, Volume 7, Issue 3, pp 250–257 | Cite as

Autism and oxytocin: New developments in translational approaches to therapeutics

  • Joshua J. Green
  • Eric HollanderEmail author
Review Article


Autism is a neurodevelopmental disorder characterized by dysfunction in three core symptom domains: speech and communication deficits, repetitive or compulsive behaviors with restricted interests, and social impairment. The neuropeptide oxytocin, along with the structurally similar peptide arginine vasopressin, may play a role in the etiology of autism, and especially in the social impairment domain. Oxytocin is a non-apeptide (i.e., it has nine amino acids). It is synthesized in magnocellular neurons in the paraventricular nucleus and the supraoptic nucleus of the hypothalamus and is released into the bloodstream by way of axon terminals in the posterior pituitary. Oxytocin is released both peripherally, where it is involved in milk letdown and the facilitation of uterine contractions, and centrally, where it acts as a neuromodulator along with arginine vasopressin. Here, we discuss relevant translational research pertaining to the role of oxytocin in social and repetitive behaviors and consider clinical implications. We also discuss current research limitations, review recent preliminary findings from studies involving oxytocin in autism spectrum disorder patient populations, and point to possible directions for future research.

Key Words

Autism ASD oxytocin translational model repetitive behavior social behavior social cognition social functioning therapeutics arginine vasopressin epigenetic 


