Skip to main content
SpringerLink
Log in

The Importance of Experimental Investigation of the CNS Oxytocin System

  • Protocol
  • First Online:
Oxytocin

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2384))

Abstract

This chapter provides an overview of the oxytocinergic system and its role in social behavior. We first consider the relationship between oxytocin and social behavior in neurotypical individuals, focusing on studies that have looked at effects of intranasal oxytocin treatment, as well as research investigating the genetic and epigenetic mechanisms associated with individual differences in social behavior. We then outline the proposed role of the oxytocinergic system in autism spectrum disorder and Williams syndrome, two neurodevelopmental disorders where a dysfunctional oxytocinergic system is thought to lead to difficulties in social behavior. Given the contrasting social phenotypes of these disorders, they provide an intriguing comparison through which we can better understand the role of the oxytocinergic system in social behavior. Finally, we consider how future research can best harness the potential of oxytocin, both by addressing measurement and administration issues inherent in many studies, and by developing our understanding of the oxytocinergic system so we are better able to identify the people who are likely to benefit from oxytocin treatment, and intervene at the right time.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 139.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Carter CS (2014) Oxytocin pathways and the evolution of human behavior. Annu Rev Psychol 65(1):17–39

    Article  PubMed  Google Scholar 

  2. Ross HE, Young LJ (2009) Oxytocin and the neural mechanisms regulating social cognition and affiliative behavior. Front Neuroendocrinol 30(4):534–547

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Carter CS, Porges SW (2013) The biochemistry of love: an oxytocin hypothesis. EMBO Rep 14(1):12–16

    Article  CAS  PubMed  Google Scholar 

  4. Shamay-Tsoory SG, Abu-Akel A (2016) The social salience hypothesis of oxytocin. Biol Psychiatry 79(3):194–202

    Article  CAS  PubMed  Google Scholar 

  5. Feldman R, Zagoory-Sharon O, Weisman O, Schneiderman I, Gordon I, Maoz R et al (2012) Sensitive parenting is associated with plasma oxytocin and polymorphisms in the OXTR and CD38 genes. Biol Psychiatry 72(3):175–181

    Article  CAS  PubMed  Google Scholar 

  6. Leonzino M, Ponzoni L, Braida D, Gigliucci V, Busnelli M, Ceresini I et al (2019) Impaired approach to novelty and striatal alterations in the oxytocin receptor deficient mouse model of autism. Horm Behav 114:104543

    Article  CAS  PubMed  Google Scholar 

  7. Ferguson JN, Aldag JM, Insel TR, Young LJ (2001) Oxytocin in the medial amygdala is essential for social recognition in the mouse. J Neurosci 21(20):8278–8285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bartz JA, Zaki J, Bolger N, Ochsner KN (2011) Social effects of oxytocin in humans: context and person matter. Trends Cogn Sci 15(7):301–309

    CAS  PubMed  Google Scholar 

  9. Guastella AJ, MacLeod C (2012) A critical review of the influence of oxytocin nasal spray on social cognition in humans: evidence and future directions. Horm Behav 61(3):410–418

    Article  PubMed  CAS  Google Scholar 

  10. Macdonald K, Macdonald TM (2010) The peptide that binds: a systematic review of oxytocin and its prosocial effects in humans. Harv Rev Psychiatry 18(1):12–21

    Article  Google Scholar 

  11. Bartz JA, Zaki J, Bolger N, Hollander E, Ludwig NN, Kolevzon A et al (2010) Oxytocin selectively improves empathic accuracy. Psychol Sci 21(10):1426–1428

    Article  PubMed  Google Scholar 

  12. Auyeung B, Lombardo MV, Heinrichs M, Chakrabarti B, Sule A, Deakin JB et al (2015) Oxytocin increases eye contact during a real-time, naturalistic social interaction in males with and without autism. Transl Psychiatry 5(2):e507

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Guastella AJ, Mitchell PB, Dadds MR (2008) Oxytocin increases gaze to the eye region of human faces. Biol Psychiatry 63(1):3–5

    Article  CAS  PubMed  Google Scholar 

  14. Bartz JA, Nitschke JP, Krol SA, Tellier P-P (2019) Oxytocin selectively improves empathic accuracy: a replication in men and novel insights in women. Biol Psychiatry Cogn Neurosci Neuroimaging 4(12):1042–1048

