund et al., 1999 ; Wei et al., 2013).

Overall, non-noxious somatosensory stimulation in rodents and humans and its resulting context-adapted OT response appear to reduce sympathetic nervous system activity and also activate the parasympathetic nervous system, including in the mother-infant relationship, providing the infant with a state of growth and relaxation or a state of rest and connection with the parent, - a state that is optimal both for the growing infant and for the parents caring for it

Ventral-to-ventral child-parent contact (belly to belly, skin to skin) has been shown to increase salivary OT levels in parents and infants and decrease salivary cortisol levels, producing less distress in the infant and more synchronous and responsive behavior in the parents (Cong et al., 2015 ; Vittner et al., 2018 ).

In addition, analogous to mechanisms found in rodents ( Alberts, May, 1984 ; Kojima and Alberts, 2009 , 2011 ; Kojima et al., 2012 ; Meyer and Alberts, 2016 ), the provision of skin warmth by the mother during ventral-to-ventral (belly-to-belly) contact activates cutaneous nerves in the infant, leading to OT release in the infant, which reduces sympathetic nervous system activity, which in turn reduces vasoconstriction in the infant, which, by dilating superficial vessels, leads to an increase in the infant’s skin temperature ( Bystrova et al., 2003 , 2007 ; Moberg et al., 2020). Detailed analysis of maternal chest temperature after birth demonstrates both a higher temperature than the infant’s and greater pulsatile variability during skin-to-skin contact. This pulsatile pattern is largely adapted to stimulate an increase in the infant’s temperature, because changing temperature activates the infant’s cutaneous sensory nerves more effectively than a stable temperature, leading to synchronization of maternal and infant temperatures ( Bystrova et al., 2003 ).

With regard to the specific mechanotactile maternal behavior involving licking and grooming in rodents, the human equivalent is considered to be gentle maternal stroking of the infant at low speed and pressure, which has been shown to activate a class of touch-sensitive nerve fibers called C-tactile afferents, producing epigenetic and stress-regulating effects similar to those found in studies of licking and care (grooming) in rodents ( Murgatroyd et al., 2015 ; Sharp et al., 2015 ; Pickles et al., 2017 ).

Although this has not yet been quantitatively studied, incidental observations and video documentation ( Bigelow and Gillis, 2010 ) demonstrate a tendency for parents to perform gentle child-oriented touches specifically in the form of light stroking, which, as is now known, primarily stimulates the C-tactile system.

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5. Bystrova K., Matthiesen A.-S., Vorontsov I., Widström A.-M., Ransjö-Arvidson A.-B., Uvnäs-Moberg K. (2007). Maternal axillar and breast temperature after giving birth: Effects of delivery ward practices and relation to infant temperature. Birth 34 291–300. 10.1111/j.1523-536X.2007.00187.x https://www.ncbi.nlm.nih.gov/pubmed/18021144

6. Bystrova K., Widström A. M., Matthiesen A. S., Ransjö-Arvidson A. B., Welles-Nyström B., Wassberg C., et al. (2003). Skin-to-skin contact may reduce negative consequences of “the stress of being born”: A study on temperature in newborn infants, subjected to different ward routines in St. Petersburg. Acta Paediatr. 92 320–326. 10.1080/08035250310009248 https://www.ncbi.nlm.nih.gov/pubmed/12725547

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8. Holst S., Lund I., Petersson M., Uvnäs-Moberg K. (2005). Massage-like stroking influences plasma levels of gastrointestinal hormones, including insulin, and increases weight gain in male rats. Auton. Neurosci. Basic Clin. 120 73–79. 10.1016/j.autneu.2005.04.007 https://www.ncbi.nlm.nih.gov/pubmed/15925549

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10. Kojima S., Alberts J. R. (2011). Warmth from skin-to-skin contact with mother is essential for the acquisition of filial huddling preference in preweanling rats. Dev. Psychobiol. 53 813–827. 10.1002/dev.20565 https://www.ncbi.nlm.nih.gov/pubmed/21594869

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12. Lund I., Lundeberg T., Kurosawa M., Uvnäs-Moberg K. (1999). Sensory stimulation (massage) reduces blood pressure in unanaesthetized rats. J. Auton. Nervous Syst. 78 30–37. 10.1016/s0165-1838(99)00055-7 https://www.ncbi.nlm.nih.gov/pubmed/10589821

13. Meyer P. M., Alberts J. R. (2016). Non-nutritive, thermotactile cues induce odor preference in infant mice (Mus musculus). J. Comp. Psychol. 130 369–379. 10.1037/com0000044 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5108687/

14. Moberg K. U., Handlin L., Petersson M. (2020). Neuroendocrine mechanisms involved in the physiological effects caused by skin-to-skin contact—With a particular focus on the oxytocinergic system. Infant Behav. Dev. 61:101482. 10.1016/j.infbeh.2020.101482 https://www.ncbi.nlm.nih.gov/pubmed/32919112

15. Murgatroyd C., Quinn J. P., Sharp H. M., Pickles A., Hill J. (2015). Effects of prenatal and postnatal depression, and maternal stroking, at the glucocorticoid receptor gene. Transl. Psychiatry 5:e560. 10.1038/tp.2014.140 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4471282/

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18. Vittner D., McGrath J., Robinson J., Lawhon G., Cusson R., Eisenfeld L., et al. (2018). Increase in oxytocin from skin-to-skin contact enhances development of parent-infant relationship. Biol. Res. Nurs. 20 54–62. 10.1177/1099800417735633 https://www.ncbi.nlm.nih.gov/pubmed/29017336

19. Wei B., Tai F., Liu X., Ma L., Yang X., Jia R., et al. (2013). Neonatal tactile stimulation alleviates the negative effects of neonatal isolation on novel object recognition, sociability and neuroendocrine levels in male adult mandarin voles (Microtus mandarinus). Physiol. Behav. 11 14–22. 10.1016/j.physbeh.2013.02.005 https://www.ncbi.nlm.nih.gov/pubmed/23438372

Unmyelinated Tactile Cutaneous Nerves Signal Erotic Sensations.

Interpersonal touch is a powerful tool for communicating emotions and can, among other things, evoke feelings of eroticism and sexual arousal. The peripheral neural mechanisms for signaling erotic touch are less well studied. C-tactile afferents (unmyelinated low-threshold mechanoreceptors), which are known to underlie the pleasant aspects of touch processing, also play an important role here.

In Study No. 1 (n = 20), five different stroking velocities were applied to the forearm and inner thigh. Participants answered questions about partnership, mood, and touch. In Study No. 2 (n = 46), the same five stroking velocities were applied to the forearm. Participants answered questions about partnership, touch, and sexuality.

Results: both the eroticism of touch and pleasantness were rated significantly higher for C-tactile-optimal velocities than for suboptimal velocities. No difference was found between ratings for the thigh and forearm. Velocity-dependent rating curves for pleasantness, intensity, and eroticism differed from one another. Pleasantness was best explained by a quadratic fit, intensity - by a linear fit, and eroticism - by both. A linear transformation of pleasantness and intensity reliably predicted the observed eroticism ratings. Erotic ratings were negatively correlated with relationship duration.

Conclusion: touch was rated as most erotic when it was perceived as pleasant or weak. In human hairy skin, the perception of pleasantness correlates with the firing rate of C-tactile afferents, whereas the perception of intensity correlates with the firing rate of Aβ afferents (associated with localization of tactile sensations but not with their affective content). Accordingly, eroticism may be perceived most readily for sensory stimuli that evoke high activity in C-tactile fibers and low activity in Aβ fibers.

1. Jönsson EH, Backlund Wasling H, Wagnbeck V, Dimitriadis M, Georgiadis JR, Olausson H, Croy I. J Sex Med. 2015 Jun; 12 (6): 1338-45. DOI: 10.1111 / jsm.12905. Epub 2015 May 12. PMID: 25970018

A Preliminary Increase in Brain Oxytocin Concentration Enhances Pleasant Sensations from Activation of the Cutaneous C-Tactile Afferent System.

Manual massage can significantly increase endogenous oxytocin concentrations and neural activity in regions involved in social cognition and reward, while intranasal oxytocin can increase the pleasantness of social touch. Chen Y et al. (2020) investigated whether intranasal oxytocin modulates behavioral and neural responses to foot massage administered manually or by machine. Intranasal oxytocin significantly increased subjective ratings of the pleasantness of manual massage, but not machine massage, and enhanced neural responses in key regions involved in reward (orbitofrontal cortex, dorsal striatum, and ventral tegmental area). social cognition (superior temporal sulcus and inferior parietal lobule), emotion and salience appraisal (amygdala, anterior cingulate cortex, and insula), and the default mode network (medial prefrontal cortex, parahippocampal gyrus, posterior cingulate gyrus, and precuneus), as well as in a number of sensory and motor processing regions. Both the neural and behavioral effects of oxytocin occurred regardless of whether participants thought the massage had been administered by a male or female masseur. These findings support the importance of oxytocin in enhancing positive behavioral and neural responses to social touch in the form of manual massage and suggest that the combination of intranasal oxytocin and massage may have therapeutic potential in autism.

1. Chen Y, Li Q, Zhang Q, Kou J, Zhang Y, Cui H, Wernicke J, Montag C, Becker B, Kendrick KM, Yao S. The Effects of Intranasal Oxytocin on Neural and Behavioral Responses to Social Touch in the Form of Massage. Front Neurosci. 2020 Dec 4;14:589878. doi: 10.3389/fnins.2020.589878. PMID: 33343285; PMCID: PMC7746800.