  1. 1.
    American Psychiatric Association; Task Force on DSM-IV. Diagnostic and statistical manual of mental disorders (DSM-IV). 4th ed. Washington, DC: American Psychiatric Association, 1994.Google Scholar
  2. 2.
    Bartz J, Hollander E. Oxytocin and experimental therapeutics in autism spectrum disorders. Prog Brain Res 2008;170: 451–462.CrossRefPubMedGoogle Scholar
  3. 3.
    Szatmari P, Tuff L, Finlayson MA, Bartolucci G. Asperger’s syndrome and autism: neurocognitive aspects. J Am Acad Child Adolesc Psychiatry 1990;1: 130–136.CrossRefGoogle Scholar
  4. 4.
    Davies S, Bishop D, Manstead AS, Tantam D. Face perception in children with autism and Asperger’s syndrome. J Child Psychol Psychiatry 1994;6: 1033–1057.CrossRefGoogle Scholar
  5. 5.
    Barton JJ. Disorders of face perception and recognition. Neurol Clin 2003;2: 521–548.CrossRefGoogle Scholar
  6. 6.
    Weeks SJ, Hobson RP. The salience of facial expression for autistic children. J Child Psychol Psychiatry 1987;28: 137–151.CrossRefPubMedGoogle Scholar
  7. 7.
    Tantam D, Monaghan L, Nicholson H, Stirling. Autistic children’s ability to interpret faces: a research note. J Child Psychol Psychiatry 1989;30: 623–630.CrossRefPubMedGoogle Scholar
  8. 8.
    Hammock EA, Young LJ. Oxytocin, vasopressin and pair bonding: implications for autism. Philos Trans R Soc Lond B Biol Sci 2006;361: 2187–2198.CrossRefPubMedGoogle Scholar
  9. 9.
    Hollander E, Bartz J, Chaplin W, et al. Oxytocin increases retention in social cognition in autism. Biol Psychiatry 2007;61: 498–450.CrossRefPubMedGoogle Scholar
  10. 10.
    Hollander E, Novotny S, Hanratty M, et al. Oxytocin infusion reduces repetitive behaviors in adults with autistic and Asperger’ s disorders. Neuropsychopharmacology 2003;28: 193–198.CrossRefPubMedGoogle Scholar
  11. 11.
    Insel TR. A neurobiological basis of social attachment. Am J Psychiatry 1997;154: 726–735.PubMedGoogle Scholar
  12. 12.
    Insel TR, O’Brien DJ, Leckman JF. Oxytocin, vasopressin and autism: Is there a connection? Biol Psychiatry 1999;45: 145–157.CrossRefPubMedGoogle Scholar
  13. 13.
    Lim MM, Bielsky IF, Young LJ. Neuropeptides and the social brain: potential rodent models of autism. Int J Dev Neurosci 2005;23: 235–243.CrossRefPubMedGoogle Scholar
  14. 14.
    McCarthy MM, Altemus M. Central nervous system actions of oxytocin and modulation of behavior in humans. Mol Med Today 1997;3: 269–275.CrossRefPubMedGoogle Scholar
  15. 15.
    Panksepp J. Oxytocin effects on emotional processes: separation distress, social bonding, and relationships to psychiatric disorders. Ann N Y Acad Sci 1992;652: 243–252.CrossRefPubMedGoogle Scholar
  16. 16.
    Waterhouse L, Fein D, Modahl C. Neurofunctional mechanisms in autism. Psychol Rev 1996;103: 457–489.CrossRefPubMedGoogle Scholar
  17. 17.
    Insel TR, Young LJ. Neuropeptides and the evolution of social behavior. Curr Opin Neurobiol 2000;10: 784–789.CrossRefPubMedGoogle Scholar
  18. 18.
    Burbach JPH, Young LJ, Russell JA. Oxytocin: synthesis, secretion, and reproductive functions. In: Neill JD, editor. Knobil and Neill’s physiology of reproduction. 3rd ed. Amsterdam: Elsevier, 2006: 3055–3128.CrossRefGoogle Scholar
  19. 19.
    Kendrick KM, Da Costa APC, Broad KD, et al. Neural control of maternal behaviour and olfactory recognition of offspring. Brain Res Bull 1997;44: 383–395.CrossRefPubMedGoogle Scholar
  20. 20.
    Ferguson JN, Young LJ, Hearn EF, Matzuk MM, Insel TR, Winslow JT. Social amnesia in mice lacking the oxytocin gene. Nat Genet 2000;25: 284–288.CrossRefPubMedGoogle Scholar
  21. 21.
    Donaldson ZR, Young LJ. Oxytocin, vasopressin, and the neurogenetics of sociality. Science 2008;322: 900–904.CrossRefPubMedGoogle Scholar
  22. 22.
    Young LJ, Wang Z. The neurobiology of pair bonding. Nat Neurosci 2004;7: 1048–1054.CrossRefPubMedGoogle Scholar
  23. 23.
    Perdersen CA, Range AJ Jr. Induction of maternal behavior in virgin rats after intracerebroventricular administration of oxytocin. Proc Natl Acad Sci U S A 1979;76: 6661–6665.CrossRefGoogle Scholar
  24. 24.