    PubMed  Google Scholar 

  15. Grace SA, Rossell SL, Heinrichs M, Kordsachia C, Labuschagne I (2018) Oxytocin and brain activity in humans: a systematic review and coordinate-based meta-analysis of functional MRI studies. Psychoneuroendocrinology 96:6–24

    Article  CAS  PubMed  Google Scholar 

  16. Wigton R, Jocham Radua PA, Averbeck B, Meyer-Lindenberg A, McGuire P, Shergill SS et al (2015) Neurophysiological effects of acute oxytocin administration: systematic review and meta-analysis of placebo-controlled imaging studies. J Psychiatry Neurosci 40(1):E1

    Article  PubMed  PubMed Central  Google Scholar 

  17. Rilling JK, DeMarco AC, Hackett PD, Thompson R, Ditzen B, Patel R et al (2012) Effects of intranasal oxytocin and vasopressin on cooperative behavior and associated brain activity in men. Psychoneuroendocrinology 37(4):447–461

    Article  CAS  PubMed  Google Scholar 

  18. Leppanen J, Ng KW, Tchanturia K, Treasure J (2017) Meta-analysis of the effects of intranasal oxytocin on interpretation and expression of emotions. Neurosci Biobehav Rev 78:125–144

    Article  CAS  PubMed  Google Scholar 

  19. Rajamani KT, Wagner S, Grinevich V, Harony-Nicolas H (2018) Oxytocin as a modulator of synaptic plasticity: implications for neurodevelopmental disorders. Front Synaptic Neurosci 10:17

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. DeMayo MM, Young LJ, Hickie IB, Song YJC, Guastella AJ (2019) Circuits for social learning: a unified model and application to autism spectrum disorder. Neurosci Biobehav Rev 107:388–398

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Du P, He Z, Cai Z, Hao X, Dong N, Yaun W et al (2017) Chronic central oxytocin infusion impairs sociability in mandarin voles. Pharmacol Biochem Behav 161:38–46

    Article  CAS  PubMed  Google Scholar 

  22. Lefevre A, Sirigu A (2016) The two fold role of oxytocin in social developmental disorders: a cause and a remedy? Neurosci Biobehav Rev 63:168–176

    Article  CAS  PubMed  Google Scholar 

  23. Quintana DS, Rokicki J, van der Meer D, Alnaes D, Kaufmann T, Cordova-Palomera A et al (2019) Oxytocin pathway gene networks in the human brain. Nat Commun 10(1):668

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zhang R, Zhang HF, Han JS, Han SP (2017) Genes related to oxytocin and arginine-vasopressin pathways: associations with autism spectrum disorders. Neurosci Bull 33(2):238–246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Cataldo I, Azhari A, Esposito G (2018) A review of oxytocin and arginine-vasopressin receptors and their modulation of autism spectrum disorder. Front Mol Neurosci 11:27

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Schneiderman I, Kanat-Maymon Y, Ebstein RP, Feldman R (2013) Cumulative risk on the oxytocin receptor gene (OXTR) underpins empathic communication difficulties at the first stages of romantic love. Soc Cogn Affect Neurosci 9(10):1524–1529

    Article  PubMed  PubMed Central  Google Scholar 

  27. Chen FS, Kumsta R, Dvorak F, Domes G, Yim OS, Ebstein RP et al (2015) Genetic modulation of oxytocin sensitivity: a pharmacogenetic approach. Transl Psychiatry 5:e664

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Tops S, Habel U, Radke S (2019) Genetic and epigenetic regulatory mechanisms of the oxytocin receptor gene (OXTR) and the (clinical) implications for social behavior. Horm Behav 108:84–93

    Article  CAS  PubMed  Google Scholar 

  29. Feldman R, Monakhov M, Pratt M, Ebstein RP (2016) Oxytocin pathway genes: evolutionary ancient system impacting on human affiliation, sociality, and psychopathology. Biol Psychiatry 79(3):174–184

    Article  CAS  PubMed  Google Scholar 

  30. van Ijzendoorn MH, Bakermans-Kranenburg MJ, Ebstein RP (2011) Methylation matters in child development: toward developmental behavioral epigenetics. Child Dev Perspect 5(4):305–310