Effects of MDMA on Attention to Positive Social Cues and the Pleasantness of Affective Touch

MDMA – a drug that markedly increases the brain concentrations and activity of two neurohormones – serotonin and oxytocin, while also partly enhancing noradrenergic and dopaminergic activity. The psychostimulant drug ± 3,4-methylenedioxymethamphetamine (MDMA) is reported to produce distinctive feelings of empathy and closeness with others. MDMA increases social behavior in animal models and has shown promise in psychiatric disorders such as autism spectrum disorder (ASD) and post-traumatic stress disorder (PTSD). How MDMA produces its prosocial effects is unknown. However, MDMA is known to provoke the release of serotonin, oxytocin, as well as dopamine and other mediators, whereas another psychostimulant, methamphetamine, leads to the release only of dopamine. Bershad et al., 2019, examined the effects of MDMA compared with the prototypical stimulant methamphetamine (MA) on two measures of social behavior in healthy young adults: 1) responses to socially meaningful “affective” touch and 2) visual attention to emotional faces. Men and women (N = 36) attended four sessions in which they received MDMA (0,75 or 1,5 mg / kg), MA (20 mg), or placebo in randomized order under double-blind conditions. Responses to experienced and observed affective touch (for example, being touched or observing others being touched) were assessed using objective facial electromyography (EMG), which is an indicator of affective state. Responses to emotional faces were assessed using electrooculography (EOG) by the degree of attentional bias. Subjective ratings were also included. The authors hypothesized that MDMA, but not MA, would increase ratings of pleasantness and psychophysiological responses to affective touch and increase attentional bias toward positive facial expressions. Consistent with this, they found that MDMA, but not MA, selectively increased ratings of the pleasantness of experienced affective touch. Neither drug affected ratings of the pleasantness of observed touch. On the EOG attentional-bias measure, MDMA, but not MA, increased attention to happy faces. These findings provide new evidence that MDMA enhances the experience of positive social interaction; in this case - the pleasantness of physical touch and an attentional bias toward positive facial expressions. The findings are consistent with evidence that prosocial effects are unique to MDMA compared with another stimulant, and these effects appear to be associated with oxytocin, although serotonin may also participate in them.

1. Bershad AK, Mayo LM, Van Hedger K, McGlone F, Walker SC, de Wit H. Effects of MDMA on attention to positive social cues and pleasantness of affective touch. Neuropsychopharmacology. 2019 Sep;44(10):1698-1705. doi: 10.1038/s41386-019-0402-z. Epub 2019 Apr 30. PMID: 31042696; PMCID: PMC6785008.

Unlike other common amphetamines, MDMA primarily affects mechanisms of serotonin neuroregulation— with a predominantly selective action on serotonergic neurons of the nigrostriatal system. However, the effect of strong serotonin release does not fully explain such unusual psychoactivity of MDMA. The precise mechanism of action is not fully known and is an area of active research. A number of additional neuroeffects of MDMA have been identified that follow serotonin release or occur simultaneously with it, including release of neurotransmitters such as dopamine (although MDMA is 6 times less effective in this respect than methamphetamine, norepinephrine (this effect is partly responsible for MDMA’s stimulant properties), and acetylcholine.

Laboratory experiments in animals have shown that MDMA also activates pituitary oxytocin neurons, mainly through stimulation of serotonergic 5-HT1A receptors. Some experiments provide evidence that the empathy effect caused by MDMA is directly associated with release of the “attachment hormone” oxytocin. The friendliness of people under the influence of MDMA was found to be directly temporally correlated with oxytocin levels, and its release was found to be associated with ambient temperature — the higher it is, the stronger the oxytocin release (which increases this effect in clubs)

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Compared with placebo, intranasal oxytocin selectively enhanced the subjective pleasantness of partner touch and also selectively increased the objective response to partner touch (as assessed by fMRI) in the nucleus accumbens (NAcc) and anterior cingulate cortex.

1. Kreuder AK, Scheele D, Wassermann L, Wollseifer M, Stoffel-Wagner B, Lee MR, Hennig J, Maier W, Hurlemann R. How the brain codes intimacy: The neurobiological substrates of romantic touch. Hum Brain Mapp. 2017 Sep;38(9):4525-4534. doi: 10.1002/hbm.23679. Epub 2017 Jun 5. PMID: 28580708; PMCID: PMC6867116.

Salivary oxytocin concentration is positively associated with the subjective sense of body ownership during the rubber hand illusion. Brain regions associated with social recognition and empathy (for example, the insular cortex) are activated in the rubber hand illusion (RHI), which involves illusory ownership of a rubber hand induced by brush strokes applied simultaneously both to the rubber hand (visible to the participant) and to one of the participant’s hands (which is hidden from the participant’s view). Participants who had high salivary oxytocin concentrations tended to experience strong ownership of the rubber hand. We also found that participants with a high Autism-Spectrum Quotient (AQ), who particularly experienced difficulties with social skills and communication, tended to feel weak ownership of the rubber hand. We noted that illusory body ownership is closely associated with social communication and with a neuroendocrine basis. The results of the present study show that a person’s salivary oxytocin concentration may predict the extent to which the person experiences the rubber hand illusion within visuotactile integration.

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Oxytocin Release in Positive Human Relationships

Oxytocin levels may increase as a result of closeness between mother and infant when they are attached to one another; oxytocin levels also increase when they simply see, hear, or even think about one another ( Swain et al., 2007 ; Kim et al., 2014 ).

A similar response also occurs in adults, since warm contact with a partner has been demonstrated to be associated with oxytocin release and anti-stress effects. In fact, oxytocin may be released when people of both sexes and all ages touch one another, provided that the relationship is perceived as positive. Oxytocin may even be released when one sees, hears, or simply thinks about another loved person ( Carter and Keverne, 2002 ; Grewen et al., 2005 ; Light et al., 2005 ; Holt-Lunstad et al., 2008).). In stable long-term relationships, oxytocin levels may be persistently elevated, and some studies show that basal oxytocin levels are higher in people who live together. A high oxytocin level is most likely a consequence of cohabitation, but, of course, it cannot be ruled out that people with high oxytocin levels choose cohabitation more often than people with low oxytocin levels ( Humble et al., 2013 ).

Many studies demonstrate that the health profile of people living in good relationships is better than that of those who live alone. They have, for example, lower blood pressure and a reduced risk of cardiovascular disease. They have fewer infections and a reduced risk of some types of cancer. People living in good relationships may even look younger and live longer than those who live alone. However, it is important to note that for these positive health consequences to develop, the relationships must be warm and of good quality. Relationships characterized by fear and mistrust may lead to an increased risk of cardiovascular disease, especially in women ( Seeman, 1996 ; Uchino and Garvey, 1997 ; Christenfeld and Gerin, 2000 ; Blom et al., 2003 ; Danoff-Burg and Revenson, 2005 ).

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Oxytocin and Sex

Sexual relationships are associated with oxytocin release. Data obtained in both animals and humans demonstrate that large amounts of oxytocin are released in response to sexual activity in both women and men. In humans, the oxytocin peak appears to coincide with orgasm ( Carmichael et al., 1987 ). Oxytocin has been demonstrated to facilitate sexual functioning and increase sexual desire, facilitate ejaculation and egg transport, as well as the sensation of orgasm in both men and women. In addition, oxytocin has been demonstrated to be associated with bonding between people induced by sex, as well as with reduced anxiety and improved well-being and calming induced by sexual intercourse ( Carmichael et al., 1987 ; Anderson, 2006). Long-term studies show that people who have a good sex life are healthier and live longer than those who do not. It is likely that oxytocin release during sex contributes to improved health, but the effects may also be indirectly mediated by strengthening of relationships and attachment, which are often consequences of a good sex life ( Brody, 2010 ).

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Oxytocin Release Resulting from Human-Animal Interaction and the Discovery of Oxytocin’s Two-Phase Action

Oxytocin levels reach pronounced peaks in both dog owners and dogs when the owner and dog interact, and in particular when the owner strokes and caresses the dog ( Odendaal and Meintjes, 2003 ; Miller et al., 2009 ; Handlin et al., 2011).). However, oxytocin is also released when dogs see their owner and want to approach them. These two separate phases of oxytocin release are described in the following experiments. Dogs underwent a brief separation from a familiar person and were then reunited with that person after 30 minutes. When the familiar person returned, the mere sight of that person elicited a peak-like oxytocin release as well as an increase in cortisol levels in the dogs. After reunion, the familiar person either ignored the approaching dogs, had verbal contact without touching them, or talked to and had physical contact with the dogs. Only in the third scenario, when the dogs received physical contact from the familiar person, did oxytocin levels continue to rise. In addition, cortisol levels decreased in these dogs (those receiving affection), demonstrating that oxytocin release induced by tactile stimulation is associated with anti-stress effects. In the other two scenarios, where the familiar person did not touch the dogs because they either ignored them or merely had verbal contact with them, oxytocin was no longer released and the dogs’ cortisol levels remained high (Rehn et al., 2014 ).

In another experiment, children with severe attachment problems faced a stressful task. Cortisol levels were measured in saliva to track the stress response. When these children performed the stress test, they were allowed support from either a trained and persistent person, a friendly therapy dog, or a soft toy dog. The results showed that salivary cortisol levels were significantly lower in children who had a friendly therapy dog as a companion during the stress test than in children who had a friendly person or a toy dog. In addition, the reduction in cortisol observed in children who had a dog during the stress test correlated with the amount of physical contact between the child and the dog ( Beetz et al., 2012). The finding that people failed to calm the child and lower cortisol levels may be related to the fact that children with severe attachment problems were too afraid of people to receive any support from them. In contrast, interaction with a live therapy dog was accompanied by reduced cortisol levels. Because stroking releases oxytocin and oxytocin reduces cortisol release, the reduction in cortisol observed in boys who physically interacted with dogs was likely secondary to touch-induced oxytocin release. A stuffed dog did not have the same stress-buffering effect as a real dog. This may be because merely seeing and approaching a friendly therapy dog produces an oxytocin peak in the child, as occurred in dogs when they were reunited with their familiar person, as described above. When encountering the plush dog, this “trigger” oxytocin peak was absent, and stroking the toy dog did not initiate oxytocin release as effectively and, consequently, no reduction in cortisol levels was induced.