    Fleming AS, Anderson V. Affect and nurturance: mechanisms mediating maternal behavior in two female mammals. Prog Neuropsychopharmacol Biol Psychiatry 1987;11: 121–127.CrossRefPubMedGoogle Scholar
  25. 25.
    Perdersen CA, Ascher JA, Monroe YL, Prange AJ Jr. Oxytocin induces maternal behavior in virgin female rats. Science 1982;216: 648–650.CrossRefGoogle Scholar
  26. 26.
    Insel TR. Oxytocin: a neuropeptide for affiliation: evidence from behavioral, receptor autoradiographic, and comparative studies. Psychoneuroendocrinology 1992;17: 3–35.CrossRefPubMedGoogle Scholar
  27. 27.
    Champagne F, Diorio J, Sharma S, Meaney MJ. Naturally occurring variations in maternal behavior in the rat are associated differences in estrogen-inducible central oxytocin receptors. Proc Natl Acad Sci U S A 2001;98: 12736–12741.CrossRefPubMedGoogle Scholar
  28. 28.
    Takayanagi Y, Yoshida M, Bielsky IF, et al. Pervasive social deficits, but normal parturition, in oxytocin receptor-deficient mice. Proc Natl Acad Sci U S A 2005;102: 16096–16101.CrossRefPubMedGoogle Scholar
  29. 29.
    Young LJ, Winslow JT, Wang Z, et al. Gene targeting approaches to neuroendocrinology: oxytocin, maternal behavior, and affiliation. Horm Behav 1997;31: 221–331.CrossRefPubMedGoogle Scholar
  30. 30.
    Liu HX, Lopatina O, Higashida C, et al. Locomotor activity, ultrasonic vocalization and oxytocin level in infant CD38 knockout mice. Neurosci Lett 2008;448: 67–70.CrossRefPubMedGoogle Scholar
  31. 31.
    Choleris E, Gustafsson JA, Korach KS, Muglia LJ, Pfaff DW, Ogawa S. An estrogen-dependent four-gene micronet regulating social recognition: a study with oxytocin and estrogen receptor-alpha and -beta knockout mice. Proc Natl Acad Sci U S A 2003;100: 6192–6197.CrossRefPubMedGoogle Scholar
  32. 32.
    Ferguson JN, Aldag JM, Insel TR, Young LJ. Oxytocin in the medial amygdala is essential for social recognition in the mouse. J Neurosci 2001;21: 8278–8285.PubMedGoogle Scholar
  33. 33.
    Lim MM, Wang Z, Olazábal DE, Ren X, Terwilliger EF, Young LJ. Enhanced partner preference in promiscuous species by manipulating the expression of a single gene. Nature 2004;429: 754–757.CrossRefPubMedGoogle Scholar
  34. 34.
    Olazábal DE, Young LJ. Variability in “spontaneous” maternal behavior is associated with anxiety-like behavior and affiliation in naïve juvenile and adult female prairie voles (Microtus ochrogaster). Dev Psychobiol 2005;47: 166–178.CrossRefPubMedGoogle Scholar
  35. 35.
    Young KA, Liu Y, Wang Z. The neurobiology of social attachment: a comparative approach to behavioral, neuroanatomical, and neurochemical studies. Comp Biochem Physiol C Toxicol Pharmacol 2008;148: 401–410.CrossRefPubMedGoogle Scholar
  36. 36.
    Getz LL, Hofmann JR. Social organization in free living prairie voles, Microtus ochrogaster. Behav Ecol Sociobiol 1986;18: 275–282.CrossRefGoogle Scholar
  37. 37.
    Getz LL, Carter CS, Gavish L. The mating system of the prairie vole Microtus ochrogaster: field and laboratory evidence for pair-bonding. Behav Ecol Sociobiol 1981;8: 189–194.CrossRefGoogle Scholar
  38. 38.
    Pizzuto T, Getz LL. Female prairie voles (Microtus ochrogaster) fail to form a new pair after loss of mate. Behav Proc 1998;43: 79–96.CrossRefGoogle Scholar
  39. 39.
    Getz LL, Carter CS. Prairie-vole partnerships. Am Sci 1996;84: 56–62.Google Scholar
  40. 40.
    Insel TR, Shapiro LE. Oxytocin receptor distribution reflects social organization in monogamous and polygamous voles. Proc Natl Acad Sci U S A 1992;89: 5981–5985.CrossRefPubMedGoogle Scholar
  41. 41.
    Williams JR, Insel TR, Harbaugh CR, Carter CS. Oxytocin administered centrally facilitates formation of a partner preference in female prairie voles (Microtus ochrogaster). J Neuroendocrinol 1994;6: 247–250.CrossRefPubMedGoogle Scholar
  42. 42.
    Insel TR, Hulihan TJ. A gender-specific mechanism for pair bonding: oxytocin and prater preference formation in monogamous voles. Behav Neurosci 1995;109: 782–789.CrossRefPubMedGoogle Scholar
  43. 43.
    Olazábal DE, Young LJ. Oxytocin receptors in the nucleus accumbens facilitated “spontaneous” maternal behavior in adult female prairie voles. Neuroscience 2006;141: 559–568.CrossRefPubMedGoogle Scholar
  44. 44.
    Meisenberg G, Simmons WH. Centrally mediated effects of neurohypophyseal hormones. Neurosci Biobehav 1983;7: 263–280.CrossRefGoogle Scholar
  45. 45.
    Drago F, Pedersen CA, Caldwell JD, Range AJ Jr. Oxytocin potently enhances novelty-induced grooming behavior in the rat. Brain Res 1986;368: 287–295.CrossRefPubMedGoogle Scholar
  46. 46.
    Insel TR, Winslow JT. Central administration of oxytocin modulates the infant rat’s response to social isolation. Eur J Pharmacol 1991;203: 149–152.CrossRefPubMedGoogle Scholar
  47. 47.
    Nelson E, Alberts JR. Oxytocin-induced paw sucking in infant rats. Ann N Y Acad Sci 1997;807: 543–545.CrossRefPubMedGoogle Scholar
  48. 48.
    Van Wimersma Greidanus TB, Kroodsma JM, Pot ML, Stevens M, Maigret C. Neurohypophyseal hormones and excessive grooming behaviour. Eur J Pharmacol 1990;187: 1–8.CrossRefPubMedGoogle Scholar
  49. 49.
    McDougle CJ, Barr LC, Goodman WK, Price LH. Possible role of neuropeptides in obsessive compulsive disorder. Psychoneuroendocrinology 1999;24: 1–24.CrossRefPubMedGoogle Scholar
  50. 50.
    Crawley JN. Designing mouse behavioral tasks relevant to autistic-like behaviors. Ment Retard Dev Disabil Res Rev 2004;10: 248–258.CrossRefPubMedGoogle Scholar
  51. 51.
    Ashwood P, Wills S, Van de Water J. The immune response in autism: a new frontier for autism research. J Leukoc Biol 2006;80: 1–15.CrossRefPubMedGoogle Scholar
  52. 52.
    Kosfeld M, Heinrichs M, Zak PJ, Fischbacher U, Fehr E. Oxytocin increases trust in humans. Nature 2005;435: 673–676.CrossRefPubMedGoogle Scholar
  53. 53.
    Baumgartner T, Heinrichs M, Vonlanthen A, Fischbacher U, Fehr E. Oxytocin shapes the neural circuitry of trust and trust adaptation in humans. Neuron 2008;58: 639–650.CrossRefPubMedGoogle Scholar
  54. 54.
    Domes G, Heinrichs M, Michel A, Berger C, Herpertz SC. Oxytocin improves “mind-reading” in humans. Biol Psychiatry 2007;61: 731–733.CrossRefPubMedGoogle Scholar
  55. 55.
    Baron-Cohen S, Wheelwright S, Hill J, Raste Y, Plumb I. The “Reading the Mind in The Eyes” Test revised version: a study with normal adults, and adults with Asperger syndrome or high-functioning autism. J Child Psychol Psychiatry 2001;42: 241–251.CrossRefPubMedGoogle Scholar
  56. 56.
    Theodoridou A, Rowe AC, Penton-Voak IS, et al. Oxytocin and social perception: oxytocin increases perceived facial trustworthiness and attractiveness. Horm Behav 2009;56: 128–132.CrossRefPubMedGoogle Scholar
  57. 57.
    Heinrichs M, Baumgartner T, Kirschbaum C, Ehlert U. Social support and oxytocin interact to suppress cortisol and subjective responses to psychosocial stress. Biol Psychiatry 2003;54: 1389–1398.CrossRefPubMedGoogle Scholar
  58. 58.
    Modahl C, Green L, Fein D, et al. Plasma oxytocin levels in autistic children. Biol Psychiatry 1998;43: 270–277.CrossRefPubMedGoogle Scholar
  59. 59.
    Jansen LM, Gispen-De Wied CC, Wiegant VM, Westenberg HG, Lahuis BE, van Engeland H. Autonomic and neuroendocrine responses to a psychosocial stressor in adults with autistic spectrum disorder. J Autism Dev Disord 2006;36: 891–899.CrossRefPubMedGoogle Scholar
  60. 60.
    Green L, Fein D, Modahl C, Feinstein C, Waterhouse L, Morris M. Oxytocin and autistic disorder: alterations in peptide forms. Biol Psychiatry 2001;50: 609–613.CrossRefPubMedGoogle Scholar
  61. 61.
    Bartz J, Young L. Oxytocin, social cognition, and autism. 2010 (in press).Google Scholar
  62. 62.
    Taylor SE, Gonzaga GC, Klein LC, Hu P, Greendale GA, Seeman TE. Relation of oxytocin to psychological stress responses and hypothalamic-pituitary-adrenocortical axis activity in older women. Psychosom Med 2006;68: 238–245.CrossRefPubMedGoogle Scholar
  63. 63.
    Turner RA, Altemus M, Enos T, Cooper B, McGuinness T. Preliminary research on plasma oxytocin in normal cycling women: investigating emotion and interpersonal distress. Psychiatry 1999;62: 97–113.PubMedGoogle Scholar
  64. 64.
    Hoge EA, Pollack MH, Kaufman RE, Zak PJ, Simon NM. Oxytocin levels in social anxiety disorder. CNS Neurosci Ther 2008;14: 165–170.CrossRefPubMedGoogle Scholar
  65. 65.
    Kirsch P, Esslinger C, Chen Q, et al. Oxytocin modulates neural circuitry for social cognition and fear in humans. J Neurosci 2005;25: 11489–11493.CrossRefPubMedGoogle Scholar
  66. 66.
    Domes G, Heinrichs M, Gläscher J, Büchel C, Braus DF, Herpertz SC. Oxytocin attenuates amygdala responses to emotional faces regardless of valence. Biol Psychiatry 2007;62: 1187–1190.CrossRefPubMedGoogle Scholar
  67. 67.
    Petrovic P, Kalisch R, Singer T, Dolan RJ. Oxytocin attenuates affective evaluations of conditioned faces and amygdala activity. J Neurosci 2008;28: 6607–6615.CrossRefPubMedGoogle Scholar
  68. 68.
    Singer T, Snozzi R, Bird G, et al. Effects of oxytocin and prosocial behavior on brain responses to direct and vicariously experienced pain. Emotion 2008;8: 781–791.CrossRefPubMedGoogle Scholar
  69. 69.
    Domes G, Lischke A, Berger C, et al. Effects of intranasal oxytocin on emotional face processing in women. Psychoneuroendocrinology 2010;35: 83–93.CrossRefPubMedGoogle Scholar
  70. 70.
    Lintas C, Persico AM. Autistic phenotypes and genetic testing: state-of-the-art for the clinical geneticist. J Med Genet 2009;46: 1–8.CrossRefPubMedGoogle Scholar
  71. 71.
    Folstein S. Twin and adoption studies in child and adolescent psychiatric disorders. Curr Opin Pediatr 1996;8: 339–347.CrossRefPubMedGoogle Scholar
  72. 72.
    Bailey A, Le Couteur A, Gottesman I, et al. Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med 1995;25: 63–77.CrossRefPubMedGoogle Scholar
  73. 73.
    Wu S, Jia M, Ruan Y, et al. Positive association of the oxytocin receptor gene (OXTR) with autism in the Chinese Han population. Biol Psychiatry 2005;58: 74–77.CrossRefPubMedGoogle Scholar
  74. 74.
    Jacob S, Brune CW, Carter CS, Leventhal BL, Lord C, Cook EH Jr. Association of the oxytocin receptor gene (OXTR) in Caucasian children and adolescents with autism. Neurosci Lett 2007;417: 6–9.CrossRefPubMedGoogle Scholar
  75. 75.
    Lerer E, Levi S, Salomon S, Darvasi A, Yirmiya N, Ebstein RP. Association between the oxytocin receptor (OXTR) gene and autism: relationship to Vineland Adaptive Behavior Scales and cognition. Mol Psychiatry 2008;13: 980–988.CrossRefPubMedGoogle Scholar
  76. 76.
    Wermter AK, Kamp-Becker I, Hesse P, et al. Evidence for the involvement of genetic variation in the oxytocin receptor gene (OXTR) in the etiology of autistic disorders on high-functioning level. Am J Med Genet B Neuropsychiatr Genet 2010;153B: 629–639.PubMedGoogle Scholar
  77. 77.
    Gregory SG, Connelly JJ, Towers A, et al. Genomic and epigenetic evidence for oxytocin receptor deficiency in autism. BMC Med 2009;7: 62.CrossRefPubMedGoogle Scholar
  78. 78.
    Hobson RP, Ouston J, Lee A. Emotion recognition in autism: coordinating faces and voices. Psychol Med 1988;18: 911–923.CrossRefPubMedGoogle Scholar
  79. 79.
    Rutherford MD, Baron-Cohen S, Wheelwright S. Reading the mind in the voice: a study with normal adults and adults with Asperger syndrome and high functioning autism. J Autism Dev Disord 2002;32: 189–194.CrossRefPubMedGoogle Scholar
  80. 80.
    Guastella AJ, Einfeld SL, Gray KM, et al. Intranasal oxytocin improves emotion recognition for youth with autism spectrum disorders. Biol Psychiatry 2010;67: 692–694.CrossRefPubMedGoogle Scholar
  81. 81.
    Neumann D, Spezio ML, Piven J, Adolphs R. Looking you in the mouth: abnormal gaze in autism resulting from impaired top-down modulation of visual attention. Soc Cogn Affect Neurosci 2006;1: 194–202.CrossRefPubMedGoogle Scholar
  82. 82.
    Guastella AJ, Mitchell PB, Dadds MR. Oxytocin increases gaze to the eye region of human faces. Biol Psychiatry 2007;1: 3–5.Google Scholar
  83. 83.
    Rimmele U, Hediger K, Heinrichs M, Klaver P. Oxytocin makes a face in memory familial. J Neurosci 2009;29: 38–42.CrossRefPubMedGoogle Scholar
  84. 84.
    Benvenuto A, Moavero R, Alessandrelli R, Manzi B, Curatolo P. Syndromic autism: causes and pathogenetic pathways. World J Pediatr 2009;5: 169–176.CrossRefPubMedGoogle Scholar

Copyright information

© Springer 2010

Authors and Affiliations

  1. 1.Montefiore Medical CenterUniversity Hospital of Albert Einstein College of MedicineBronx

Personalised recommendations