    Article  Google Scholar 

  31. Kumsta R, Hummel E, Chen F, Heinrichs M (2013) Epigenetic regulation of the oxytocin receptor gene: implications for behavioral neuroscience. Front Neurosci 7:83

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Fujisawa TX, Nishitani S, Takiguchi S, Shimada K, Smith AK, Tomoda A (2019) Oxytocin receptor DNA methylation and alterations of brain volumes in maltreated children. Neuropsychopharmacology 44(12):2045–2053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Maud C, Ryan J, McIntosh JE, Olsson CA (2018) The role of oxytocin receptor gene (OXTR) DNA methylation (DNAm) in human social and emotional functioning: a systematic narrative review. BMC Psychiatry 18(1):154

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders, 5th edn. American Psychiatric Association, Washington, DC

    Book  Google Scholar 

  35. Baio J, Wiggins L, Christensen DL, Maenner MJ, Daniels J, Warren Z et al (2018) Prevalence of autism spectrum disorder among children aged 8 years—autism and developmental disabilities monitoring network, 11 sites, United States, 2014. Morb Mortal Wkly Rep 67(6):1–23

    Google Scholar 

  36. Howlin P, Goode S, Hutton J, Rutter M (2004) Adult outcome for children with autism. J Child Psychol Psychiatry 45(2):212–229

    Article  PubMed  Google Scholar 

  37. McStay RL, Trembath D, Dissanayake C (2014) Stress and family quality of life in parents of children with autism spectrum disorder: parent gender and the double ABCX model. J Autism Dev Disord 44:3101–3118

    Article  PubMed  Google Scholar 

  38. Hedley D, Young R (2006) Social comparison processes and depressive symptoms in children and adolescents with Asperger syndrome. Autism 10(2):139–153

    Article  PubMed  Google Scholar 

  39. Green L, Fein D, Modahl C, Feinstein C, Waterhouse L, Morris M (2001) Oxytocin and autistic disorder: alterations in peptide forms. Biol Psychiatry 50(8):609–613

    Article  CAS  PubMed  Google Scholar 

  40. Modahl C, Green LA, Fein D, Morris M, Waterhouse L, Feinstein C et al (1998) Plasma oxytocin levels in autistic children. Biol Psychiatry 43(4):270–277

    Article  CAS  PubMed  Google Scholar 

  41. Cataldo I, Azhari A, Lepri B, Esposito G (2018) Oxytocin receptors (OXTR) and early parental care: an interaction that modulates psychiatric disorders. Res Dev Disabil 82:27–38

    Article  PubMed  Google Scholar 

  42. Hernandez LM, Krasileva K, Green SA, Sherman LE, Ponting C, McCarron R et al (2017) Additive effects of oxytocin receptor gene polymorphisms on reward circuitry in youth with autism. Mol Psychiatry 22(8):1134–1139

    Article  CAS  PubMed  Google Scholar 

  43. Gregory SG, Connelly JJ, Towers AJ, Johnson J, Biscocho D, Markunas CA, Lintas C et al (2009) Genomic and epigenetic evidence for oxytocin receptor deficiency in autism. BMC Med 7:62

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Rijlaarsdam J, van IJzendoorn MH, Verhulst FC, Jaddoe VW, Felix JF, Tiemeier H et al (2017) Prenatal stress exposure, oxytocin receptor gene (OXTR) methylation, and child autistic traits: The moderating role of OXTR rs53576 genotype. Autism Res 10(3):430–438

    Article  PubMed  Google Scholar 

  45. Andari E, Nishitani S, Kaundinya G, Caceres GA, Morrier MJ, Ousley O et al (2020) Epigenetic modification of the oxytocin receptor gene: implications for autism symptom severity and brain functional connectivity. Neuropsychopharmacology

    Google Scholar 

  46. Guastella AJ, Einfeld SL, Gray KM, Rinehart NJ, Tonge BJ, Lambert TJ et al (2010) Intranasal oxytocin improves emotion recognition for youth with autism spectrum disorders. Biol Psychiatry 67(7):692–694

    Article  CAS  PubMed  Google Scholar 

  47. Domes G, Kumbier E, Heinrichs M, Herpertz SC (2014) Oxytocin promotes facial emotion recognition and amygdala reactivity in adults with asperger syndrome. Neuropsychopharmacology 39(3):698–706

