Skip to main content
SpringerLink
Log in

Targeting the Oxytocin System to Treat Addictive Disorders: Rationale and Progress to Date

  • Leading Article
  • Published:
CNS Drugs Aims and scope Submit manuscript

Abstract

The neuropeptide oxytocin plays a role in reward, stress, social affiliation, learning, and memory processes. As such, there is increasing interest in oxytocin as a potential treatment for addictions. The endogenous oxytocin system is itself altered by short- or long-term exposure to drugs of abuse. A large number of preclinical studies in rodents have investigated the effect of oxytocin administration on various drug-induced behaviors to determine whether oxytocin can reverse the neuroadaptations occurring with repeated drug and alcohol use. In addition, the mechanisms by which oxytocin acts to modify the behavioral response to drugs of abuse are beginning to be understood. More recently, a few small clinical studies have been conducted in cocaine, cannabis, and alcohol dependence. This review summarizes the preclinical as well as clinical literature to date on the oxytocin system and its relevance to drug and alcohol addiction.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Meyer-Lindenberg A, Domes G, Kirsch P, Heinrichs M. Oxytocin and vasopressin in the human brain: social neuropeptides for translational medicine. Nat Rev Neurosci. 2011;12(9):524–38.

    Article  CAS  PubMed  Google Scholar 

  2. Ludwig M, Leng G. Dendritic peptide release and peptide-dependent behaviours. Nat Rev Neurosci. 2006;7(2):126–36.

    Article  CAS  PubMed  Google Scholar 

  3. Gimpl G, Fahrenholz F. The oxytocin receptor system: structure, function, and regulation. Physiol Rev. 2001;81(2):629–83.

    CAS  PubMed  Google Scholar 

  4. Stoop R. Neuromodulation by oxytocin and vasopressin in the central nervous system as a basis for their rapid behavioral effects. Curr Opin Neurobiol. 2014;29:187–93.

    Article  CAS  PubMed  Google Scholar 

  5. Pinol RA, Bateman R, Mendelowitz D. Optogenetic approaches to characterize the long-range synaptic pathways from the hypothalamus to brain stem autonomic nuclei. J Neurosci Methods. 2012;210(2):238–46.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Ross HE, Young LJ. Oxytocin and the neural mechanisms regulating social cognition and affiliative behavior. Front Neuroendocrinol. 2009;30(4):534–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Neumann ID, Maloumby R, Beiderbeck DI, Lukas M, Landgraf R. Increased brain and plasma oxytocin after nasal and peripheral administration in rats and mice. Psychoneuroendocrinology. 2013;38(10):1985–93.

    Article  CAS  PubMed  Google Scholar 

  8. Beets I, Janssen T, Meelkop E, Temmerman L, Suetens N, Rademakers S, et al. Vasopressin/oxytocin-related signaling regulates gustatory associative learning in C. elegans. Science. 2012;338(6106):543–5.

    Article  CAS  PubMed  Google Scholar 

  9. Kimura T, Tanizawa O, Mori K, Brownstein MJ, Okayama H. Structure and expression of a human oxytocin receptor. Nature. 1992;356(6369):526–9.

    Article  CAS  PubMed  Google Scholar 

  10. Lee HJ, Macbeth AH, Pagani JH, Young WS 3rd. Oxytocin: the great facilitator of life. Prog Neurobiol. 2009;88(2):127–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Smith AL, Freeman SM, Stehouwer JS, Inoue K, Voll RJ, Young LJ, et al. Synthesis and evaluation of C-11, F-18 and I-125 small molecule radioligands for detecting oxytocin receptors. Bioorg Med Chem. 2012;20(8):2721–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Manning M, Stoev S, Chini B, Durroux T, Mouillac B, Guillon G. Peptide and non-peptide agonists and antagonists for the vasopressin and oxytocin V1a, V1b, V2 and OT receptors: research tools and potential therapeutic agents. Prog Brain Res. 2008;170:473–512.

    Article  CAS  PubMed  Google Scholar 

  13. Pedersen CA, Ascher JA, Monroe YL, Prange AJ Jr. Oxytocin induces maternal behavior in virgin female rats. Science. 1982;216(4546):648–50.

    Article  CAS  PubMed  Google Scholar 

  14. Pedersen CA, Prange AJ Jr. Induction of maternal behavior in virgin rats after intracerebroventricular administration of oxytocin. Proc Natl Acad Sci USA. 1979;76(12):6661–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 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(3):247–50.

    Article  CAS  PubMed  Google Scholar 

  16. Insel TR, Shapiro LE. Oxytocin receptor distribution reflects social organization in monogamous and polygamous voles. Proc Natl Acad Sci USA. 1992;89(13):5981–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Liu Y, Wang ZX. Nucleus accumbens oxytocin and dopamine interact to regulate pair bond formation in female prairie voles. Neuroscience. 2003;121(3):537–44.

    Article  CAS  PubMed  Google Scholar 

  18. 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(4):1026–35.

    Article  PubMed  Google Scholar 

  19. Wei D, Lee D, Cox CD, Karsten CA, Penagarikano O, Geschwind DH, et al. Endocannabinoid signaling mediates oxytocin-driven social reward. Proc Natl Acad Sci USA. 2015;112(45):14084–9.

    Article  CAS  PubMed  Google Scholar 

  20. Tracy LM, Georgiou-Karistianis N, Gibson SJ, Giummarra MJ. Oxytocin and the modulation of pain experience: implications for chronic pain management. Neurosci Biobehav Rev. 2015;55:53–67.

    Article  CAS  PubMed  Google Scholar 

  21. 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(3):553–66.

    Article  CAS  PubMed  Google Scholar 

  22. Arletti R, Bertolini A. Oxytocin acts as an antidepressant in two animal models of depression. Life Sci. 1987;41(14):1725–30.

    Article  CAS  PubMed  Google Scholar 

  23. Yoshida M, Takayanagi Y, Inoue K, Kimura T, Young LJ, Onaka T, et al. Evidence that oxytocin exerts anxiolytic effects via oxytocin receptor expressed in serotonergic neurons in mice. J Neurosci. 2009;29(7):2259–71.

    Article  CAS  PubMed  Google Scholar 

  24. Burkett JP, Young LJ. The behavioral, anatomical and pharmacological parallels between social attachment, love and addiction. Psychopharmacology. 2012;224(1):1–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Liu Y, Young KA, Curtis JT, Aragona BJ, Wang Z. Social bonding decreases the rewarding properties of amphetamine through a dopamine D1 receptor-mediated mechanism. J Neurosci. 2011;31(22):7960–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Liu Y, Aragona BJ, Young KA, Dietz DM, Kabbaj M, Mazei-Robison M, et al. Nucleus accumbens dopamine mediates amphetamine-induced impairment of social bonding in a monogamous rodent species. Proc Natl Acad Sci USA. 2010;107(3):1217–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hostetler CM, Ryabinin AE. Social partners prevent alcohol relapse behavior in prairie voles. Psychoneuroendocrinology. 2014;39:152–7.

    Article  PubMed  Google Scholar 

  28. Anacker AM, Ahern TH, Hostetler CM, Dufour BD, Smith ML, Cocking DL, et al. Drinking alcohol has sex-dependent effects on pair bond formation in prairie voles. Proc Natl Acad Sci USA. 2014;111(16):6052–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. McCullough ME, Churchland PS, Mendez AJ. Problems with measuring peripheral oxytocin: can the data on oxytocin and human behavior be trusted? Neurosci Biobehav Rev. 2013;37(8):1485–92.

    Article  CAS  PubMed  Google Scholar 

  30. Johns JM, Caldwell JD, Pedersen CA. Acute cocaine treatment decreases oxytocin levels in the rat hippocampus. Neuropeptides. 1993;24(3):165–9.

    Article  CAS  PubMed  Google Scholar 

  31. Meyers RA, Zavala AR, Neisewander JL. Dorsal, but not ventral, hippocampal lesions disrupt cocaine place conditioning. Neuroreport. 2003;14(16):2127–31.

    Article  PubMed  Google Scholar 

  32. Sarnyai Z, Kovacs GL. Role of oxytocin in the neuroadaptation to drugs of abuse. Psychoneuroendocrinology. 1994;19(1):85–117.

    Article  CAS  PubMed  Google Scholar 

  33. Georgiou P, Zanos P, Ehteramyan M, Hourani S, Kitchen I, Maldonado R, et al. Differential regulation of mGlu5 R and MuOPr by priming- and cue-induced reinstatement of cocaine-seeking behaviour in mice. Addict Biol. 2015;20(5):902–12.