Taken together, these two experiments concerning interactions between humans and dogs demonstrated that interaction between two individuals consists of two separate phases of oxytocin release. The first oxytocin peak is induced when you see and hear the “other person” (a dog or a human) and is associated with active approach. If the approach phase is followed by physical interaction, a second phase of oxytocin release is activated. This second phase of oxytocin release is associated with reduced stress levels, for example, reduced cortisol levels. Nevertheless, the two phases, the approach phase and the interaction / closeness phase, are not completely independent of each other. Physical interaction with a toy dog did not produce the same reduction in stress (as a consequence of oxytocin release) as interaction with a real dog. This is probably because the stuffed dog was not as attractive as the real dog, and in the absence of a phase of joyful approach there was no induced oxytocin release. In contrast, the real dog elicited an initial oxytocin impulse. This situation is analogous to observations of the presence or absence of oxytocin release in response to skin-to-skin contact between mother and infant depending on the type of delivery. During normal vaginal delivery, oxytocin is released, and oxytocin is subsequently also released after postnatal skin-to-skin contact (when the infant is held to the breast). When there is no oxytocin release during delivery, as, for example, after an elective cesarean section, oxytocin will not be released during skin-to-skin contact or breastfeeding in the postpartum period either ( Velandia et al., 2012 ). However, this effect was restored in mothers who had delivered by cesarean section if they received infusions of exogenous oxytocin after delivery.

This two-phase model of oxytocin release during interactions, as described above, is most likely related not only to interactions between dogs and humans but is of general significance and is also most likely present during interactions between people in various situations when, for example, human skin-to-skin contact or touch in any situation is facilitated by a preceding oxytocin release. Specifically, previously induced “trigger” release of oxytocin in the NTS opens the possibility for further oxytocin release in response to tactile stimulation and closeness as well. It should be noted that this two-phase oxytocin release occurs as long as the person perceives the situation positively. If the situation is perceived as stressful or threatening, oxytocin release will be absent.

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Oxytocin Release Induced by Massage

Oxytocin release, which normally occurs in response to closeness in good relationships, can to some extent be mimicked by massage and skin stroking. Indeed, massage treatment is associated with oxytocin release. If repeated blood samples are taken at the beginning of a massage session, oxytocin pulses can be observed both in the individual receiving the massage and in the masseur ( Uvnäs-Moberg, 2004 ). Massage treatment is accompanied by several positive effects. During a massage session, anxiety levels decrease, the sense of well-being improves, and pain decreases. In addition, both blood pressure and cortisol levels decrease. Repeated massage sessions are associated with long-term manifestation of all these effects ( Field, 2002 ,2014 ). Massage also increases the capacity for friendly social interaction and can even be used to resolve family conflicts ( Ditzen et al., 2007 ). Infant massage has been shown to reduce maternal depression, improve bonding between mother and infant, and alleviate stress responses and colic in infants ( O’Higgins et al., 2008 ; Field et al., 2009 ). Oxytocin released into the brain in response to massage should be an important mediator of the aforementioned effects.

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Effects of Intranasal Oxytocin on Neural and Behavioral Responses to Social Touch in the Form of Massage

Manual massage can significantly increase endogenous oxytocin concentrations and neural activity in regions of social cognition and reward, while intranasal oxytocin can increase the pleasantness of social touch. Chen et al., 2020 investigated whether intranasal oxytocin modulates behavioral and neural responses to foot massage administered manually or by machine, using a randomized placebo-controlled pharmaco-fMRI design. 46 male participants underwent blocks of each type of massage, during which they both received foot massage from a person or a machine that they could not see. Intranasal oxytocin significantly increased subjective ratings of the pleasantness of manual massage, but not machine massage, as well as the magnitude of neural responses in key regions involved in reward (orbitofrontal cortex, dorsal striatum, and ventral tegmental area), in social cognition networks (superior temporal sulcus and inferior parietal lobule), emotion and salience networks (amygdala, anterior cingulate gyrus, and insula), and the default mode network (medial prefrontal cortex, parahippocampal gyrus, posterior cingulate gyrus, and precuneus), as well as in a number of sensory and motor brain regions. Both the neural and behavioral effects of oxytocin occurred regardless of whether participants thought the massage had been administered by a male or female masseur. These results support the importance of oxytocin in enhancing positive behavioral and neural responses to social touch in the form of manual massage and suggest that the combination of intranasal oxytocin and massage may have therapeutic potential in autism. emotions and salience (amygdala, anterior cingulate gyrus, and insula) and the default mode network (medial prefrontal cortex, parahippocampal gyrus, posterior cingulate gyrus, and precuneus), as well as a number of sensory and motor processing regions.

1. Chen Y, Li Q, Zhang Q, Kou J, Zhang Y, Cui H, Wernicke J, Montag C, Becker B, Kendrick KM, Yao S. The Effects of Intranasal Oxytocin on Neural and Behavioral Responses to Social Touch in the Form of Massage. Front Neurosci. 2020 Dec 4;14:589878. doi: 10.3389/fnins.2020.589878. PMID: 33343285; PMCID: PMC7746800.

Oxytocin Release Resulting from Food Intake

Food intake is also associated with oxytocin release, and several mechanisms are involved in food-intake-induced oxytocin release. When food contacts the oral mucosa, oxytocin is released following activation of sensory receptors in the oral cavity, and when swallowed food reaches the gastrointestinal tract, the hormone cholecystokinin (CCK) is released from the duodenum, particularly in response to proteins and fat. Sensory fibers of the vagus nerves are activated by cholecystokinin. Sensory fibers of the vagus nerve relay to the NTS, from which neurons project to the PVN, where oxytocin is released both into the blood and into the brain (for references, see Uvnäs-Moberg and Prime, 2013 ).

Suckling is also associated with oxytocin release, because the act of sucking itself causes oxytocin release through activation of sensory receptors in the oral cavity ( Lupoli et al., 2001 ). Oxytocinergic mechanisms may be involved in the calming, anti-stress, and growth-promoting effects of sucking in breastfed infants, as well as in response to sucking on a pacifier ( Uvnäs-Moberg et al., 1987 ). Attachment between infant and mother may also, in a primitive sense, be associated with breastfeeding-induced oxytocin release. It is even possible that dependence on other types of behavior associated with breastfeeding, for example cigarette smoking and even alcohol consumption ( Uvnäs-Moberg et al., 1993b), may include an oxytocin-related component triggered by imitation of the act of sucking, rather than only the pharmacological effects of nicotine and alcohol. It should also be noted here (in connection with socionics) that in some psychotypes (IEE and, to some extent, ILE) the rudimentary infant sucking reflex often persists into adulthood. Both types belong to the “Judicious” pole (the socionic analogue of the Agreeableness factor in the Big Five). It may probably be expected that oxytocin activity in these psychotypes may be higher than in others.

Food intake is followed by “postprandial sedation,” or a state in which people feel calm and satisfied in a broad sense and often become open to social interaction and even to the establishment of bonding and attachment (which is why shared meals are often used for business negotiations). Some of these effects are associated with oxytocinergic mechanisms ( Uvnäs-Moberg, 1994 ). Because food has an obvious rewarding as well as relaxing effect, it represents an important route to achieving well-being and relieving stress, and eating or overeating for self-soothing is very common. Unfortunately, overweight and obesity are long-term consequences of overeating.

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The common denominator of breastfeeding, skin-to-skin contact between mother and infant, warm interaction with or without sex between adults, tactile interaction with a friendly or beloved dog, and even massage or other types of tactile procedures, which represent different kinds of relationships with other living beings, is that they are accompanied by oxytocin release through activation of sensory nerves. This thereby activates a number of oxytocin-mediated effects, such as enhanced social interactive behavior, well-being, analgesia, and anti-stress effects. In addition, interindividual attachment / bonding (attachment) may develop, in which oxytocinergic mechanisms are involved. These situations associated with sensory stimulation and oxytocin release are also associated in the long term with good mental and physical health. Breastfeeding is associated with a “dose-dependent” reduction in cardiovascular disease and type 2 diabetes mellitus in mothers. Skin-to-skin contact between mother and infant is associated with increased social interaction and calmness. In addition, tactile closeness in early childhood may facilitate the development of secure attachment. Adults with secure attachment demonstrate less anxiety and depression, less pain and inflammation, and a lower risk of cardiovascular disease. A similar spectrum of positive effects has been demonstrated for adults who are in warm and positive relationships, including a good sex life, and they also live longer. Interestingly, the same positive health pattern is seen in people who have a pet, such as a dog.

In the absence of close and well-functioning social relationships with people or dogs, alternative routes may be used to achieve well-being and relieve stress. Interestingly, massage or other types of tactile intervention produce a spectrum of effects similar to the positive interactions listed above and may therefore be used to improve well-being, reduce anxiety and stress levels, and improve social interactive behavior. Many people also use yoga, various types of relaxation techniques, and physical exercise to achieve such a positive effect. Some other types of “interaction” with ingested or inhaled material, for example food, cigarettes, and even alcohol, may also be used to compensate for the beneficial effects normally achieved in good interpersonal relationships.