    Article  CAS  PubMed  Google Scholar 

  48. Andari E, Duhamel J, Zalla T, Herbrecht E, Leboyer M, Sirigu A (2010) Promoting social behavior with oxytocin in high-functioning autism spectrum disorders. Proc Natl Acad Sci USA 107(9):4389–4394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hollander E, Bartz J, Chaplin W, Phillips A, Sumner J, Soorya L et al (2007) Oxytocin increases retention of social cognition in autism. Biol Psychiatry 61(4):498–503

    Article  CAS  PubMed  Google Scholar 

  50. Alvares GA, Quintana DS, Whitehouse AJ (2017) Beyond the hype and hope: critical considerations for intranasal oxytocin research in autism spectrum disorder. Autism Res 10(1):25–41

    Article  PubMed  Google Scholar 

  51. Guastella AJ, Hickie IB (2016) Oxytocin treatment, circuitry, and autism: a critical review of the literature placing oxytocin into the autism context. Biol Psychiatry 79(3):234–242

    Article  CAS  PubMed  Google Scholar 

  52. DeMayo MM, Song YJC, Hickie IB, Guastella AJ (2017) A review of the safety, efficacy and mechanisms of delivery of nasal oxytocin in children: therapeutic potential for autism and prader-willi syndrome, and recommendations for future research. Paediatr Drugs 19(5):391–410

    Article  PubMed  Google Scholar 

  53. Anagnostou E, Soorya L, Brian J, Dupuis A, Mankad D, Smile S et al (2014) Intranasal oxytocin in the treatment of autism spectrum disorders: a review of literature and early safety and efficacy data in youth. Brain Res 1580:188–198

    Article  CAS  PubMed  Google Scholar 

  54. Anagnostou E, Soorya L, Chaplin W, Bartz J, Halpern D, Wasserman S et al (2012) Intranasal oxytocin versus placebo in the treatment of adults with autism spectrum disorders: a randomized controlled trial. Mol Autism 3(1):16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Watanabe T, Kuroda M, Kuwabara H, Aoki Y, Iwashiro N, Tatsunobu N et al (2015) Clinical and neural effects of six-week administration of oxytocin on core symptoms of autism. Brain 138(11):3400–3412

    Article  PubMed  Google Scholar 

  56. Guastella AJ, Gray KM, Rinehart NJ, Alvares GA, Tonge BJ, Hickie IB et al (2015) The effects of a course of intranasal oxytocin on social behaviors in youth diagnosed with autism spectrum disorders: a randomized controlled trial. J Child Psychol Psychiatry 56(4):444–452

    Article  PubMed  Google Scholar 

  57. Keech B, Crowe S, Hocking DR (2018) Intranasal oxytocin, social cognition and neurodevelopmental disorders: a meta-analysis. Psychoneuroendocrinology 87:9–19

    Article  CAS  PubMed  Google Scholar 

  58. Wang Y, Wang M-J, Rong Y, He H-Z, Yang C-J (2019) Oxytocin therapy for core symptoms in autism spectrum disorder: an updated meta-analysis of randomized controlled trials. Res Autism Spectr Disord 64:63–75

    Article  Google Scholar 

  59. Kosaka H, Okamoto Y, Munesue T, Yamasue H, Inohara K, Fujioka T et al (2016) Oxytocin efficacy is modulated by dosage and oxytocin receptor genotype in young adults with high-functioning autism: a 24-week randomized clinical trial. Transl Psychiatry 6(8):e872

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Watanabe T, Otowa T, Abe O, Kuwabara H, Aoki Y, Natsubori T et al (2017) Oxytocin receptor gene variations predict neural and behavioral response to oxytocin in autism. Soc Cogn Affect Neurosci 12(3):496–506

    Article  PubMed  Google Scholar 

  61. Parker KJ, Oztan O, Libove RA, Sumiyoshi RD, Jackson LP, Karhson DS et al (2017) Intranasal oxytocin treatment for social deficits and biomarkers of response in children with autism. Proc Natl Acad Sci USA 114(30):8119–8124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Ewart AK, Morris CA, Atkinson D, Jin W, Sternes K, Spallone P, Stock AD et al (1993) Hemizygosity at the elastin locus in a developmental disorder, Williams syndrome. Nat Genet 5:11–16

