Neuropsychopharmacology Reviews | Published:

Sex-dependent regulation of social reward by oxytocin: an inverted U hypothesis

Neuropsychopharmacologyvolume 44pages97110 (2019) | Download Citation


The rewarding properties of social interactions are essential for the expression of social behavior and the development of adaptive social relationships. Here, we review sex differences in social reward, and more specifically, how oxytocin (OT) acts in the mesolimbic dopamine system (MDS) to mediate the rewarding properties of social interactions in a sex-dependent manner. Evidence from rodents and humans suggests that same-sex social interactions may be more rewarding in females than in males. We propose that there is an inverted U relationship between OT dose, social reward, and neural activity within structures of the MDS in both males and females, and that this dose–response relationship is initiated at lower doses in females than males. As a result, depending on the dose of OT administered, OT could reduce social reward in females, while enhancing it in males. Sex differences in the neural mechanisms regulating social reward may contribute to sex differences in the incidence of a large number of psychiatric and neurodevelopmental disorders. This review addresses the potential significance of a sex-dependent inverted U dose–response function for OT’s effects on social reward and in the development of gender-specific therapies for these disorders.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Additional information

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


  1. 1.

    White NM. Reward or reinforcement: what’s the difference? Neurosci Biobehav Rev. 1989;13:181–6.

  2. 2.

    Panksepp J, Yovell Y. Preclinical modeling of primal emotional affects (Seeking, Panic and Play): gateways to the development of new treatments for depression. Psychopathology. 2014;47:383–93.

  3. 3.

    Trezza V, Campolongo P, Vanderschuren LJ. Evaluating the rewarding nature of social interactions in laboratory animals. Dev Cogn Neurosci. 2011;1:444–58.

  4. 4.

    Young LJ, Wang Z. The neurobiology of pair bonding. Nat Neurosci. 2004;7:1048–54.

  5. 5.

    Gingrich B, Liu Y, Cascio C, Wang Z, Insel TR. Dopamine D2 receptors in the nucleus accumbens are important for social attachment in female prairie voles (Microtus ochrogaster). Behav Neurosci. 2000;114:173–83.

  6. 6.

    Gray CL, Norvelle A, Larkin T, Huhman KL. Dopamine in the nucleus accumbens modulates the memory of social defeat in Syrian hamsters (Mesocricetus auratus). Behav Brain Res. 2015;286:22–8.

  7. 7.

    Greenberg GD, Steinman MQ, Doig IE, Hao R, Trainor BC. Effects of social defeat on dopamine neurons in the ventral tegmental area in male and female California mice. Eur J Neurosci. 2015;42:3081–94.

  8. 8.

    Gil M, Nguyen NT, McDonald M, Albers HE. Social reward: interactions with social status, social communication, aggression, and associated neural activation in the ventral tegmental area. Eur J Neurosci. 2013;38:2308–18.

  9. 9.

    Douglas LA, Varlinskaya EI, Spear LP. Rewarding properties of social interactions in adolescent and adult male and female rats: impact of social versus isolate housing of subjects and partners. Dev Psychobiol. 2004;45:153–62.

  10. 10.

    Feng C, Hackett PD, DeMarco AC, Chen X, Stair S, Haroon E, et al. Oxytocin and vasopressin effects on the neural response to social cooperation are modulated by sex in humans. Brain Imaging Behav. 2015;9:754–64.

  11. 11.

    Novacek DM, Gooding DC, Pflum MJ. Hedonic capacity in the broader autism phenotype: should social anhedonia be considered a characteristic feature? Front Psychol. 2016;7:666

  12. 12.

    Ramtekkar UP, Reiersen AM, Todorov AA, Todd RD. Sex and age differences in attention-deficit/hyperactivity disorder symptoms and diagnoses: implications for DSM-V and ICD-11. J Am Acad Child Adolesc Psychiatry. 2010;49:217–28 e211-213.

  13. 13.

    Stavropoulos KK, Carver LJ. Research review: social motivation and oxytocin in autism–implications for joint attention development and intervention. J Child Psychol Psychiatry. 2013;54:603–18.

  14. 14.

    Dichter GS, Felder JN, Green SR, Rittenberg AM, Sasson NJ, Bodfish JW. Reward circuitry function in autism spectrum disorders. Soc Cogn Affect Neurosci. 2012;7:160–72.

  15. 15.

    Phoenix CH, Goy RW, Gerall AA, Young WC. Organizing action of prenatally administered testosterone propionate on the tissues mediating mating behavior in the female guinea pig. Endocrinology. 1959;65:369–82.

  16. 16.

    McCarthy MM, Pickett LA, VanRyzin JW, Kight KE. Surprising origins of sex differences in the brain. Horm Behav. 2015;76:3–10.

  17. 17.

    De Vries GJ. Minireview: sex differences in adult and developing brains: compensation, compensation, compensation. Endocrinology. 2004;145:1063–8.

  18. 18.

    Terranova JI, Song Z, Larkin TE 2nd, Hardcastle N, Norvelle A, Riaz A, et al. Serotonin and arginine-vasopressin mediate sex differences in the regulation of dominance and aggression by the social brain. Proc Natl Acad Sci USA. 2016;113:13233–8.