The functional activity of the oxytocin system differs among people; too much or too little oxytocin may be released, and oxytocin receptors may be insufficient. Such differences may be genetic or epigenetic in origin. People whose oxytocin-system function is reduced for various reasons may have an insecure attachment type, have relationship problems, or feel depressed or anxious for other reasons; they may experience a stronger need than others to improve their mood and obtain relief in order to overcome feelings of stress, tension, or pain. Different people use different routes to achieve these goals. Some people have too much sex, others eat too much. Both of these behaviors ultimately lead to negative consequences with respect to the ability to establish positive relationships or maintain a normal weight.

1. Uvnäs-Moberg Kerstin, Handlin Linda, Petersson Maria. Self-soothing behaviors with particular reference to oxytocin release induced by non-noxious sensory stimulation. Frontiers in Psychology. V.5 (2015) P.1529 https://www.frontiersin.org/article/10.3389/fpsyg.2014.01529 DOI=10.3389/fpsyg.2014.01529

Main Behavioral and Psychological Effects of Oxytocin Activity:

The main effects of individually high oxytocin activity noted in the literature are as follows:

• high subjective pleasantness of sensations from stimulation of the subject’s cutaneous C-tactile afferents by slow, light touches; hence also – a love of “cuddles,” tactile caresses;

• rapid development of interpersonal attachments (in love and friendship);

• love of children;

• increased suggestibility, trust (especially during initial contacts);

• improved recognition of other people’s emotions;

• reduced anxiety;

• peacefulness, a friendly disposition, and caring toward close others;

• expectation of support from one’s immediate social group.

In healthy people, intranasal administration of OT has demonstrated an anxiolytic effect ( Heinrichs et al., 2003 ),

improved recognition of emotional facial expressions ( Kirsch et al., 2005 ; Bartz et al., 2010 ; Hurlemann et al., 2010 ; Marsh et al., 2010 ),

increased interpersonal trust, especially among group members ( Kosfeld et al., 2005 ; De Dreu et al., 2010 ),

and increased empathic concern for conspecifics ( MacDonald and MacDonald, 2010 ).

A recent study examined pair formation in marmosets and found that group-formation behavior increased with administration of an oxytocin receptor agonist but decreased with administration of an oxytocin antagonist ( Smith et al., 2010 ).

Primate studies examining peripheral oxytocin levels during social interactions provide indirect evidence for oxytocin involvement in affiliative sensory behavior (although it remains unclear whether peripheral OT levels indicate central OT levels; see Jokinen et al., 2012 ; Neumann and Landgraf, 2012 ; Kagerbauer et al., 2013 ). In rhesus macaques, participation in social care activity (grooming) is positively correlated with oxytocin levels in blood plasma ( Maestripieri et al., 2009 ) and cerebrospinal fluid ( Winslow et al., 2003).) In wild chimpanzees, elevated urinary oxytocin has been reported to be associated with grooming, mediated by the strength of the bond between grooming partners; in particular, grooming interactions between animals with closer social bonds showed a greater increase in urinary oxytocin ( Crockford et al., 2013). Another study found no association between plasma oxytocin and social behavior in free-ranging macaques ( Schwandt et al., 2007 ). A recent study of pair bonding in “cotton-top tamarin” monkeys showed that interindividual urinary oxytocin levels are closely associated with grooming and reciprocal contact in females and with sexual behavior in males ( Snowdon et al., 2010). One study showed higher urinary oxytocin levels during social contact than during social isolation ( Seltzer and Ziegler, 2007 ). Together, these studies are consistent with the view that oxytocin release is associated with facilitating the course of and reducing the symptoms of negative states caused by social isolation or rejection and that, conversely, low oxytocin levels may promote increased seeking of social support ( Panksepp et al., 1997 ; Tops et al., 2007 ). It has been suggested that oxytocin release during social interaction may involve two “phases” - first, release associated with the social salience of the situation during approach motivation, and second, if this leads to physical affiliative contact, release associated with relieving anti-stress effects ( Uvnas-Moberg et al., 2014). This model is based on reports of oxytocin release in dogs and dog owners, first in response to auditory and visual signals that the other “individual” is nearby, and then again when the owner is already stroking and caressing the dog, when oxytocin rises again simultaneously and together with a decrease in plasma cortisol ( Miller et al., 2009 ; Handlin et al., 2011 ; Beetz et al., 2012 ; Rehn et al., 2014 ).

The behavioral effects of oxytocin administration appear to vary depending on context and affective states ( Bartz et al., 2011 ). In rodents, oxytocin is associated both with protective behavior toward offspring and with aggression against intruders ( Campbell, 2008 ). Intranasal oxytocin in humans increases recognition of both positive ( Unkelbach et al., 2008 ; Marsh et al., 2010 ) and negative emotions ( Bartz et al., 2010 ; Fischer-Shofty et al., 2010 ; Leknes et al., 2013 ), and enhances empathy and cooperation with in-group members, but in a defensive situation (and only during defense), and especially in mothers with children or females with offspring, may increase aggression toward out-group members (De Dreu and Kret, 2015 ). Oxytocin has been found to promote a “sharpening” of social impressions of other people compared with non-social contact ( Ellingsen et al., 2014 ). Nevertheless, a single dose (40 IU) of oxytocin did not affect the pleasantness or intensity of actual touch sensations. However, a recent study showed that in a group of heterosexual men, intranasal oxytocin increased the pleasantness of sensual caresses, particularly when they believed that a woman was touching them ( Scheele et al., 2014). However, oxytocin did not affect touch pleasantness when participants believed that the person caressing them was a man, further emphasizing the importance of multisensory context in oxytocin functioning.

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Variants of the oxytocin receptor gene have been demonstrated, some of which have been associated with different abilities to recognize facial expressions ( Kumsta and Heinrichs, 2013 ).

1. Kumsta, R., and Heinrichs, M. (2013). Oxytocin, stress and social behavior: neurogenetics of the human oxytocin system. Curr. Opin. Neurobiol. 23, 11–16. doi: 10.1016/j.conb.2012.09.004 http://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?db=pubmed&cmd=prlinks&retmode=ref&id=23040540

Increase in Trust under Intranasal Oxytocin

Baumgartner et al., 2008, investigated the neural circuitry of trusting behavior by combining intranasal double-blind administration of oxytocin with fMRI. We found that subjects in the oxytocin group showed no change in their trusting behavior after learning that their trust had been violated several times, whereas subjects receiving placebo reduced their trust. This difference in trust adaptation is associated with a specific reduction in activation of the amygdala, midbrain regions, and dorsal striatum in subjects receiving oxytocin. The authors suggest that neural systems mediating fear processing (the amygdala and midbrain regions) and behavioral adaptations to feedback information (posterior striatum) modulate the effect of oxytocin on trust. The increase in trust under the influence of oxytocin has also been confirmed in a number of other studies.

1. Baumgartner T, Heinrichs M, Vonlanthen A, Fischbacher U, Fehr E. Oxytocin shapes the neural circuitry of trust and trust adaptation in humans. Neuron. 2008 May 22;58(4):639-50. doi: 10.1016/j.neuron.2008.04.009. PMID: 18498743.

2. Meyer-Lindenberg A. Impact of prosocial neuropeptides on human brain function. Prog Brain Res. 2008;170:463-70. doi: 10.1016/S0079-6123(08)00436-6. PMID: 18655902 Review.

3. Kosfeld M, Heinrichs M, Zak PJ, Fischbacher U, Fehr E. Oxytocin increases trust in humans. Nature. 2005 Jun 2;435(7042):673-6. doi: 10.1038/nature03701. PMID: 15931222

Higher oxytocin levels promote more affectionate contact with the infant in both men and women (measured by the number of affectionate contacts and the duration of gaze synchrony), whereas higher vasopressin levels (in both men and women) promote more stimulating contact with the infant (measured by the number of stimulating contacts, joint attention to objects, and increased salience of an object by the parent after the infant looks at it).

1. Apter-Levi Y, Zagoory-Sharon O, Feldman R. Oxytocin and vasopressin support distinct configurations of social synchrony. Brain Res. 2014 Sep 11;1580:124-32. doi: 10.1016/j.brainres.2013.10.052. Epub 2013 Nov 1. PMID: 24184577.

All parameters of the vasopressin VP system (VP and V1aR) are generally higher in males (males of all species), whereas sex differences in the OT system do not always follow the same direction, often showing higher OT expression in females but higher OT receptor expression in males. Moreover, the VP and OT receptor systems show distinct and largely non-overlapping expression in the rodent brain, which may result in these receptors performing either complementary or opposing functional roles in the sex-specific regulation of social behavior. Although all the details still require further study.

1. Dumais KM, Veenema AH. Vasopressin and oxytocin receptor systems in the brain: Sex differences and sex-specific regulation of social behavior. Front Neuroendocrinol. 2016 Jan;40:1-23. doi: 10.1016/j.yfrne.2015.04.003. Epub 2015 May 4. PMID: 25951955; PMCID: PMC4633405.

Oxytocin and vasopressin are regulators of anxiety, stress, and social activity. They are released in hypothalamic and limbic regions from dendrites, axons, and perikarya independently of, or in coordination with, secretion from neurohypophyseal terminals. Central oxytocin exerts anxiolytic and antidepressant effects, whereas vasopressin tends to exert anxiogenic and depressogenic effects. Evidence from pharmacological and genetic association studies supports their involvement in individual variation in emotional traits extending into psychopathology. Based on their opposing effects on emotional behavior, we suggest that balanced activity of both brain neuropeptide systems is important for appropriate emotional behavior.

1. Neumann ID, Landgraf R. Balance of brain oxytocin and vasopressin: implications for anxiety, depression, and social behaviors. Trends Neurosci. 2012 Nov;35(11):649-59. doi: 10.1016/j.tins.2012.08.004. Epub 2012 Sep 11. PMID: 22974560.

Oxytocin is involved in social selectivity, including increased aggression toward outside social groups and reduced huddling with unfamiliar individuals Oxytocin may support existing social structures or relationships at the expense of other groups and relationships. The effects of OT extend beyond maternal attachment and pair bonding and play a role in affiliative behavior underlying “friendship,” the organization of broad social structures, and the maintenance of established social relationships with individuals or groups.

1. Anacker AM, Beery AK. Life in groups: the roles of oxytocin in mammalian sociality. Front Behav Neurosci. 2013 Dec 11;7:185. doi: 10.3389/fnbeh.2013.00185. PMID: 24376404; PMCID: PMC3858648.

In kindergarten boys, salivary oxytocin levels are NEGATIVELY correlated with their generosity in distributing candy – both to children from their own kindergarten group and to children from other groups. However, in girls, salivary oxytocin is POSITIVELY correlated with generosity toward children in their own group, but shows no correlations with generosity toward children from other groups.

1. Fujii T, Schug J, Nishina K, Takahashi T, Okada H, Takagishi H. Relationship between Salivary Oxytocin Levels and Generosity in Preschoolers. Sci Rep. 2016 Dec 8;6:38662. doi: 10.1038/srep38662. PMID: 27929138; PMCID: PMC5144141.

In nonhuman mammals, oxytocin plays a decisive role in recognition of peers and social approach. In humans, oxytocin has been found to increase trust and the ability to interpret the emotions of other people. It has been suggested that oxytocin may improve face processing by increasing attention to the eye region of human faces.

In a double-blind randomized placebo-controlled between-subjects study, the authors tracked the eye movements of 52 healthy male volunteers who were presented with 24 neutral human faces after intranasal administration of 24 IU oxytocin or placebo.

Results: Participants receiving oxytocin showed a greater number of fixations and greater total gaze time toward the eye region compared with participants receiving placebo.

Conclusions: Oxytocin specifically increases gaze toward the eye region of human faces. This may be one of the mechanisms by which oxytocin improves emotion recognition, interpersonal communication, and social behavior in humans. The findings suggest a possible role for oxytocin in the treatment of disorders characterized by gaze avoidance and deficits in face processing.

1. Adam J. Guastella, Philip B. Mitchell, Mark R. Dadds. Oxytocin Increases Gaze to the Eye Region of Human Faces. Biological Psychiatry. Volume 63, Issue 1, 2008, Pages 3-5, ISSN 0006-3223, https://doi.org/10.1016/j.biopsych.2007.06.026. (https://www.sciencedirect.com/science/article/pii/S0006322307006178)

In addition to various reproductive stimuli, the neuropeptide oxytocin (OXT) is released both from the neurohypophyseal terminal into the bloodstream and in discrete brain regions in response to stressful or social stimuli. Brain OXT-receptor-mediated actions have been shown to be substantially involved in the regulation of diverse behaviors. The article discusses additional methodological approaches that have been used to identify, for example, anxiolytic and anti-stress effects of OCT in both females and males, effects localized in the central amygdala and the paraventricular nucleus of the hypothalamus. In addition, in male rats, activation of the brain OXT system is important for regulation of sexual behavior. and increased activity of the OXT system during mating is directly associated with attenuation of anxiety-related behavior. Moreover, during late pregnancy and lactation, central OXT is involved in establishing and precisely maintaining maternal care and maternal aggression. In monogamous prairie voles, brain OXT is important for mating induced by mating, particularly in females. Another example of the behavioral actions of intracerebral OXT is the facilitation of social memory processes and recognition of specific features found in rats, mice, sheep, and voles. Experimental evidence suggests that in humans, brain OXT exerts similar behavioral effects. Thus, the brain OXT system appears to be a potential target for the development of therapeutics for disorders associated with anxiety and depression, or abnormal social behavior, including autism.

1. Neumann ID. Brain oxytocin: a key regulator of emotional and social behaviours in both females and males. J Neuroendocrinol. 2008 Jun;20(6):858-65. doi: 10.1111/j.1365-2826.2008.01726.x. PMID: 18601710. https://pubmed.ncbi.nlm.nih.gov/18601710/

Despite the dominant role of the hormone oxytocin (OT) in social behavior, little is known about the role of OT in the perception of social relationships. In addition, it is unclear whether there are sex differences in how OT affects social perception. Here we used a double-blind, placebo-controlled crossover design to investigate the effect of OT on accurate social perception. After treatment, 62 participants completed an interpersonal perception task - a method for assessing the accuracy of social judgments that requires identifying relationships between people interacting in real video clips, divided into three categories: kinship, intimacy, and competition. The findings suggest that OT generally influenced improvement in accurate perception of social interactions. Moreover, we show that OT also incorporates sex characteristics. The interaction between oxytocin treatment, task category, and sex showed that OT selectively improves recognition of kinship in women but not in men, whereas men’s performance improves after OT only for recognition of competitive relationships. It is concluded that the sex-related findings presented here may indicate certain biosocial differences in the effect of OT, which may be expressed in women’s propensity for communal and familial social behavior as opposed to men’s propensity for competitive social behavior.

1. Fischer-Shofty M, Levkovitz Y, Shamay-Tsoory SG. Oxytocin facilitates accurate perception of competition in men and kinship in women. Soc Cogn Affect Neurosci. 2013 Mar;8(3):313-7. doi: 10.1093/scan/nsr100. Epub 2012 Mar 24. PMID: 22446301; PMCID: PMC3594723. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3594723/

Human amygdala function is strongly modulated by oxytocin. The authors used functional magnetic resonance imaging to visualize amygdala activation by fear-inducing visual stimuli in 15 healthy men after double-blind crossover intranasal administration of placebo or oxytocin. Compared with placebo, oxytocin significantly reduced amygdala activation and reduced connectivity of the amygdala with brainstem regions involved in autonomic and behavioral manifestations of fear. Our results indicate a neural mechanism for the effect of oxytocin on social cognition in the human brain and provide a methodology and rationale for studying therapeutic strategies for disorders involving abnormal amygdala function, such as social phobia or autism. oxytocin significantly reduces amygdala activation and reduces connectivity of the amygdala with brainstem regions involved in autonomic and behavioral manifestations of fear.

1. Kirsch P, Esslinger C, Chen Q, Mier D, Lis S, Siddhanti S, Gruppe H, Mattay VS, Gallhofer B, Meyer-Lindenberg A. Oxytocin modulates neural circuitry for social cognition and fear in humans. J Neurosci. 2005 Dec 7;25(49):11489-93. doi: 10.1523/JNEUROSCI.3984-05.2005. PMID: 16339042; PMCID: PMC6725903. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6725903/

Use of Oxytocin for the Treatment of Mental Disorders and Correction of Mental States:

Oxytocin may be useful for reducing undesirable symptoms or improving the condition in mental disorders, including:

autism ( Meyer-Lindenberg et al., 2011 ; Geng et al., 2018 ),

depression ( MacDonald et al., 2013 ; Kim et al. ., 2014 ),

anxiety ( Jones et al., 2017 ),

social phobia, schizophrenia ( Jarskog et al., 2017 ),

To date, the most consistent positive results have been demonstrated with respect to the treatment of alcohol dependence ( Pedersen et al., 2013 ; Pedersen, 2017 )

and autism (Hollander et al., 2003 , 2007 ; Guastella et al., 2010 ; Tauber et al., 2011 ; Aoki et al., 2014 ; Watanabe et al., 2015 ; Yamasue, 2016 ; Higashida et al., 2019 ).

Administration of high doses of OT (80 IU / day) for several weeks has a significant positive effect on schizophrenia ( Zheng et al., 2019 ).

Likewise, repeated intranasal administration of oxytocin during the early post-trauma period reduces the subsequent development of post-traumatic stress disorder symptoms in recently traumatized emergency department patients with pronounced acute post-traumatic stress disorder symptoms ( Frijling, 2017 ).

The mixed results of OT administration for some social disorders are partly attributed to an enhanced “social salience effect,” whereby OT increases the salience of both positive and negative social stimuli, leading to enhanced prosocial behavior in a positive environment but eliciting defensive and, purportedly, “antisocial behavior” in a negative (competitive or potentially dangerous) environment, which, however, when the behavior is considered in context, represents an adaptive response to socially unsafe or provocative cues ( Bartz et al., 2011 ; Bakermans-Kranenburg et al., 2012 ; Bakermans-Kranenburg et al., 2013 ; Tabak, 2013 ; Ne’eman et al., 2016). Although OT is primarily associated with prosocial behavior, it also acts as a “boundary-setting” hormone, influencing, for example, maternal aggression toward intruders experimentally placed in a maternal cage with offspring present ( Bosch, 2013 ). For example, in highly anxious female rodents, levels of intracerebral OT release correlate with maternal aggression toward an intruder ( Bosch et al., 2005 ), whereas in low-anxiety strains - infusion of synthetic OT into the paraventricular nucleus by retrodialysis. increases maternal aggression directed at an intruder ( Bosch and Neumann, 2012 ). Attachment status, history (experience) of care (participation in grooming), and genotype also influence different outcomes of OT administration ( Macdonald, 2012 ;Riem et al., 2013 ; Feldman and Bakermans-Kranenburg, 2017 ). Most research on OT administration has been based on single-dose treatment, whereas many of the conditions that have been targeted for treatment are considered persistent or long-lasting, requiring prolonged treatment - for a review of chronic OT administration. see Horta et al. (2020) . Moreover, as animal studies show, differential effects of OT across species are partly mediated by different species-specific distributions of OT receptors ( Insel, 2010).).

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Oxytocin in Behavior Modification

Oxytocin (OT) has been one of the most intensively studied neuropeptides over the past three decades. In a favorable social context, OT exerts a range of desirable socioemotional, stress-reducing, and immunoregulatory effects in mammals and humans and influences their parenting. Developmental programming studies conducted in rodent mothers (rats, mice) have demonstrated the susceptibility of offspring endogenous OT systems to maternal somatosensory stimulation, with consequences for behavioral, epigenetic, cognitive, and neurological outcomes. Prolonged physical contact with healthy full-term infants for several months after birth (carrying the infant) may represent the human equivalent of this specific rodent maternal behavior, which has been found to positively affect developing OT systems.

Key Points:

• Oxytocin is involved in positive physiological and psychological adaptation with significant health consequences across the lifespan.

• Oxytocin systems are shaped by early bidirectional parent-infant somatosensory stimulation.

• Increasing clinical support for parents of full-term newborns in skin-to-skin contact represents a promising route for influencing oxytocin systems.

1. Norholt H. Delivering Clinically on Our Knowledge of Oxytocin and Sensory Stimulation: The Potential of Infant Carrying in Primary Prevention. Front Psychol. 2021 Apr 29;11:590051. doi: 10.3389/fpsyg.2020.590051. PMID: 33995157; PMCID: PMC8116555.

SOCIAL AFFILIATIVE EFFECTS OF OXYTOCIN AND C-TACTILE TOUCH MEDIATED THROUGH INCREASED OXYTOCIN CONCENTRATION AND ACTIVITY (affiliativeness - a person’s need to create warm, trusting, emotionally meaningful relationships with other people)

Touching another person can evoke strong emotions. People are remarkably accurate at detecting a wide range of emotional messages even when they are conveyed exclusively through touch ( Hertenstein et al., 2006a ). A series of observational studies has shown that brief, incidental touch from strangers can have positive behavioral effects in people and even make them more generous. Restaurant patrons give larger tips if a waitress touches them while returning change ( Crusco and Wetzel, 1984 ), and people are more satisfied with a library visit if the librarian lightly touches their hand ( Fisher et al., 1976 ). Similar studies show that when touched incidentally, people are more likely to return money left in a public telephone (Kleinke, 1977 ), spend money in a supermarket ( Hornik, 1992 ), evaluate salespeople in car dealerships more positively ( Erceau and Guguen, 2007 ), or give away cigarettes ( Joule and Gueguen, 2007 ). There are also studies indicating positive health effects of touch in therapeutic relationships ( Whitcher and Fisher, 1979 ; Eaton et al., 1986 ; Monroe, 2009 ) and in romantic couples ( Grewen et al., 2003 ; Ditzen et al., 2007).

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5. Hornik J. (1992). Tactile stimulation and consumer response. J. Consum. Res. 19 449–458. 10.1086/209314 https://dx.doi.org/10.1086%2F209314

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12. Ditzen B., Neumann I. D., Bodenmann G., von Dawans B., Turner R. A., Ehlert U., et al. (2007). Effects of different kinds of couple interaction on cortisol and heart rate responses to stress in women. Psychoneuroendocrinology 32 565–574. 10.1016/j.psyneuen.2007.03.011 https://www.ncbi.nlm.nih.gov/pubmed/17499441

Oxytocin increases trust, but only during initial contact, that is, under conditions of uncertainty and information scarcity ( Tops et al., 2014 ). One study showed that participants’ salivary oxytocin while awaiting a cognitive task was positively correlated with state trust during the initial session but negatively correlated with trust during a subsequent session when participants were familiar with the task (Tops et al., 2013 ). Similarly, another study reported that intranasal oxytocin increased affiliative behavior in a clinical interview for depression during the first visit, but not during the follow-up visit ( Brune et al., 2015 ).

1. Tops M., Koole S. L., IJzerman H., Buisman-Pijlman F. T. A. (2014). Why social attachment and oxytocin protect against addiction and stress: Insights from the dynamics between ventral and dorsal corticostriatal systems. Pharmacol. Biochem. 119 39–48. 10.1016/j.pbb.2013.07.015 https://www.ncbi.nlm.nih.gov/pubmed/23916423

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3. Brune M., Kolb M., Ebert A., Roser P., Edel M. A. (2015). Nonverbal communication of patients with borderline personality disorder during clinical interviews a double-blind placebo-controlled study using intranasal oxytocin. J. Nerv. Ment. Dis. 203 107–111. 10.1097/NMD.0000000000000240 https://www.ncbi.nlm.nih.gov/pubmed/25594788

A series of studies assessing endogenous peripheral oxytocin levels suggests a role for oxytocin in affiliative human contact ( Lupoli et al., 2001 ; Matthiesen et al., 2001 ; Uvnas-Moberg, 2004 ; Light et al., 2005 ), although the precise mechanisms are unclear ( Feldman, 2012 ). One study showed that maternal plasma oxytocin levels during pregnancy and the early postpartum period predict maternal bonding behaviors such as gaze, high-pitched vocalizations, and affectionate touch toward the infant ( Feldman et al., 2007). Another study reported that higher plasma oxytocin levels correlated with more frequent stimulating touches directed toward infants by newlywed fathers and with more frequent affectionate touches (for example, hugging, kissing, and stroking) by new mothers ( Gordon et al. , 2010 ). In addition, one study showed that couples instructed to perform 30 minutes of reciprocal “warm, sensual” touching of their partner’s neck, shoulders, and arms three days per week for 4 weeks had elevated salivary oxytocin levels after the intervention, as well as reductions in stress-sensitive markers such as blood pressure, plasma cortisol, and alpha-amylase, compared with a control group ( Holt-Lunstad et al., 2008).

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People who have a well-developed oxytocin system will interact with others in a safe and trusting manner, and their ability to cope with stressful situations will be optimized (Uvnäs-Moberg, 1996 , 2006 ; Tops et al., 2007 , 2014 ). Findings from some studies showing higher oxytocin levels in people with secure attachment than in people with insecure attachment support the role of a well-functioning oxytocin system in securely attached individuals ( Tops et al., 2007 ; Gordon et al., 2008 ) . In addition, administration of an oxytocin spray has been demonstrated to improve the security of interpersonal attachment ( Buchheim et al., 2009 ).

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Social Touch Facilitates Communication Between Females Through Activation of Parvocellular Oxytocin Neurons.

Oxytocin (OT) is an excellent aid in social life, but although its effects on socially relevant brain regions have been widely studied, the activity of OT neurons during real social interactions remains unstudied. Most OT neurons are magnocellular neurons that simultaneously project to pituitary and forebrain regions involved in social behavior. Tang et al., 2020, showed that a much smaller population of OT neurons, parvocellular neurons, which project not to the pituitary but synapses onto magnocellular neurons, are preferentially activated by somatosensory stimuli. This activation is transmitted to the larger population of magnocellular neurons, which consequently show a coordinated increase in their activity during social interactions between virgin female rats. Selective activation of these parvocellular neurons promotes social motivation, whereas their inhibition reduces social interactions. Thus, parvocellular OT neurons receive specific inputs for controlling social behavior by coordinating the responses of a much larger population of magnocellular OT neurons.

1. Tang Y, Benusiglio D, Lefevre A, Hilfiger L, Althammer F, Bludau A, Hagiwara D, Baudon A, Darbon P, Schimmer J, Kirchner MK, Roy RK, Wang S, Eliava M, Wagner S, Oberhuber M, Conzelmann KK, Schwarz M, Stern JE, Leng G, Neumann ID, Charlet A, Grinevich V. Social touch promotes interfemale communication via activation of parvocellular oxytocin neurons. Nat Neurosci. 2020 Sep;23(9):1125-1137. doi: 10.1038/s41593-020-0674-y. Epub 2020 Jul 27. PMID: 32719563.

Social contact reduces the stress response in social animals. Mice (females) engage in caring allogrooming toward socially defeated conspecifics. Following allogrooming behavior, the percentage of oxytocin-receptor-expressing neurons expressing c-Fos protein was significantly increased in the anterior olfactory nucleus, cingulate cortex, insular cortex, and so on. lateral septum and medial amygdala of female mice. This suggests that oxytocin-receptor-expressing neurons in these regions were activated during allogrooming behavior toward distressed conspecifics. The duration of allogrooming correlated with the percentage of oxytocin-receptor-expressing neurons expressing c-Fos protein in the anterior olfactory nucleus, insular cortex, lateral septum, and medial amygdala. In oxytocin-receptor-deficient mice, allogrooming behavior toward socially defeated cage mates was markedly reduced in female mice but not in male mice, indicating the importance of the oxytocin receptor for allogrooming behavior in female mice toward distressed conspecifics. The results suggest that the oxytocin receptor is involved in female-mouse allogrooming behavior toward “beaten” conspecifics - possibly in the anterior olfactory nucleus, insular cortex, lateral septum, and / or medial amygdala,

1. Matsumoto M, Yoshida M, Jayathilake BW, Inutsuka A, Nishimori K, Takayanagi Y, Onaka T. Indispensable role of the oxytocin receptor for allogrooming toward socially distressed cage mates in female mice. J Neuroendocrinol. 2021 May 14;33(6):e12980. doi: 10.1111/jne.12980. Epub ahead of print. PMID: 34057769; PMCID: PMC8243938.

How the Brain Codes Intimacy: The Neurobiological Basis of Romantic Touch. Oxytocin Enhances Preference for Close Familiar People by Increasing Pleasure from Contact with Them (but Not with Strangers).

Humans belong to the minority of mammalian species that have monogamous pair bonds, enabling biparental care of offspring. The high value of interpersonal closeness and touch in couples is a key mechanism facilitating the maintenance of strong romantic bonds. Surprisingly, however, the neurobiological substrates mediating the unique experience of touch from a romantic partner remain unknown. In this randomized placebo-controlled between-group pharmacofunctional magnetic resonance imaging (fMRI) study involving 192 healthy volunteers (96 heterosexual couples), 24 IU of the hypothalamic peptide oxytocin (OXT) was administered intranasally to either the man or the woman. Participants were then scanned while they believed they were being touched by their romantic partners or by unfamiliar people of the opposite sex, although in reality an identical pattern of touch was always delivered by the same experimenter. The results show that intranasal OXT compared with placebo selectively enhanced the subjective pleasantness of touch only from the imagined romantic partner. Importantly, intranasal OXT selectively increased the response to partner touch in the nucleus accumbens (NAcc) and anterior cingulate cortex. Under intranasal oxytocin, NAcc activation for partner touch positively correlated with participants’ ratings of the quality of their relationships. The results suggest that OXT may facilitate the maintenance of monogamous relationships in humans by simultaneously increasing the value of partner touch and reducing the hedonic quality of touch from a stranger.

1. Kreuder AK, Scheele D, Wassermann L, Wollseifer M, Stoffel-Wagner B, Lee MR, Hennig J, Maier W, Hurlemann R. How the brain codes intimacy: The neurobiological substrates of romantic touch. Hum Brain Mapp. 2017 Sep;38(9):4525-4534. doi: 10.1002/hbm.23679. Epub 2017 Jun 5. PMID: 28580708; PMCID: PMC6867116.

Oxytocin and Stress

In humans, oxytocin reduces the release of adrenocorticotropic hormone (ACTH; Chiodera and Coiro, 1987 ) and cortisol ( Legros et al., 1988 ) in response to stressful stimuli. In rats, central oxytocin blockade increases basal and stress-induced release of ACTH and corticosterone ( Neumann et al., 2000b). However, a study using local injection of an oxytocin antagonist indicates different effects on stress responses depending on the brain site. Local blockade of the paraventricular nuclei (PVN) led to an increase in basal ACTH levels but reduced stress-induced ACTH release, possibly because of the increase in baseline levels. On the other hand, injections into the amygdala and mediolateral septum, which project directly or indirectly to the PVN, do not alter basal ACTH levels but reduce stress-induced ACTH ( Neumann et al., 2000a ). Because oxytocin influences both stress regulation and social bonding, it has been suggested that the calming and anxiolytic effects of stroking in mammals are mediated by oxytocin ( Uvnas-Moberg et al., 2014 ). In squirrel monkeys, intranasal oxytocin suppressed the increase in plasma ACTH levels in response to (stressful) social isolation. However, plasma cortisol levels were not affected ( Parker et al., 2005 ).

Oxytocin may counteract stress-axis activity in many ways. It is well known that oxytocin released from nerves in the hypothalamus and in the anterior pituitary inhibits the secretion of CRF and ACTH, respectively, and that circulating oxytocin can inhibit cortisol secretion directly by the adrenal glands ( Stachowiak et al., 1995 ; Petersson et al., 1999 ; Neumann, 2002 ).

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2. Legros J. J., Chiodera P., Geenen V. (1988). Inhibitory action of exogenous oxytocin on plasma cortisol in normal human subjects: evidence of action at the adrenal level. Neuroendocrinology 48 204–206. 10.1159/000125009 https://www.ncbi.nlm.nih.gov/pubmed/2851753

3. Neumann I. D., Wigger A., Torner L., Holsboer F., Landgraf R. (2000b). Brain oxytocin inhibits basal and stress-induced activity of the hypothalamo-pituitary-adrenal axis in male and female rats: partial action within the paraventricular nucleus. J. Neuroendocrinol. 12 235–243. 10.1046/j.1365-2826.2000.00442.x https://www.ncbi.nlm.nih.gov/pubmed/10718919

4. Neumann I. D., Kromer S. A., Toschi N., Ebner K. (2000a). Brain oxytocin inhibits the (re)activity of the hypothalamo-pituitary-adrenal axis in male rats: involvement of hypothalamic and limbic brain regions. Regul. Pept. 96 31–38. 10.1016/S0167-0115(00)00197-X https://www.ncbi.nlm.nih.gov/pubmed/11102649

5. Uvnas-Moberg K., Handlin L., Petersson M. (2014). Self-soothing behaviors with particular reference to oxytocin release induced by non-noxious sensory stimulation. Front. Psychol. 5:1529 10.3389/fpsyg.2014.01529 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4290532/

6. Parker K. J., Buckmaster C. L., Schatzberg A. F., Lyons D. M. (2005). Intranasal oxytocin administration attenuates the ACTH stress response in monkeys. Psychoneuroendocrinology 30 924–929. 10.1016/j.psyneuen.2005.04.002 https://www.ncbi.nlm.nih.gov/pubmed/15946803

7. Stachowiak, A., Macchi, C., Nussdorfer, G. G., and Malendowicz, L. K. (1995).Effects of oxytocin on the function and morphology of the rat adrenal cortex:in vitro and in vivo investigations. Res. Exp. Med. (Berl.) 195, 265–274. doi:10.1007/BF02576797

8. Petersson, M., Hulting, A. L., and Uvnäs-Moberg, K. (1999). Oxytocin causes asustained decrease in plasma levels of corticosterone in rats. Neurosci. Lett. 264,41–44. doi: 10.1016/S0304-3940(99)00159-7

9. Neumann, I. D. (2002). Involvement of the brain oxytocin system in stress coping: interactions with the hypothalamo-pituitary-adrenal axis. Prog. Brain Res. 139, 147–162. doi: 10.1016/S0079-6123(02)39014-9

10. Neumann, I. D. (2002). Involvement of the brain oxytocin system in stress coping:interactions with the hypothalamo-pituitary-adrenal axis. Prog. Brain Res. 139,147–162. doi: 10.1016/S0079-6123(02)39014-9

Consequences of Low Oxytocin-System Function

Of particular interest is that some people with insecure interpersonal attachment not only have lower oxytocin levels than people with secure attachment, but also have an increased risk of developing certain symptoms and diseases. People with insecure attachment more often report high levels of anxiety, depression, and stress than those who are securely attached (see review Julius et al., 2013 ). In addition, they have an increased risk of pain and inflammation ( Davies et al., 2009 ). For example, women with insecure attachment more often experience pain during labor contractions and during sexual intercourse (dyspareunia; Granot et al., 2011 ; Costa-Martins et al., 2014) than those with secure attachment. Because oxytocin released in the brain from nerves originating in the PVN is involved not only in regulation of social interaction and anxiety but also in regulation of pain and inflammation, low oxytocinergic-system function may underlie or at least contribute to the expression of the corresponding symptoms in people with insecure interpersonal attachment.

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In addition, impaired oxytocin-system function has been demonstrated in certain medical conditions that may in fact overlap to some extent with insecure attachment. Low oxytocin levels, for example, have been demonstrated in individuals with borderline mental disorder, certain types of depression, and schizophrenia (see review in Kim et al., 2013 ). Some pain syndromes, such as fibromyalgia and recurrent abdominal pain in children, are also associated with low oxytocin levels ( Alfven et al., 1994 ; Anderberg and Uvnäs-Moberg, 2000 ). In addition, previous experience of psychotraumatic events is associated with an increased incidence of low oxytocin levels or stress-related decreases in oxytocin levels ( Pierrehumbert et al., 2010 ).

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However, it is important to note that low and high oxytocin levels cannot always be categorized as bad or good. Because peripheral oxytocin levels, as well as the effects of oxytocin, depend on many different factors, other relationships also exist ( Bartz et al., 2011 ). For example, oxytocin levels show two peaks during encounters with other people: one when meeting and approaching another person, and another during close contact and receipt of sensory stimulation from another person. The first peak is associated with arousal and increased stress-axis activity, whereas the second peak is associated with reduced stress levels ( Rehn et al., 2014). From this perspective, a high oxytocin level may represent either the “frustrated approach or reward seeking” aspect of oxytocin or the “satisfied calmness” aspect arising from receipt of rewarding sensory stimulation.

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Effects of Oxytocin on Social Hierarchy

Several animal studies have demonstrated an effect of oxytocin on the formation and maintenance of social hierarchy. Consistent with their social hierarchy, dominant female rhesus macaques had higher serum oxytocin levels than subordinate monkeys (Michopoulos et al., 2011 ). Likewise, mRNA expression of genes associated with the oxytocin receptor in the medial amygdala of subordinate rats was lower than in dominant rats (Timmer et al.,2011 ). However, the precise functional role of oxytocin in the perception and learning of social dominance remains unclear.

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Mutual Influence of Serotonin and Oxytocin:

Oxytocin modulates serotonergic activity ( Yoshida et al., 2009 ). Oxytocin infusion in mice promoted serotonin release in the median raphe nucleus and reduced anxiety-related behavior. A serotonin 2A / 2C receptor antagonist blocked the anxiolytic effect of oxytocin, from which it follows that activation of the oxytocin receptor mediates the anxiolytic effects of oxytocin specifically in serotonergic neurons and through effects on the serotonin system (activating it). This is the first demonstration that oxytocin can regulate serotonin release and exert an anxiolytic effect through direct activation of the oxytocin receptor expressed in serotonergic neurons of the raphe nuclei.

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1. Yoshida M., Takayanagi Y., Inoue K., Kimura T., Young L. J., Onaka T., et al. (2009). Evidence that oxytocin exerts anxiolytic effects via oxytocin receptor expressed in serotonergic neurons in mice. J. Neurosci. 29, 2259–2271. 10.1523/JNEUROSCI.5593-08.2009 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6666325/

It is suggested that oxytocin secretion occurring during activation of serotonin 5-HT1A receptors may contribute to the prosocial, anti-aggressive, and anxiolytic effects observed during activation of serotonin 5-HT₁A receptors:

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Activation of 5-HT2A Receptors in the Hypothalamus Causes an Increase in Oxytocin Levels:

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Serotonin receptors of the 5-HT 2C type may also participate in oxytocin release. In rats, restraint stress (which can cause depressive symptoms if chronic) causes secretion of prolactin, ACTH, vasopressin, and oxytocin that is partially mediated by the 5-HT 2C receptor. Responses during conditions such as dehydration or hemorrhage cause oxytocin release through a serotonergic response that is partially mediated by 5-HT 2C.

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Laboratory experiments in animals have shown that MDMA also activates pituitary oxytocin neurons, mainly through stimulation of serotonergic 5-HT1A receptors. Some experiments provide evidence that the empathy effect caused by MDMA is directly associated with release of the “attachment hormone” oxytocin, which occurs because of stimulation of 5-HT1A receptors by serotonin released under the influence of MDMA.

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Thus, there are grounds to suppose that a number of serotonin effects may be mediated by release of the hormone oxytocin induced by serotonin. However, we were unable to find in the literature any data on correlations between levels of oxytocin and serotonin (or its metabolites) in the body’s biological fluids.

Pharmacological studies indicate a functional interaction between the serotonergic and oxytocinergic systems. In particular, some selective serotonin (5-HT) reuptake inhibitors, such as citalopram and fluvoxamine, appear to exert their antidepressant action partly through oxytocin (OT) release. In addition, administration of fenfluramine, a serotonergic agonist, to healthy subjects increases plasma OT levels. Interestingly, immunocytochemical and double immunofluorescence methods revealed a high degree of overlap between fibers labeled with the 5-HT transporter (SERT) and OT-containing cells of the paraventricular and supraoptic nuclei of the primate hypothalamus. These data suggest that the influence of 5-HT on the OT system may be mediated by SERT. Marazziti et al., 2012, investigated the possible existence of a relationship between OT and SERT in humans using two peripheral markers, platelet SERT measured by [³H] -paroxetine ([³H] -Par) binding, and plasma OT levels. With respect to [³H] -Par binding parameters, Bmax (mean ± standard deviation, fmol / mg protein) was 1155 + 130, and Kd (mean ± standard deviation, nM) was 1,31 ± 0,61. Plasma OT levels (mean ± standard deviation, pg / ml) were 1,14 ± 1,07. A significant and positive correlation was found between plasma OT levels and Kd values (correlation coefficient: r: 0,466, p = 0,038). This result represents the first evidence of an interaction between oxytocin (OT) and the serotonin transporter SERT, which is measured by [³H] -Par binding at peripheral levels in humans.

1. Marazziti D, Baroni S, Giannaccini G, Betti L, Massimetti G, Carmassi C, Catena-Dell’Osso M. A link between oxytocin and serotonin in humans: supporting evidence from peripheral markers. Eur Neuropsychopharmacol. 2012 Aug;22(8):578-83. doi: 10.1016/j.euroneuro.2011.12.010. Epub 2012 Jan 31. PMID: 22297159.

The interaction of serotonin (5-HT) and oxytocin (OXT) in the regulation of emotional behavior was studied by administering OXT or placebo to 24 healthy men and mapping the cerebral 5-HT system using the 5-HT1A receptor antagonist 2’-methoxyphenyl- (N-2’-pyridinyl) -p- [ (18) F] fluorobenzamidoethylpiperazine ([(18) F] MPPF).

OXT increased the nondisplaceable binding potential of [(18) F] MPPF (BPND) in the dorsal raphe nucleus (DRN), the central region of 5-HT synthesis, as well as in the amygdala / hippocampal complex, insula, and orbitofrontal cortex. Importantly, the amygdala occupies a central position in the regulation of 5-HT by OXT: [(18) F] MPPF BPND changes in the DRN correlate with changes in the right amygdala, which in turn correlated with changes in the hippocampus, insula, subgenual and orbitofrontal cortex, a circuit involved in the control of stress, mood, and social behavior. OXT administration is known to suppress amygdala activity and lead to reduced anxiety, whereas high amygdala activity and dysregulation of 5-HT are associated with increased anxiety. The 5-HT and OXT systems are both involved in the avoidance / approach motivational system: 5-HT is involved in regulation of defensive, repulsive behavior and harm-avoidance behavior, whereas OXT is known for its role in affiliative behavior and closeness. care and caregiving. The present study reveals a previously unidentified form of interaction between these two systems in the human brain, namely the role of OXT in the inhibitory regulation of 5-HT signaling

1. Raphaelle Mottolese, Jérôme Redouté, Nicolas Costes, Didier Le Bars, and Angela Sirigu. Switching brain serotonin with oxytocin. PNAS June 10, 2014 111 (23) 8637-8642; first published May 27, 2014; https://doi.org/10.1073/pnas.1319810111

Serum serotonin and oxytocin levels were simultaneously studied in two mixed-sex groups: patients with obesity (N=47), and a control group (N=24). In the obesity group, levels of both serotonin and oxytocin were simultaneously reduced, while negative correlations with body mass index for both hormones within the obesity group were high in absolute magnitude and significant (within the control group – non-significant). In the group of patients with obesity, there was also a high positive and significant correlation between serotonin and oxytocin levels. Within the control group, a positive correlation between serotonin and oxytocin was also observed, although of smaller magnitude.

1. Rasha Hasan Jasim. A New Biochemical Trying to Evaluate Levels of Oxytocin and Serotonin in the Serum of Patients Undergoing to Different Strategies for Reducing. Journal of Pharmaceutical Sciences and Research 10(3). March 2018. https://www.researchgate.net/publication/324068635_A_New_Biochemical_Trying_to_Evaluate_Levels_of_Oxytocin_and_Serotonin_in_the_Serum_of_Patients_Undergoing_to_Different_Strategies_for_Reducing_Weight

Interaction Between Central Serotonin and Oxytocin Systems in Social Monitoring

Oxytocin is broadly involved in social cognition, influencing several stages of social processing, including social attention and evaluation ( Piva & Chang, 2018 ). Oxytocin has been shown to increase attention to social stimuli ( Dal Monte et al., 2017 ; Parr et al., 2016 ), especially to the eye region ( Dal Monte, Noble, Costa, & Averbeck, 2014 ; Kotani et al., 2017 ), as well as to increase attention ( Putnam et al., 2016 ; Tollenaar, Chatzimanoli, van der Wee, & Putman, 2013 ). Increased central OT also appears to enhance social preferences ( Chang, Barter, Ebitz, Watson, & Platt, 2012 ), regulate social vigilance (Ebitz, Watson, & Platt, 2013 ; Landman, Sharma, Sur, & Desimone, 2014 ), and differentially affect attention and brain activation depending on facial expression ( Domes, Steiner, Porges, & Heinrichs, 2013 ; Liu et al., 2015 ; Parr, Modi, Siebert, & Young, 2013 ).

Oxytocin and serotonin are increasingly being studied in tandem. Studies have shown that OT receptors are expressed in serotonergic cells in the rodent DRN ( Pagani et al., 2015 ; Yoshida et al., 2009 ), and that fibers containing the serotonin transporter overlap with oxytocin-labeled cells in nonhuman primates ( Emiliano , Cruz, Pannoni, & Fudge, 2007 ). It has also been shown that increasing central serotonin release by various methods, including serotonin receptor agonists, causes OT release in rodents, nonhuman primates, and humans ( Bagdy & Kalogeras, 1993 ; Jørgensen, Riis, Knigge, Kjaer & Warberg , 2003 ; Marazziti et al., 2012.). Mottolese and colleagues also found that administration of OT, compared with placebo, increases serotonin binding potential in regions associated with social processing, attention, and evaluation in humans: the DRN, amygdala / hippocampal complex, insula, and orbitofrontal cortex ( Mottolese, Redouté, Costes , Le Bars and Sirigu, 2014 ). This relationship is also present in the macaque brain ( Lefevre, Richard, et al., 2017 ). However, recruitment of 5-HT by OT appears to be severely impaired in people with autism spectrum disorders, suggesting that interaction between OT and 5-HT is critical for typical social behavior, including monitoring others ( Lefevre, Mottolese, et al. , 2017). In addition, Dölen and colleagues found that in mice, coordinated activity between OT and 5-HT in the nucleus accumbens is necessary to enhance social interactions ( Dölen, Darvishzadeh, Huang, & Malenka, 2013 ). Thus, it has been hypothesized that both oxytocin and serotonin influence social attention and social monitoring in tandem. It would be interesting to further study the interaction between OT and 5-HT and their influence on social behavior, particularly social monitoring and aggressive behavior, in the future.

See review in:
Weinberg-Wolf H, Chang SWC. Differences in how macaques monitor others: Does serotonin play a central role? Wiley Interdiscip Rev Cogn Sci. 2019 Jul;10(4):e1494. doi: 10.1002/wcs.1494. Epub 2019 Feb 18. PMID: 30775852; PMCID: PMC6570566.