    Article  CAS  PubMed  Google Scholar 

  34. Zanos P, Wright SR, Georgiou P, Yoo JH, Ledent C, Hourani SM, et al. Chronic methamphetamine treatment induces oxytocin receptor up-regulation in the amygdala and hypothalamus via an adenosine A2A receptor-independent mechanism. Pharmacol Biochem Behav. 2014;119:72–9.

    Article  CAS  PubMed  Google Scholar 

  35. Light KC, Grewen KM, Amico JA, Boccia M, Brownley KA, Johns JM. Deficits in plasma oxytocin responses and increased negative affect, stress, and blood pressure in mothers with cocaine exposure during pregnancy. Addict Behav. 2004;29(8):1541–64.

    Article  PubMed  PubMed Central  Google Scholar 

  36. You ZD, Li JH, Song CY, Wang CH, Lu CL. Chronic morphine treatment inhibits oxytocin synthesis in rats. Neuroreport. 2000;11(14):3113–6.

    Article  CAS  PubMed  Google Scholar 

  37. Zanos P, Georgiou P, Wright SR, Hourani SM, Kitchen I, Winsky-Sommerer R, et al. The oxytocin analogue carbetocin prevents emotional impairment and stress-induced reinstatement of opioid-seeking in morphine-abstinent mice. Neuropsychopharmacology. 2014;39(4):855–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lynn JM. Intravenous alcohol infusion for premature labor. J Am Osteopath Assoc. 1970;70(2):167–70.

    CAS  PubMed  Google Scholar 

  39. Marchesi C, Chiodera P, Brusamonti E, Volpi R, Coiro V. Abnormal plasma oxytocin and beta-endorphin levels in alcoholics after short and long term abstinence. Prog Neuropsychopharmacol Biol Psychiatry. 1997;21(5):797–807.

    Article  CAS  PubMed  Google Scholar 

  40. Sivukhina EV, Dolzhikov AA, Morozov IuE, Jirikowski GF, Grinevich V. Effects of chronic alcoholic disease on magnocellular and parvocellular hypothalamic neurons in men. Horm Metab Res. 2006;38(6):382–90.

    Article  CAS  PubMed  Google Scholar 

  41. Butovsky E, Juknat A, Elbaz J, Shabat-Simon M, Eilam R, Zangen A, et al. Chronic exposure to Delta9-tetrahydrocannabinol downregulates oxytocin and oxytocin-associated neurophysin in specific brain areas. Mol Cell Neurosci. 2006;31(4):795–804.

    Article  CAS  PubMed  Google Scholar 

  42. Dumont GJ, Sweep FC, van der Steen R, Hermsen R, Donders AR, Touw DJ, et al. Increased oxytocin concentrations and prosocial feelings in humans after ecstasy (3,4-methylenedioxymethamphetamine) administration. Soc Neurosci. 2009;4(4):359–66.

    Article  CAS  PubMed  Google Scholar 

  43. Broadbear JH, Tunstall B, Beringer K. Examining the role of oxytocin in the interoceptive effects of 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) using a drug discrimination paradigm in the rat. Addict Biol. 2011;16(2):202–14.

    Article  CAS  PubMed  Google Scholar 

  44. van Nieuwenhuijzen PS, Long LE, Hunt GE, Arnold JC, McGregor IS. Residual social, memory and oxytocin-related changes in rats following repeated exposure to gamma-hydroxybutyrate (GHB), 3,4-methylenedioxymethamphetamine (MDMA) or their combination. Psychopharmacology. 2010;212(4):663–74.

    Article  PubMed  Google Scholar 

  45. Koob GF, Buck CL, Cohen A, Edwards S, Park PE, Schlosburg JE, et al. Addiction as a stress surfeit disorder. Neuropharmacology. 2014;76(Pt B):370–82.

  46. Hoge EA, Pollack MH, Kaufman RE, Zak PJ, Simon NM. Oxytocin levels in social anxiety disorder. CNS Neurosci Ther. 2008;14(3):165–70.

    Article  CAS  PubMed  Google Scholar 

  47. Taylor SE, Saphire-Bernstein S, Seeman TE. Are plasma oxytocin in women and plasma vasopressin in men biomarkers of distressed pair-bond relationships? Psychol Sci. 2010;21(1):3–7.

    Article  PubMed  Google Scholar 

  48. Bohus B, Kovacs GL, de Wied D. Oxytocin, vasopressin and memory: opposite effects on consolidation and retrieval processes. Brain Res. 1978;157(2):414–7.

    Article  CAS  PubMed  Google Scholar 

  49. Carson DS, Cornish JL, Guastella AJ, Hunt GE, McGregor IS. Oxytocin decreases methamphetamine self-administration, methamphetamine hyperactivity, and relapse to methamphetamine-seeking behaviour in rats. Neuropharmacology. 2010;58(1):38–43.

    Article  CAS  PubMed  Google Scholar 

  50. Carson DS, Hunt GE, Guastella AJ, Barber L, Cornish JL, Arnold JC, et al. Systemically administered oxytocin decreases methamphetamine activation of the subthalamic nucleus and accumbens core and stimulates oxytocinergic neurons in the hypothalamus. Addict Biol. 2010;15(4):448–63.

    Article  CAS  PubMed  Google Scholar 

  51. Qi J, Yang JY, Song M, Li Y, Wang F, Wu CF. Inhibition by oxytocin of methamphetamine-induced hyperactivity related to dopamine turnover in the mesolimbic region in mice. Naunyn Schmiedebergs Arch Pharmacol. 2008;376(6):441–8.

    Article  CAS  PubMed  Google Scholar 

  52. Qi J, Yang JY, Wang F, Zhao YN, Song M, Wu CF. Effects of oxytocin on methamphetamine-induced conditioned place preference and the possible role of glutamatergic neurotransmission in the medial prefrontal cortex of mice in reinstatement. Neuropharmacology. 2009;56(5):856–65.

    Article  CAS  PubMed  Google Scholar 

  53. Bahi A. The oxytocin receptor impairs ethanol reward in mice. Physiol Behav. 2015;139:321–7.

    Article  CAS  PubMed  Google Scholar 

  54. Baracz SJ, Cornish JL. Oxytocin modulates dopamine-mediated reward in the rat subthalamic nucleus. Horm Behav. 2013;63(2):370–5.

    Article  CAS  PubMed  Google Scholar 

  55. Baracz SJ, Rourke PI, Pardey MC, Hunt GE, McGregor IS, Cornish JL. Oxytocin directly administered into the nucleus accumbens core or subthalamic nucleus attenuates methamphetamine-induced conditioned place preference. Behav Brain Res. 2012;228(1):185–93.

    Article  CAS  PubMed  Google Scholar 

  56. Han WY, Du P, Fu SY, Wang F, Song M, Wu CF, et al. Oxytocin via its receptor affects restraint stress-induced methamphetamine CPP reinstatement in mice: involvement of the medial prefrontal cortex and dorsal hippocampus glutamatergic system. Pharmacol Biochem Behav. 2014;119:80–7.

    Article  CAS  PubMed  Google Scholar 

  57. Manbeck KE, Shelley D, Schmidt CE, Harris AC. Effects of oxytocin on nicotine withdrawal in rats. Pharmacol Biochem Behav. 2014;116:84–9.

    Article  CAS  PubMed  Google Scholar 

  58. Kovacs GL, Sarnyai Z, Izbeki F, Szabo G, Telegdy G, Barth T, et al. Effects of oxytocin-related peptides on acute morphine tolerance: opposite actions by oxytocin and its receptor antagonists. J Pharmacol Exp Ther. 1987;241(2):569–74.

    CAS  PubMed  Google Scholar 

  59. Kovacs GL, Izbeki F, Horvath Z, Telegdy G. Effects of oxytocin and a derivative (Z-prolyl-d-leucine) on morphine tolerance/withdrawal are mediated by the limbic system. Behav Brain Res. 1984;14(1):1–8.

    Article  CAS  PubMed  Google Scholar 

  60. Kovacs GL, Horvath Z, Sarnyai Z, Faludi M, Telegdy G. Oxytocin and a C-terminal derivative (Z-prolyl-d-leucine) attenuate tolerance to and dependence on morphine and interact with dopaminergic neurotransmission in the mouse brain. Neuropharmacology. 1985;24(5):413–9.

    Article  CAS  PubMed  Google Scholar 

  61. Sarnyai Z, Viski S, Krivan M, Szabo G, Kovacs GL, Telegdy G. Endogenous oxytocin inhibits morphine tolerance through limbic forebrain oxytocin receptors. Brain Res. 1988;463(2):284–8.

    Article  CAS  PubMed  Google Scholar 

  62. Kovacs GL, Faludi M, Telegdy G. Oxytocin diminishes heroin tolerance in mice. Psychopharmacology. 1985;86(3):377–9.

    Article  CAS  PubMed  Google Scholar 

  63. Kovacs GL, Borthaiser Z, Telegdy G. Oxytocin reduces intravenous heroin self-administration in heroin-tolerant rats. Life Sci. 1985;37(1):17–26.

    Article  CAS  PubMed  Google Scholar 

  64. Ibragimov R, Kovacs GL, Szabo G, Telegdy G. Microinjection of oxytocin into limbic-mesolimbic brain structures disrupts heroin self-administration behavior: a receptor-mediated event? Life Sci. 1987;41(10):1265–71.

    Article  CAS  PubMed  Google Scholar 

  65. Moaddab M, Hyland BI, Brown CH. Oxytocin enhances the expression of morphine-induced conditioned place preference in rats. Psychoneuroendocrinology. 2015;53:159–69.

    Article  CAS  PubMed  Google Scholar 

  66. Bicknell RJ, Leng G, Lincoln DW, Russell JA. Naloxone excites oxytocin neurones in the supraoptic nucleus of lactating rats after chronic morphine treatment. J Physiol. 1988;396:297–317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Sarnyai Z, Szabo G, Kovacs GL, Telegdy G. Opposite actions of oxytocin and vasopressin in the development of cocaine-induced behavioral sensitization in mice. Pharmacol Biochem Behav. 1992;43(2):491–4.

    Article  CAS  PubMed  Google Scholar 

  68. Sarnyai Z, Biro E, Babarczy E, Vecsernyes M, Laczi F, Szabo G, et al. Oxytocin modulates behavioural adaptation to repeated treatment with cocaine in rats. Neuropharmacology. 1992;31(6):593–8.

    Article  CAS  PubMed  Google Scholar 

  69. Kovacs GL, Sarnyai Z, Barbarczi E, Szabo G, Telegdy G. The role of oxytocin-dopamine interactions in cocaine-induced locomotor hyperactivity. Neuropharmacology. 1990;29(4):365–8.

    Article  CAS  PubMed  Google Scholar 

  70. Sarnyai Z, Szabo G, Kovacs GL, Telegdy G. Oxytocin attenuates the cocaine-induced exploratory hyperactivity in mice. Neuroreport. 1990;1(3–4):200–2.

    Article  CAS  PubMed  Google Scholar 

  71. Sarnyai Z, Babarczy E, Krivan M, Szabo G, Kovacs GL, Barth T, et al. Selective attenuation of cocaine-induced stereotyped behaviour by oxytocin: putative role of basal forebrain target sites. Neuropeptides. 1991;19(1):51–6.

    Article  CAS  PubMed  Google Scholar 

  72. De Groot AN, Vree TB, Hekster YA, Pesman GJ, Sweep FC, Van Dongen PJ, et al. Bioavailability and pharmacokinetics of sublingual oxytocin in male volunteers. J Pharm Pharmacol. 1995;47(7):571–5.

    Article  PubMed  Google Scholar 

  73. Mens WB, Witter A, van Wimersma Greidanus TB. Penetration of neurohypophyseal hormones from plasma into cerebrospinal fluid (CSF): half-times of disappearance of these neuropeptides from CSF. Brain Res. 1983;262(1):143–9.

    Article  CAS  PubMed  Google Scholar 

  74. Zhou L, Sun WL, Young AB, Lee K, McGinty JF, See RE. Oxytocin reduces cocaine seeking and reverses chronic cocaine-induced changes in glutamate receptor function. Int J Neuropsychopharmacol. 2014. doi:10.1093/ijnp/pyu009 (Epub 2014 Oct 31).

    Google Scholar 

  75. Qi J, Han WY, Yang JY, Wang LH, Dong YX, Wang F, et al. Oxytocin regulates changes of extracellular glutamate and GABA levels induced by methamphetamine in the mouse brain. Addict Biol. 2012;17(4):758–69.

    Article  CAS  PubMed  Google Scholar 

  76. Morales-Rivera A, Hernandez-Burgos MM, Martinez-Rivera A, Perez-Colon J, Rivera R, Montalvo J, et al. Anxiolytic effects of oxytocin in cue-induced cocaine seeking behavior in rats. Psychopharmacology. 2014;231(21):4145–55.

    Article  CAS  PubMed  Google Scholar 

  77. Baracz SJ, Everett NA, Cornish JL. The involvement of oxytocin in the subthalamic nucleus on relapse to methamphetamine-seeking behaviour. PloS One. 2015;10(8):e0136132.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Baracz SJ, Everett NA, McGregor IS, Cornish JL. Oxytocin in the nucleus accumbens core reduces reinstatement of methamphetamine-seeking behaviour in rats. Addict Biol. 2014. doi:10.1111/adb.12198

  79. Bowen MT, Peters ST, Absalom N, Chebib M, Neumann ID, McGregor IS. Oxytocin prevents ethanol actions at delta subunit-containing GABAA receptors and attenuates ethanol-induced motor impairment in rats. Proc Natl Acad Sci USA. 2015;112(10):3104–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Szabo G, Kovacs GL, Szekeli S, Telegdy G. The effects of neurohypophyseal hormones on tolerance to the hypothermic effect of ethanol. Alcohol. 1985;2(4):567–74.

    Article  CAS  PubMed  Google Scholar 

  81. Szabo G, Kovacs GL, Telegdy G. Intraventricular administration of neurohypophyseal hormones interferes with the development of tolerance to ethanol. Acta Physiol Hung. 1989;73(1):97–103.

    CAS  PubMed  Google Scholar 

  82. Hoffman PL, Ritzmann RF, Walter R, Tabakoff B. Arginine vasopressin maintains ethanol tolerance. Nature. 1978;276(5688):614–6.

    Article  CAS  PubMed  Google Scholar 

  83. Szabo G, Kovacs GL, Telegdy G. Effects of neurohypophyseal peptide hormones on alcohol dependence and withdrawal. Alcohol Alcohol. 1987;22(1):71–4.

    CAS  PubMed  Google Scholar 

  84. Peters S, Slattery DA, Flor PJ, Neumann ID, Reber SO. Differential effects of baclofen and oxytocin on the increased ethanol consumption following chronic psychosocial stress in mice. Addict Biol. 2013;18(1):66–77.

    Article  CAS  PubMed  Google Scholar 

  85. McGregor IS, Bowen MT. Breaking the loop: oxytocin as a potential treatment for drug addiction. Horm Behav. 2012;61(3):331–9.

    Article  CAS  PubMed  Google Scholar 

  86. Banks WA. Peptides and the blood–brain barrier. Peptides. 2015;72:16–9.

    Article  CAS  PubMed  Google Scholar 

  87. Born J, Lange T, Kern W, McGregor GP, Bickel U, Fehm HL. Sniffing neuropeptides: a transnasal approach to the human brain. Nat Neurosci. 2002;5(6):514–6.

    Article  CAS  PubMed  Google Scholar 

  88. Striepens N, Kendrick KM, Hanking V, Landgraf R, Wullner U, Maier W, et al. Elevated cerebrospinal fluid and blood concentrations of oxytocin following its intranasal administration in humans. Sci Rep. 2013;3:3440.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Dal Monte O, Noble PL, Turchi J, Cummins A, Averbeck BB. CSF and blood oxytocin concentration changes following intranasal delivery in macaque. PloS One. 2014;9(8):e103677.

  90. Pedersen CA, Smedley KL, Leserman J, Jarskog LF, Rau SW, Kampov-Polevoi A, et al. Intranasal oxytocin blocks alcohol withdrawal in human subjects. Alcohol Clin Exp Res. 2013;37(3):484–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. McRae-Clark AL, Baker NL, Maria MM, Brady KT. Effect of oxytocin on craving and stress response in marijuana-dependent individuals: a pilot study. Psychopharmacology. 2013;228(4):623–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Flanagan JC, Baker NL, McRae-Clark AL, Brady KT, Moran-Santa Maria MM. Effects of adverse childhood experiences on the association between intranasal oxytocin and social stress reactivity among individuals with cocaine dependence. Psychiatry Res. 2015;229(1–2):94–100.

    Article  CAS  PubMed  Google Scholar 

  93. Kirkpatrick MG, Lee R, Wardle MC, Jacob S, de Wit H. Effects of MDMA and Intranasal oxytocin on social and emotional processing. Neuropsychopharmacology. 2014;39(7):1654–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Lee MR, Glassman M, King-Casas B, Kelly DL, Stein EA, Schroeder J, et al. Complexity of oxytocins effects in a chronic cocaine dependent population. Eur Neuropsychopharmacol. 2014;24(9):1483–91.

    Article  CAS  PubMed  Google Scholar 

  95. Insel TR. Is social attachment an addictive disorder? Physiol Behav. 2003;79(3):351–7.

    Article  CAS  PubMed  Google Scholar 

  96. Volkow ND, Wang GJ, Telang F, Fowler JS, Logan J, Childress AR, et al. Cocaine cues and dopamine in dorsal striatum: mechanism of craving in cocaine addiction. J Neurosci. 2006;26(24):6583–8.

    Article  CAS  PubMed  Google Scholar 

  97. Liberzon I, Trujillo KA, Akil H, Young EA. Motivational properties of oxytocin in the conditioned place preference paradigm. Neuropsychopharmacology. 1997;17(6):353–9.

    Article  CAS  PubMed  Google Scholar 

  98. MacDonald E, Dadds MR, Brennan JL, Williams K, Levy F, Cauchi AJ. A review of safety, side-effects and subjective reactions to intranasal oxytocin in human research. Psychoneuroendocrinology. 2011;36(8):1114–26.

    Article  CAS  PubMed  Google Scholar 

  99. Laszlo K, Kovacs A, Zagoracz O, Ollmann T, Peczely L, Kertes E, et al. Positive reinforcing effect of oxytocin microinjection in the rat central nucleus of amygdala. Behav Brain Res. 2016;296:279–85.

    Article  CAS  PubMed  Google Scholar 

  100. 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(12):1389–98.

    Article  CAS  PubMed  Google Scholar 

  101. Bowen MT, Carson DS, Spiro A, Arnold JC, McGregor IS. Adolescent oxytocin exposure causes persistent reductions in anxiety and alcohol consumption and enhances sociability in rats. PloS One. 2011;6(11):e27237.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Hicks C, Cornish JL, Baracz SJ, Suraev A, McGregor IS. Adolescent pre-treatment with oxytocin protects against adult methamphetamine-seeking behavior in female rats. Addict Biol. 2014. doi:10.1111/adb.12197

  103. Windle RJ, Kershaw YM, Shanks N, Wood SA, Lightman SL, Ingram CD. Oxytocin attenuates stress-induced c-fos mRNA expression in specific forebrain regions associated with modulation of hypothalamo-pituitary-adrenal activity. J Neurosci. 2004;24(12):2974–82.

  104. Ibragimov R, Kovacs G. Effect of oxytocin microinjections into the lateral septal nucleus on intravenous heroin self-administration in heroin-tolerant rats [in Russian]. Fiziologicheskii Zh SSSR Im I M Sechenova. 1987;73(12):1625–9.

    CAS  Google Scholar 

  105. Tirelli E, Jodogne C, Legros JJ. Oxytocin blocks the environmentally conditioned compensatory response present after tolerance to ethanol-induced hypothermia in mice. Pharmacol Biochem Behav. 1992;43(4):1263–7.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, National Institute on Alcohol Abuse and Alcoholism, and National Institute on Drug Abuse, 10 Center Drive, MSC-1108, Bethesda, MD, 20892-1108, USA

    Mary R. Lee, Matthew C. H. Rohn & Lorenzo Leggio

  2. Medication Development Program, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Baltimore, MD, USA

    Gianluigi Tanda

  3. Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, RI, USA

    Lorenzo Leggio

Authors
  1. Mary R. Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Matthew C. H. Rohn
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gianluigi Tanda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lorenzo Leggio
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mary R. Lee.

Ethics declarations

Funding

The work was supported by (1) a Bench-to-Bedside (B2B) Grant [primary investigator [PI]: Lee) funded by the National Institutes of Health (NIH) Office of Behavioral and Social Sciences Research (OBSSR); (2) NIH intramural funding ZIA-AA000218 (Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology; PI: Leggio), jointly supported by the Division of Intramural Clinical and Biological Research of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the Intramural Research Program (IRP) of the National Institute on Drug Abuse (NIDA); and (3) the Medication Development Program of the NIDA IRP. The content of this review is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Conflicts of interest

The authors, Mary R. Lee, Matthew C.H. Rohn, Gianluigi Tanda, and Lorenzo Leggio, declare that they have no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lee, M.R., Rohn, M.C.H., Tanda, G. et al. Targeting the Oxytocin System to Treat Addictive Disorders: Rationale and Progress to Date. CNS Drugs 30, 109–123 (2016). https://doi.org/10.1007/s40263-016-0313-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40263-016-0313-z

Keywords

Search

Navigation