  19. 19.

    Bales KL, Carter CS. Sex differences and developmental effects of oxytocin on aggression and social behavior in prairie voles (Microtus ochrogaster). Horm Behav. 2003;44:178–84.

  20. 20.

    Veenema AH, Bredewold R, De Vries GJ. Sex-specific modulation of juvenile social play by vasopressin. Psychoneuroendocrinology. 2013;38:2554–61.

  21. 21.

    Bredewold R, Smith CJ, Dumais KM, Veenema AH. Sex-specific modulation of juvenile social play behavior by vasopressin and oxytocin depends on social context. Front Behav Neurosci. 2014;8:216

  22. 22.

    Telgkamp P, Combs N, Smith GT. Serotonin in a diencephalic nucleus controlling communication in an electric fish: sexual dimorphism and relationship to indicators of dominance. Dev Neurobiol. 2007;67:339–54.

  23. 23.

    Albers HE. The regulation of social recognition, social communication and aggression: vasopressin in the social behavior neural network. Horm Behav. 2012;61:283–92.

  24. 24.

    Panzica G, Melcangi RC. Structural and molecular brain sexual differences: a tool to understand sex differences in health and disease. Neurosci Biobehav Rev. 2016;67:2–8.

  25. 25.

    Cosgrove KP, Mazure CM, Staley JK. Evolving knowledge of sex differences in brain structure, function, and chemistry. Biol Psychiatry. 2007;62:847–55.

  26. 26.

    De Vries GJ, Buijs RM, Swaab DF. Ontogeny of the vasopressinergic neurons of the suprachiasmatic nucleus and their extrahypothalamic projections in the rat brain–presence of a sex difference in the lateral septum. Brain Res. 1981;218:67–78.

  27. 27.

    Terranova JI, Ferris CF, Albers HE. Sex differences in the regulation of offensive aggression and dominance by arginine-vasopressin. Front Endocrinol. 2017;8:308

  28. 28.

    Albers HE. Species, sex and individual differences in the vasotocin/vasopressin system: relationship to neurochemical signaling in the social behavior neural network. Front Neuroendocrinol. 2015;36:49–71.

  29. 29.

    Caldwell HK, Albers HE. Effect of photoperiod on vasopressin-induced aggression in Syrian hamsters. Horm Behav. 2004;46:444–9.

  30. 30.

    Ferris CF, Melloni RH Jr., Koppel G, Perry KW, Fuller RW, Delville Y. Vasopressin/serotonin interactions in the anterior hypothalamus control aggressive behavior in golden hamsters. J Neurosci. 1997;17:4331–40.

  31. 31.

    Gutzler SJ, Karom M, Erwin WD, Albers HE. Arginine-vasopressin and the regulation of aggression in female Syrian hamsters (Mesocricetus auratus). Eur J Neurosci. 2010;31:1655–63.

  32. 32.

    Caldwell HK. Oxytocin and vasopressin: powerful regulators of social behavior. Neuroscientist. 2017.

  33. 33.

    Carter CS, Grippo AJ, Pournajafi-Nazarloo H, Ruscio MG, Porges SW. Oxytocin, vasopressin and sociality. Prog Brain Res. 2008;170:331–6.

  34. 34.

    Young LJ, Wang Z. The neurobiology of pair bonding. Nat Neurosci. 2004;7:1048–54.

  35. 35.

    Groppe SE, Gossen A, Rademacher L, Hahn A, Westphal L, Grunder G, et al. Oxytocin influences processing of socially relevant cues in the ventral tegmental area of the human brain. Biol Psychiatry. 2013;74:172–9.

  36. 36.

    Acher R, Chauvet J. The neurohypophysial endocrine regulatory cascade: precursors, mediators, receptors, and effectors. Front Neuroendocrinol. 1995;16:237–89.

  37. 37.

    Gimpl G, Fahrenholz F. The oxytocin receptor system: structure, function, and regulation. Physiol Rev. 2001;81:629–83.

  38. 38.

    Schorscher-Petcu A, Sotocinal S, Ciura S, Dupre A, Ritchie J, Sorge RE, et al. Oxytocin-induced analgesia and scratching are mediated by the vasopressin-1A receptor in the mouse. J Neurosci. 2010;30:8274–84.

  39. 39.

    Song Z, Larkin TE, Malley MO, Albers HE. Oxytocin (OT) and arginine-vasopressin (AVP) act on OT receptors and not AVP V1a receptors to enhance social recognition in adult Syrian hamsters (Mesocricetus auratus). Horm Behav. 2016;81:20–7.

  40. 40.

    Song Z, McCann KE, McNeill JK, Larkin TE, Huhman KL, Albers HE. Oxytocin induces social communication by activating arginine-vasopressin V1a receptors and not oxytocin receptors. Psychoneuroendocrinology. 2014;50C:14–9.

  41. 41.

    Song Z, Albers HE. Cross-talk among oxytocin and arginine-vasopressin receptors: relevance for basic and clinical studies of the brain and periphery. Front Neuroendocrinol. 2017.

  42. 42.

    Hazell GG, Hindmarch CC, Pope GR, Roper JA, Lightman SL, Murphy D, et al. G protein-coupled receptors in the hypothalamic paraventricular and supraoptic nuclei–serpentine gateways to neuroendocrine homeostasis. Front Neuroendocrinol. 2012;33:45–66.

  43. 43.

    van den Burg EH, Neumann ID. Bridging the gap between GPCR activation and behaviour: oxytocin and prolactin signalling in the hypothalamus. J Mol Neurosci. 2011;43:200–8.

  44. 44.

    Busnelli M, Chini B. Molecular basis of oxytocin receptor signalling in the brain: what we know and what we need to know. Curr Top Behav Neurosci. 2017.

  45. 45.

    Gravati M, Busnelli M, Bulgheroni E, Reversi A, Spaiardi P, Parenti M, et al. Dual modulation of inward rectifier potassium currents in olfactory neuronal cells by promiscuous G protein coupling of the oxytocin receptor. J Neurochem. 2010;114:1424–35.

  46. 46.

    Busnelli M, Sauliere A, Manning M, Bouvier M, Gales C, Chini B. Functional selective oxytocin-derived agonists discriminate between individual G protein family subtypes. J Biol Chem. 2012;287:3617–29.

  47. 47.

    Bangasser DA, Curtis A, Reyes BA, Bethea TT, Parastatidis I, Ischiropoulos H, et al. Sex differences in corticotropin-releasing factor receptor signaling and trafficking: potential role in female vulnerability to stress-related psychopathology. Mol Psychiatry. 2010;15:877 896-904

  48. 48.

    Caldwell HK. Oxytocin and sex differences in behavior. Curr Opin Behav Sci. 2018;23:13–28.

  49. 49.

    Dumais KM, Veenema AH. Vasopressin and oxytocin receptor systems in the brain: sex differences and sex-specific regulation of social behavior. Front Neuroendocrinol. 2016;40:1–23.

  50. 50.

    Qiao X, Yan Y, Wu R, Tai F, Hao P, Cao Y, et al. Sociality and oxytocin and vasopressin in the brain of male and female dominant and subordinate mandarin voles. J Comp Physiol A Neuroethol Sens Neural Behav Physiol. 2014;200:149–59.

  51. 51.

    Haussler HU, Jirikowski GF, Caldwell JD. Sex differences among oxytocin-immunoreactive neuronal systems in the mouse hypothalamus. J Chem Neuroanat. 1990;3:271–6.

  52. 52.

    Rosen GJ, de Vries GJ, Goldman SL, Goldman BD, Forger NG. Distribution of oxytocin in the brain of a eusocial rodent. Neuroscience. 2008;155:809–17.

  53. 53.

    Wang Z, Moody K, Newman JD, Insel TR. Vasopressin and oxytocin immunoreactive neurons and fibers in the forebrain of male and female common marmosets (Callithrix jacchus). Synapse. 1997;27:14–25.

  54. 54.

    Wang Z, Zhou L, Hulihan TJ, Insel TR. Immunoreactivity of central vasopressin and oxytocin pathways in microtine rodents: a quantitative comparative study. J Comp Neurol. 1996;366:726–37.<726::AID-CNE11>3.0.CO;2-D.

  55. 55.

    Caffe AR, Van Ryen PC, Van der Woude TP, van Leeuwen FW. Vasopressin and oxytocin systems in the brain and upper spinal cord of Macaca fascicularis. J Comp Neurol. 1989;287:302–25.

  56. 56.

    Ishunina TA, Swaab DF. Vasopressin and oxytocin neurons of the human supraoptic and paraventricular nucleus: size changes in relation to age and sex. J Clin Endocrinol Metab. 1999;84:4637–44.

  57. 57.

    van Leeuwen FW, Caffe AR, De Vries GJ. Vasopressin cells in the bed nucleus of the stria terminalis of the rat: sex differences and the influence of androgens. Brain Res. 1985;325:391–4.

  58. 58.

    Wang Z. Species differences in the vasopressin-immunoreactive pathways in the bed nucleus of the stria terminalis and medial amygdaloid nucleus in prairie voles (Microtus ochrogaster) and meadow voles (Microtus pennsylvanicus). Behav Neurosci. 1995;109:305–11.

  59. 59.

    Delville Y, Koh ET, Ferris CF. Sexual differences in the magnocellular vasopressinergic system in golden hamsters. Brain Res Bull. 1994;33:535–40.

  60. 60.

    Steinman MQ, Laredo SA, Lopez EM, Manning CE, Hao RC, Doig IE, et al. Hypothalamic vasopressin systems are more sensitive to the long term effects of social defeat in males versus females. Psychoneuroendocrinology. 2015;51:122–34.

  61. 61.

    Albers HE, Rowland CM, Ferris CF. Arginine-vasopressin immunoreactivity is not altered by photoperiod or gonadal hormones in the Syrian hamster (Mesocricetus auratus). Brain Res. 1991;539:137–42.

  62. 62.

    Knobloch HS, Grinevich V. Evolution of oxytocin pathways in the brain of vertebrates. Front Behav Neurosci. 2014;8:31

  63. 63.

    Ross HE, Young LJ. Oxytocin and the neural mechanisms regulating social cognition and affiliative behavior. Front Neuroendocrinol. 2009;30:534–47.

  64. 64.

    Chini B, Verhage M, Grinevich V. The action radius of oxytocin release in the mammalian CNS: from single vesicles to behavior. Trends Pharmacol Sci. 2017.

  65. 65.

    Buijs RM. Vasopressin and oxytocin - their role in neurotransmission. Pharmacol Ther. 1983;22:127–41.

  66. 66.

    Buijs RM, Swaab DF. Immuno-electron microscopical demonstration of vasopressin and oxytocin synapses in the limbic system of the rat. Cell Tissue Res. 1979;204:355–65.

  67. 67.

    Buijs RM, Van Heerikhuize JJ. Vasopressin and oxytocin release in the brain–a synaptic event. Brain Res. 1982;252:71–6.

  68. 68.

    Leng G, Ludwig M. Neurotransmitters and peptides: whispered secrets and public announcements. J Physiol. 2008;586:5625–32.

  69. 69.

    Engelmann M, Wotjak CT, Ebner K, Landgraf R. Behavioural impact of intraseptally released vasopressin and oxytocin in rats. Exp Physiol. 2000;85:125S–30S.

  70. 70.

    Castel M, Morris J, Belenky M. Non-synaptic and dendritic exocytosis from dense-cored vesicles in the suprachiasmatic nucleus. Neuroreport. 1996;7:543–7.

  71. 71.

    Donovan M, Liu Y, Wang Z. Anxiety-like behavior and neuropeptide receptor expression in male and female prairie voles: the effects of stress and social buffering. Behav Brain Res. 2018;342:70–8.

  72. 72.

    Dumais KM, Bredewold R, Mayer TE, Veenema AH. Sex differences in oxytocin receptor binding in forebrain regions: correlations with social interest in brain region- and sex- specific ways. Horm Behav. 2013;64:693–701.

  73. 73.

    Guoynes CD, Simmons TC, Downing GM, Jacob S, Solomon M, Bales KL. Chronic intranasal oxytocin has dose-dependent effects on central oxytocin and vasopressin systems in prairie voles (Microtus ochrogaster). Neuroscience. 2018;369:292–302.

  74. 74.

    Insel TR, Gelhard R, Shapiro LE. The comparative distribution of forebrain receptors for neurohypophyseal peptides in monogamous and polygamous mice. Neuroscience. 1991;43:623–30.

  75. 75.

    Tribollet E, Audigier S, Dubois-Dauphin M, Dreifuss JJ. Gonadal steroids regulate oxytocin receptors but not vasopressin receptors in the brain of male and female rats. An autoradiographical study. Brain Res. 1990;511:129–40.

  76. 76.

    De Kloet ER, Voorhuis TAM, Elands J. Estradiol induces oxytocin binding sites in rat hypothalamic ventromedial nucleus. Eur J Pharmacol. 1986;118:185–6.

  77. 77.

    Bale TL, Dorsa DM, Johnston CA. Oxytocin receptor mRNA expression in the ventromedial hypothalamus during the estrous cycle. J Neurosci. 1995;15:5058–64.

  78. 78.

    Johnson AE, Coirini H, Ball GF, McEwen BS. Anatomical localization of the effects of 17ß-estradiol on oxytocin receptor binding in the ventromedial hypothalamic nucleus. Endocrinology. 1989;124:207–11.

  79. 79.

    Witt DM, Carter CS, Lnsel TR. Oxytocin receptor binding in female prairie voles: endogenous and exogenous oestradiol stimulation. J Neuroendocrinol. 1991;3:155–61.

  80. 80.

    Bale TL, Dorsa DM. Sex differences in and effects of estrogen on oxytocin receptor messenger ribonucleic acid expression in the ventromedial hypothalamus. Endocrinology. 1995;136:27–32.

  81. 81.

    O’Connell LA, Hofmann HA. The vertebrate mesolimbic reward system and social behavior network: a comparative synthesis. J Comp Neurol. 2011;519:3599–39.

  82. 82.

    Caldwell HK, Albers HE. Oxytocin, vasopressin, and the motivational forces that drive social behaviors. Curr Top Behav Neurosci. 2016;27:51–103.

  83. 83.

    Wei D, Lee D, Li D, Daglian J, Jung KM, Piomelli D. A role for the endocannabinoid 2-arachidonoyl-sn-glycerol for social and high-fat food reward in male mice. Psychopharmacology. 2016;233:1911–9.

  84. 84.

    Mikhailova MA, Bass CE, Grinevich VP, Chappell AM, Deal AL, Bonin KD, et al. Optogenetically-induced tonic dopamine release from VTA-nucleus accumbens projections inhibits reward consummatory behaviors. Neuroscience. 2016;333:54–64.

  85. 85.

    Kummer KK, El Rawas R, Kress M, Saria A, Zernig G. Social interaction and cocaine conditioning in mice increase spontaneous spike frequency in the nucleus accumbens or septal nuclei as revealed by multielectrode array recordings. Pharmacology. 2015;95:42–9.

  86. 86.

    Grotewold SK, Wall VL, Goodell DJ, Hayter C, Bland ST. Effects of cocaine combined with a social cue on conditioned place preference and nucleus accumbens monoamines after isolation rearing in rats. Psychopharmacology. 2014;231:3041–53.

  87. 87.

    Gunaydin LA, Grosenick L, Finkelstein JC, Kauvar IV, Fenno LE, Adhikari A, et al. Natural neural projection dynamics underlying social behavior. Cell. 2014;157:1535–51.

  88. 88.

    Beier KT, Steinberg EE, DeLoach KE, Xie S, Miyamichi K, Schwarz L, et al. Circuit architecture of VTA dopamine neurons revealed by systematic input-output mapping. Cell. 2015;162:622–34.

  89. 89.

    Bjorklund A, Dunnett SB. Dopamine neuron systems in the brain: an update. Trends Neurosci. 2007;30:194–202.

  90. 90.

    Ikemoto S. Dopamine reward circuitry: two projection systems from the ventral midbrain to the nucleus accumbens-olfactory tubercle complex. Brain Res Rev. 2007;56:27–78.

  91. 91.

    El Rawas R, Klement S, Kummer KK, Fritz M, Dechant G, Saria A, et al. Brain regions associated with the acquisition of conditioned place preference for cocaine vs. social interaction. Front Behav Neurosci. 2012;6:63

  92. 92.

    Dolen G, Darvishzadeh A, Huang KW, Malenka RC. Social reward requires coordinated activity of nucleus accumbens oxytocin and serotonin. Nature. 2013;501:179–84.

  93. 93.

    Song Z, Borland JM, Larkin TE, O’Malley M, Albers HE. Activation of oxytocin receptors, but not arginine-vasopressin V1a receptors, in the ventral tegmental area of male Syrian hamsters is essential for the reward-like properties of social interactions. Psychoneuroendocrinology. 2016;74:164–72.

  94. 94.

    Hung LW, Neuner S, Polepalli JS, Beier KT, Wright M, Walsh JJ, et al. Gating of social reward by oxytocin in the ventral tegmental area. Science. 2017;357:1406–11.

  95. 95.

    Melis MR, Melis T, Cocco C, Succu S, Sanna F, Pillolla G, et al. Oxytocin injected into the ventral tegmental area induces penile erection and increases extracellular dopamine in the nucleus accumbens and paraventricular nucleus of the hypothalamus of male rats. Eur J Neurosci. 2007;26:1026–35.

  96. 96.

    Ross HE, Cole CD, Smith Y, Neumann ID, Landgraf R, Murphy AZ, et al. Characterization of the oxytocin system regulating affiliative behavior in female prairie voles. Neuroscience. 2009;162:892–903.

  97. 97.

    Knobloch HS, Charlet A, Hoffmann LC, Eliava M, Khrulev S, Cetin AH, et al. Evoked axonal oxytocin release in the central amygdala attenuates fear response. Neuron. 2012;73:553–66.

  98. 98.

    Peris J, MacFadyen K, Smith JA, de Kloet AD, Wang L, Krause EG. Oxytocin receptors are expressed on dopamine and glutamate neurons in the mouse ventral tegmental area that project to nucleus accumbens and other mesolimbic targets. J Comp Neurol. 2017;525:1094–108.

  99. 99.

    Gillies GE, Virdee K, McArthur S, Dalley JW. Sex-dependent diversity in ventral tegmental dopaminergic neurons and developmental programing: a molecular, cellular and behavioral analysis. Neuroscience. 2014;282:69–85.

  100. 100.

    McArthur S, McHale E, Gillies GE. The size and distribution of midbrain dopaminergic populations are permanently altered by perinatal glucocorticoid exposure in a sex- region- and time-specific manner. Neuropsychopharmacology. 2007;32:1462–76.

  101. 101.

    Kritzer MF, Creutz LM. Region and sex differences in constituent dopamine neurons and immunoreactivity for intracellular estrogen and androgen receptors in mesocortical projections in rats. J Neurosci. 2008;28:9525–35.

  102. 102.

    Walker QD, Rooney MB, Wightman RM, Kuhn CM. Dopamine release and uptake are greater in female than male rat striatum as measured by fast cyclic voltammetry. Neuroscience. 2000;95:1061–70.

  103. 103.

    Virdee K, McArthur S, Brischoux F, Caprioli D, Ungless MA, Robbins TW, et al. Antenatal glucocorticoid treatment induces adaptations in adult midbrain dopamine neurons, which underpin sexually dimorphic behavioral resilience. Neuropsychopharmacology. 2014;39:339–50.

  104. 104.

    Walker QD, Ray R, Kuhn CM. Sex differences in neurochemical effects of dopaminergic drugs in rat striatum. Neuropsychopharmacology. 2006;31:1193–202.

  105. 105.

    Castner SA, Becker JB. Sex differences in the effect of amphetamine on immediate early gene expression in the rat dorsal striatum. Brain Res. 1996;712:245–57.

  106. 106.

    Becker JB, Hu M. Sex differences in drug abuse. Front Neuroendocrinol. 2008;29:36–47.

  107. 107.

    Mozley LH, Gur RC, Mozley PD, Gur RE. Striatal dopamine transporters and cognitive functioning in healthy men and women. Am J Psychiatry. 2001;158:1492–9.

  108. 108.

    Laakso A, Vilkman H, Bergman J, Haaparanta M, Solin O, Syvalahti E, et al. Sex differences in striatal presynaptic dopamine synthesis capacity in healthy subjects. Biol Psychiatry. 2002;52:759–63.

  109. 109.

    Soutschek A, Beharelle AR, Burke CJ, Schreiber R, Weber SC, Karipidis II, ten Velden J, Weber B, Haker H, Kalenscher T, Tobler PN. The dopaminergic reward system underpins gender differences in social preferences. Nat Human Behav. 2017;1:819–27.

  110. 110.

    Becker JB, Cha JH. Estrous cycle-dependent variation in amphetamine-induced behaviors and striatal dopamine release assessed with microdialysis. Behav Brain Res. 1989;35:117–25.

  111. 111.

    White TL, Justice AJ, de Wit H. Differential subjective effects of D-amphetamine by gender, hormone levels and menstrual cycle phase. Pharmacol Biochem Behav. 2002;73:729–41.

  112. 112.

    Robinson TE, Camp DM, Becker JB. Gonadectomy attenuates turning behavior produced by electrical stimulation of the nigrostriatal dopamine system in female but not male rats. Neurosci Lett. 1981;23:203–8.

  113. 113.

    Becker JB, Beer ME. The influence of estrogen on nigrostriatal dopamine activity: behavioral and neurochemical evidence for both pre- and postsynaptic components. Behav Brain Res. 1986;19:27–33.

  114. 114.

    Forgie ML, Stewart J. Six differences in the locomotor-activating effects of amphetamine: role of circulating testosterone in adulthood. Physiol Behav. 1994;55:639–44.

  115. 115.

    Meisel RL, Joppa MA. Conditioned place preference in female hamsters following aggressive or sexual encounters. Physiol Behav. 1994;56:1115–8.

  116. 116.

    Borland JM, Frantz KJ, Aiani LM, Grantham KN, Song Z, Albers HE. A novel operant task to assess social reward and motivation in rodents. J Neurosci Methods. 2017;287:80–8.

  117. 117.

    Heth G, Todrank J, Johnston RE. Kin recognition in golden hamsters: evidence for phenotype matching. Anim Behav. 1998;56:409–17.

  118. 118.

    Johnston RE, Peng A. Memory for individuals: hamsters (Mesocricetus auratus) require contact to develop multicomponent representations (concepts) of others. J Comp Psychol. 2008;122:121–31.

  119. 119.

    Payne AP, Swanson HH. Agonistic behaviour between pairs of hamsters of the same and opposite sex in a neutral observation area. Behaviour. 1970;36:259–69.

  120. 120.

    Drickamer LC, Vandenbergh JG. Predictors of social dominance in the adult female golden hamster (Mesocricetus auratus). Anim Behav. 1973;21:564–70.

  121. 121.

    Drickamer LC, Vandenbergh JG, Colby DR. Predictors of dominance in the male golden hamster (Mesocricetus auratus). Anim Behav. 1973;21:557–63.

  122. 122.

    Borland JM, Grantham KN, Aiani LM, Frantz KJ, Albers HE. Role of oxytocin in the ventral tegmental area in social reinforcement. Psychoneuroendocrinology. 2018;95:128–37.

  123. 123.

    Weiss VG, Hofford RS, Yates JR, Jennings FC, Bardo MT. Sex differences in monoamines following amphetamine and social reward in adolescent rats. Exp Clin Psychopharmacol. 2015;23:197–205.

  124. 124.

    Raz S, Berger BD. Social isolation increases morphine intake: behavioral and psychopharmacological aspects. Behav Pharmacol. 2010;21:39–46.

  125. 125.

    Thiel KJ, Sanabria F, Pentkowski NS, Neisewander JL. Anti-craving effects of environmental enrichment. Int J Neuropsychopharmacol. 2009;12:1151–6.

  126. 126.

    Bregolin T, Pinheiro BS, El Rawas R, Zernig G. Preventive strength of dyadic social interaction against reacquisition/reexpression of cocaine conditioned place preference. Front Behav Neurosci. 2017;11:225

  127. 127.

    Chauvet C, Lardeux V, Goldberg SR, Jaber M, Solinas M. Environmental enrichment reduces cocaine seeking and reinstatement induced by cues and stress but not by cocaine. Neuropsychopharmacology. 2009;34:2767–78.

  128. 128.

    Westenbroek C, Perry AN, Jagannathan L, Becker JB. Effect of social housing and oxytocin on the motivation to self-administer methamphetamine in female rats. Physiol Behav. 2017.

  129. 129.

    Bozarth MA, Murray A, Wise RA. Influence of housing conditions on the acquisition of intravenous heroin and cocaine self-administration in rats. Pharmacol Biochem Behav. 1989;33:903–7.

  130. 130.

    Carson DS, Guastella AJ, Taylor ER, McGregor IS. A brief history of oxytocin and its role in modulating psychostimulant effects. J Psychopharmacol. 2013;27:231–47.

  131. 131.

    Leong KC, Zhou L, Ghee SM, See RE, Reichel CM. Oxytocin decreases cocaine taking, cocaine seeking, and locomotor activity in female rats. Exp Clin Psychopharmacol. 2016;24:55–64.

  132. 132.

    Cox BM, Young AB, See RE, Reichel CM. Sex differences in methamphetamine seeking in rats: impact of oxytocin. Psychoneuroendocrinology. 2013;38:2343–53.

  133. 133.

    Becker JB. Sex differences in addiction. Dialog Clin Neurosci. 2016;18:395–402.

  134. 134.

    Flores RJ, Pipkin JA, Uribe KP, Perez A, O’Dell LE. Estradiol promotes the rewarding effects of nicotine in female rats. Behav Brain Res. 2016;307:258–63.

  135. 135.

    Dobkin PL, De CM, Paraherakis A, Gill K. The role of functional social support in treatment retention and outcomes among outpatient adult substance abusers. Addiction. 2002;97:347–56.

  136. 136.

    Havassy BE, Wasserman DA, Hall SM. Social relationships and abstinence from cocaine in an American treatment sample. Addiction. 1995;90:699–710.

  137. 137.

    Maldonado R, Robledo P, Chover AJ, Caine SB, Koob GF. D1 dopamine receptors in the nucleus accumbens modulate cocaine self-administration in the rat. Pharmacol Biochem Behav. 1993;45:239–42.

  138. 138.

    Doherty JM, Cooke BM, Frantz KJ. A role for the prefrontal cortex in heroin-seeking after forced abstinence by adult male rats but not adolescents. Neuropsychopharmacology. 2013;38:446–54.

  139. 139.

    Uhl GR, Drgonova J, Hall FS. Curious cases: altered dose-response relationships in addiction genetics. Pharmacol Ther. 2014;141:335–46.

  140. 140.

    Bardo MT, Neisewander JL, Kelly TH. Individual differences and social influences on the neurobehavioral pharmacology of abused drugs. Pharmacol Rev. 2013;65:255–90.

  141. 141.

    Zernig G, Pinheiro BS. Dyadic social interaction inhibits cocaine-conditioned place preference and the associated activation of the accumbens corridor. Behav Pharmacol. 2015;26:580–94.

  142. 142.

    Matthews TJ, Abdelbaky P, Pfaff DW. Social and sexual motivation in the mouse. Behav Neurosci. 2005;119:1628–39.

  143. 143.

    Liberzon I, Trujillo KA, Akil H, Young EA. Motivational properties of oxytocin in the conditioned place preference paradigm. Neuropsychopharmacology. 1997;17:353–9.

  144. 144.

    Donhoffner ME, Goings SP, Atabaki K, Wood, RI. Intracerebroventricular oxytocin self-administration in female rats. J Neuroendocrinol. 2016;28.

  145. 145.

    Kent K, Arientyl V, Khachatryan MM, Wood RI. Oyxtocin induces a conditioned social preference in female mice. J Neuroendocrinol. 2013;25:803–10.

  146. 146.

    Kosaki Y, Watanabe S. Conditioned social preference, but not place preference, produced by intranasal oxytocin in female mice. Behav. Neurosci. 2016;130:182–95.

  147. 147.

    Li T, Chen X, Mascaro J, Haroon E, Rilling JK. Intranasal oxytocin, but not vasopressin, augments neural responses to toddlers in human fathers. Horm Behav. 2017;93:193–202.

  148. 148.

    Scheele D, Plota J, Stoffel-Wagner B, Maier W, Hurlemann R. Hormonal contraceptives suppress oxytocin-induced brain reward responses to the partner’s face. Soc Cogn Affect Neurosci. 2016;11:767–74.

  149. 149.

    Scheele D, Wille A, Kendrick KM, Stoffel-Wagner B, Becker B, Gunturkun O, et al. Oxytocin enhances brain reward system responses in men viewing the face of their female partner. Proc Natl Acad Sci USA. 2013;110:20308–13.

  150. 150.

    Weisman O, Zagoory-Sharon O, Feldman, R. Oxytocin administration to parent enhances infant physiological and behavioral readiness for social engagement. Biol Psychiatry.

  151. 151.

    Gregory R, Cheng H, Rupp HA, Sengelaub DR, Heiman JR. Oxytocin increases VTA activation to infant and sexual stimuli in nulliparous and postpartum women. Horm Behav. 2015;69:82–8.

  152. 152.

    Hecht EE, Robins DL, Gautam P, King TZ. Intranasal oxytocin reduces social perception in women: neural activation and individual variation. Neuroimage. 2017;147:314–29.

  153. 153.

    Poldrack RA. Inferring mental states from neuroimaging data: from reverse inference to large-scale decoding. Neuron. 2011;72:692–7.

  154. 154.

    Feng C, Lori A, Waldman ID, Binder EB, Haroon E, Rilling JK. A common oxytocin receptor gene (OXTR) polymorphism modulates intranasal oxytocin effects on the neural response to social cooperation in humans. Genes Brain Behav. 2015;14:516–25.

  155. 155.

    Altemus M, Jacobson KR, Debellis M, Kling M, Pigott T, Murphy DL, et al. Normal CSF oxytocin and NPY levels in OCD. Biol Psychiatry. 1999;45:931–3.

  156. 156.

    Cardoso C, Ellenbogen MA, Orlando MA, Bacon SL, Joober R. Intranasal oxytocin attenuates the cortisol response to physical stress: a dose-response study. Psychoneuroendocrinology. 2013;38:399–407.

  157. 157.

    Cardoso C, Orlando MA, Brown CA, Ellenbogen MA. Oxytocin and enhancement of the positive valence of social affiliation memories: an autobiographical memory study. Soc Neurosci. 2014;9:186–95.

  158. 158.

    Chen X, Gautam P, Haroon E, Rilling JK. Within vs. between-subject effects of intranasal oxytocin on the neural response to cooperative and non-cooperative social interactions. Psychoneuroendocrinology. 2017;78:22–30.

  159. 159.

    Rilling JK, Chen X, Chen X, Haroon E. Intranasal oxytocin modulates neural functional connectivity during human social interaction. Am J Primatol. 2018. In press.

  160. 160.

    Kreuder AK, Scheele D, Wassermann L, Wollseifer M, Stoffel-Wagner B, Lee MR, et al. How the brain codes intimacy: the neurobiological substrates of romantic touch. Hum Brain Mapp. 2017;38:4525–34.

  161. 161.

    Popik P, Vetulani J, van Ree JM. Low doses of oxytocin facilitate social recognition in rats. Psychopharmacology. 1992;106:71–4. PubMed:2018 Feb 10. doi: 10.1002/ajp.22740. [Epub ahead of print].

  162. 162.

    Boccia MM, Kopf SR, Baratti CM. Effects of a single administration of oxytocin or vasopressin and their interactions with two selective receptor antagonists on memory storage in mice. Neurobiol Learn Mem. 1998;69:136–46.

  163. 163.

    Dichter GS, Damiano CA, Allen JA. Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings. J Neurodev Disord. 2012;4:19

  164. 164.

    Cover KK, Maeng LY, Lebron-Milad K, Milad MR. Mechanisms of estradiol in fear circuitry: implications for sex differences in psychopathology. Transl Psychiatry. 2014;4:e422

  165. 165.

    Gobinath AR, Choleris E, Galea LA. Sex, hormones, and genotype interact to influence psychiatric disease, treatment, and behavioral research. J Neurosci Res. 2017;95:50–64.

  166. 166.

    Ferri SL, Abel T, Brodkin ES. Sex differences in autism spectrum disorder: a review. Curr Psychiatry Rep. 2018;20:9

  167. 167.

    Bangasser DA, Valentino RJ. Sex differences in stress-related psychiatric disorders: neurobiological perspectives. Front Neuroendocrinol. 2014;35:303–19.

  168. 168.

    McGregor IS, Bowen MT. Breaking the loop: oxytocin as a potential treatment for drug addiction. Horm Behav. 2012;61:331–9.

  169. 169.

    Rich ME, Caldwell HK. A role for oxytocin in the etiology and treatment of schizophrenia. Front Endocrinol. 2015;6:90

  170. 170.

    Sippel LM, Allington CE, Pietrzak RH, Harpaz-Rotem I, Mayes LC, Olff M. Oxytocin and stress-related disorders: neurobiological mechanisms and treatment opportunities. Chronic Stress. 2017. 1.

  171. 171.

    Benner S, Yamasue H. Clinical potential of oxytocin in autism spectrum disorder: current issues and future perspectives. Behav Pharmacol. 2018;29:1–2.

  172. 172.

    Gottschalk MG, Domschke K. Oxytocin and anxiety disorders. Curr Top Behav Neurosci. 2017.

  173. 173.

    Leng G, Ludwig M. Intranasal oxytocin: myths and delusions. Biol Psychiatry. 2016;79:243–50.

  174. 174.

    Baumgartner T, Heinrichs M, Vonlanthen A, Fischbacher U, Fehr E. Oxytocin shapes the neural circuitry of trust and trust adaptation in humans. Neuron. 2008;58:639–50.

Download references


We would like to thank Dr. Maurice Manning for his generous gift of the OT receptor agonist and antagonist.


This work was supported by an NIH predoctoral fellowship F31MH113367 to JMB, NIH grants MH109302 and MH110212 to HEA, NIH grant MH084068 to JKR, and funds from the Brains and Behavior Program at Georgia State University.

Author information


  1. Center for Behavioral Neuroscience, Georgia State University, Atlanta, GA, USA

    • Johnathan M. Borland
    • , James K. Rilling
    • , Kyle J. Frantz
    •  & H. Elliott Albers
  2. Neuroscience Institute, Georgia State University, Atlanta, GA, USA

    • Johnathan M. Borland
    • , Kyle J. Frantz
    •  & H. Elliott Albers
  3. Anthropology, Emory University, Atlanta, GA, USA

    • James K. Rilling
  4. Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA

    • James K. Rilling
  5. Center for Translational and Social Neuroscience, Emory University, Atlanta, GA, USA

    • James K. Rilling


  1. Search for Johnathan M. Borland in:

  2. Search for James K. Rilling in:

  3. Search for Kyle J. Frantz in:

  4. Search for H. Elliott Albers in:

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to H. Elliott Albers.

About this article

Publication history