    Article  CAS  PubMed  Google Scholar 

  63. Pober BR (2010) Williams-Beuren syndrome. N Engl J Med 362(3):239–252

    Article  CAS  PubMed  Google Scholar 

  64. Jarvinen A, Korenberg JR, Bellugi U (2013) The social phenotype of Williams syndrome. Curr Opin Neurobiol 23(3):414–422

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Fisher MH, Josol CK, Shivers CM (2020) An examination of social skills, friendship quality, and loneliness for adults with Williams syndrome. J Autism Dev Disord 50:3649–3660

    Article  PubMed  Google Scholar 

  66. Strømme P, Bjømstad PG, Ramstad K (2002) Prevalence estimation of Williams syndrome. J Child Neurol 17(4):269–271

    Article  PubMed  Google Scholar 

  67. Dai L, Carter CS, Ying J, Bellugi U, Pournajafi-Nazarloo H, Korenberg JR (2012) Oxytocin and vasopressin are dysregulated in Williams syndrome, a genetic disorder affecting social behavior. PLoS One 7(6):e38513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Haas BW, Smith AK (2015) Oxytocin, vasopressin, and Williams syndrome: epigenetic effects on abnormal social behavior. Front Genet 6:28

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Kimura R, Tomiwa K, Inoue R, Suzuki S, Nakata M, Awaya T et al (2020) Dysregulation of the oxytocin receptor gene in Williams syndrome. Psychoneuroendocrinology 115:104631

    Article  CAS  PubMed  Google Scholar 

  70. Plesa Skwerer D (2017) Social cognition in individuals with intellectual and developmental disabilities: recent advances and trends in research. Int Rev Res Dev Disabil 53:91–161

    Article  Google Scholar 

  71. Lefevre A, Hurlemann R, Grinevich V (2019) Imaging neuropeptide effects on human brain function. Cell Tissue Res 375(1):279–286

    Article  CAS  PubMed  Google Scholar 

  72. Tanaka A, Furubayashi T, Arai M, Inoue D, Kimura S, Kiriyama A et al (2018) Delivery of oxytocin to the brain for the treatment of autism spectrum disorder by nasal application. Mol Pharm 15(3):1105–1111

    Article  CAS  PubMed  Google Scholar 

  73. Quintana DS, Alvares GA, Hickie IB, Guastella AJ (2015) Do delivery routes of intranasally administered oxytocin account for observed effects on social cognition and behavior? A two-level model. Neurosci Biobehav Rev 49:182–192

    Article  CAS  PubMed  Google Scholar 

  74. Beard R, Singh N, Grundschober C, Gee AD, Tate EW (2018) High-yielding (18)F radiosynthesis of a novel oxytocin receptor tracer, a probe for nose-to-brain oxytocin uptake in vivo. Chem Commun 54(58):8120–8123

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Autism Clinic for Translational Research, Brain and Mind Centre, Children’s Hospital Westmead Clinical School, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia

    Kelsie A. Boulton & Adam J. Guastella

Authors
  1. Kelsie A. Boulton
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Adam J. Guastella
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kelsie A. Boulton .

Editor information

Editors and Affiliations

  1. School of Chemistry, The University of Sydney, Camperdown, NSW, Australia

    Eryn L. Werry

  2. Research School of Chemistry, Australian National University, Canberra, ACT, Australia

    Tristan A. Reekie

  3. School of Chemistry, The University of Sydney, Camperdown, NSW, Australia

    Michael Kassiou

Rights and permissions

Reprints and permissions

Copyright information

© 2022 Springer Science+Business Media, LLC, part of Springer Nature

About this protocol

Check for updates. Verify currency and authenticity via CrossMark

Cite this protocol

Boulton, K.A., Guastella, A.J. (2022). The Importance of Experimental Investigation of the CNS Oxytocin System. In: Werry, E.L., Reekie, T.A., Kassiou, M. (eds) Oxytocin. Methods in Molecular Biology, vol 2384. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-1759-5_4

Download citation

  • DOI: https://doi.org/10.1007/978-1-0716-1759-5_4

  • Published:

  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-1758-8

  • Online ISBN: 978-1-0716-1759-5

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation