Abstract
The pituitary neuropeptide oxytocin promotes social behavior, and is a potential adjunct therapy for social deficits in schizophrenia and autism. Oxytocin may mediate pro-social effects by modulating monoamine release in limbic and cortical areas, which was investigated herein using in vivo microdialysis, after establishing a dose that did not produce accompanying sedative or thermoregulatory effects that could concomitantly influence behavior. The effects of oxytocin (0.03–0.3 mg/kg subcutaneous) on locomotor activity, core body temperature, and social behavior (social interaction and ultrasonic vocalizations) were examined in adult male Lister-hooded rats, using selective antagonists to determine the role of oxytocin and vasopressin V1a receptors. Dopamine and serotonin efflux in the prefrontal cortex and nucleus accumbens of conscious rats were assessed using microdialysis. 0.3 mg/kg oxytocin modestly reduced activity and caused hypothermia but only the latter was attenuated by the V1a receptor antagonist, SR49059 (1 mg/kg intraperitoneal). Oxytocin at 0.1 mg/kg, which did not alter activity and had little effect on temperature, significantly attenuated phencyclidine-induced hyperactivity and increased social interaction between unfamiliar rats without altering the number or pattern of ultrasonic vocalizations. In the same rats, oxytocin (0.1 mg/kg) selectively elevated dopamine overflow in the nucleus accumbens, but not prefrontal cortex, without influencing serotonin efflux. Systemic oxytocin administration attenuated phencyclidine-induced hyperactivity and increased pro-social behavior without decreasing core body temperature and selectively enhanced nucleus accumbens dopamine release, consistent with activation of mesocorticolimbic circuits regulating associative/reward behavior being involved. This highlights the therapeutic potential of oxytocin to treat social behavioral deficits seen in psychiatric disorders such as schizophrenia.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Neumann I, Russell JA, Landgraf R. Oxytocin and vasopressin release within the supraoptic and paraventricular nuclei of pregnant, parturient and lactating rats: a microdialysis study. Neuroscience. 1993;53:65–75.
Smith CJ, Poehlmann ML, Li S, Ratnaseelan AM, Bredewold R, Veenema AH. Age and sex differences in oxytocin and vasopressin V1a receptor binding densities in the rat brain: focus on the social decision-making network. Brain Struct Funct. 2017;222:981–1006.
Borthwick AD. Oral oxytocin antagonists. J Med Chem. 2010;53:6525–38.
Grinevich V, Knobloch-Bollmann HS, Eliava M, Busnelli M, Chini B. Assembling the Puzzle: pathways of oxytocin signaling in the brain. Biol Psychiatry. 2016;79:155–64.
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;12:524–38.
Romano A, Tempesta B, Micioni Di Bonaventura MV, Gaetani S. From autism to eating disorders and more: the role of oxytocin in neuropsychiatric disorders. Front Neurosci. 2015;9:497.
Bradley ER, Woolley JD. Oxytocin effects in schizophrenia: reconciling mixed findings and moving forward. Neurosci Biobehav Rev. 2017;80:36–56.
Kirsch P. Oxytocin in the socioemotional brain: implications for psychiatric disorders. Dialogues Clin Neurosci. 2015;17:463–76.
Pedersen CA, Prange AJ Jr. Induction of maternal behavior in virgin rats after intracerebroventricular administration of oxytocin. Proc Natl Acad Sci USA. 1979;76:6661–5.
Insel TR, Hulihan TJ. A gender-specific mechanism for pair bonding: oxytocin and partner preference formation in monogamous voles. Behav Neurosci. 1995;109:782–9.
Calcagnoli F, Meyer N, de Boer SF, Althaus M, Koolhaas JM. Chronic enhancement of brain oxytocin levels causes enduring anti-aggressive and pro-social explorative behavioral effects in male rats. Horm Behav. 2014;65:427–33.
Grippo AJ, Trahanas DM, Zimmerman RR 2nd, Porges SW, Carter CS. Oxytocin protects against negative behavioral and autonomic consequences of long-term social isolation. Psychoneuroendocrinology. 2009;34:1542–53.
Insel TR, Winslow JT. Central administration of oxytocin modulates the infant rat’s response to social isolation. Eur J Pharmacol. 1991;203:149–52.
Simola N. Rat ultrasonic vocalizations and behavioral neuropharmacology: from the screening of drugs to the study of disease. Curr Neuropharmacol. 2015;13:164–79.
Wohr M, Houx B, Schwarting RK, Spruijt B. Effects of experience and context on 50-kHz vocalizations in rats. Physiol Behav. 2008;93:766–76.
Wohr M, Schwarting RK. Affective communication in rodents: ultrasonic vocalizations as a tool for research on emotion and motivation. Cell Tissue Res. 2013;354:81–97.
Wright JM, Gourdon JC, Clarke PB. Identification of multiple call categories within the rich repertoire of adult rat 50-kHz ultrasonic vocalizations: effects of amphetamine and social context. Psychopharmacol (Berl). 2010;211:1–13.
Hackler EA, Byun NE, Jones CK, Williams JM, Baheza R, Sengupta S, et al. Selective potentiation of the metabotropic glutamate receptor subtype 2 blocks phencyclidine-induced hyperlocomotion and brain activation. Neuroscience. 2010;168:209–18.
Jentsch JD, Roth RH. The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia. Neuropsychopharmacology. 1999;20:201–25.
Li Z, Boules M, Williams K, Peris J, Richelson E. The novel neurotensin analog NT69L blocks phencyclidine (PCP)-induced increases in locomotor activity and PCP-induced increases in monoamine and amino acids levels in the medial prefrontal cortex. Brain Res. 2010;1311:28–36.
Millan MJ, Brocco M, Gobert A, Joly F, Bervoets K, Rivet J, et al. Contrasting mechanisms of action and sensitivity to antipsychotics of phencyclidine versus amphetamine: importance of nucleus accumbens 5-HT2A sites for PCP-induced locomotion in the rat. Eur J Neurosci. 1999;11:4419–32.
Fernandez M, Mollinedo-Gajate I, Penagarikano O. Neural circuits for social cognition: implications for autism. Neuroscience. 2018;370:148–62.
Skuse DH, Gallagher L. Dopaminergic-neuropeptide interactions in the social brain. Trends Cogn Sci. 2009;13:27–35.
Dolen G, Darvishzadeh A, Huang KW, Malenka RC. Social reward requires coordinated activity of nucleus accumbens oxytocin and serotonin. Nature. 2013;501:179–84.
Shahrokh DK, Zhang TY, Diorio J, Gratton A, Meaney MJ. Oxytocin-dopamine interactions mediate variations in maternal behavior in the rat. Endocrinology. 2010;151:2276–86.
Insel TR. A neurobiological basis of social attachment. Am J Psychiatry. 1997;154:726–35.
Love TM. Oxytocin, motivation and the role of dopamine. Pharmacol Biochem Behav. 2014;119:49–60.
Aragona BJ, Liu Y, Yu YJ, Curtis JT, Detwiler JM, Insel TR, et al. Nucleus accumbens dopamine differentially mediates the formation and maintenance of monogamous pair bonds. Nat Neurosci. 2006;9:133–9.
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.
Liu Y, Wang ZX. Nucleus accumbens oxytocin and dopamine interact to regulate pair bond formation in female prairie voles. Neuroscience. 2003;121:537–44.
Young KA, Liu Y, Gobrogge KL, Wang H, Wang Z. Oxytocin reverses amphetamine-induced deficits in social bonding: evidence for an interaction with nucleus accumbens dopamine. J Neurosci. 2014;34:8499–506.
Leng G, Ludwig M. Intranasal oxytocin: myths and delusions. Biol Psychiatry. 2016;79:243–50.
Feifel D, Shilling PD, MacDonald K. A review of oxytocin’s effects on the positive, negative, and cognitive domains of schizophrenia. Biol Psychiatry. 2016;79:222–33.
Uhl-Bronner S, Waltisperger E, Martinez-Lorenzana G, Condes Lara M, Freund-Mercier MJ. Sexually dimorphic expression of oxytocin binding sites in forebrain and spinal cord of the rat. Neuroscience. 2005;135:147–54.
Kilkenny C, Browne W, Cuthill IC, Emerson M, Altman DG. Animal research: reporting in vivo experiments: the ARRIVE guidelines. Br J Pharmacol. 2010;160:1577–79.
Watson DJ, King MV, Gyertyan I, Kiss B, Adham N, Fone KC. The dopamine D(3)-preferring D(2)/D(3) dopamine receptor partial agonist, cariprazine, reverses behavioural changes in a rat neurodevelopmental model for schizophrenia. Eur Neuropsychopharmacol. 2016;26:208–24.
Shortall SE, Spicer CH, Ebling FJ, Green AR, Fone KC, King MV. Contribution of serotonin and dopamine to changes in core body temperature and locomotor activity in rats following repeated administration of mephedrone. Addict Biol. 2016;21:1127–39.
Angioni L, Cocco C, Ferri GL, Argiolas A, Melis MR, Sanna F. Involvement of nigral oxytocin in locomotor activity: A behavioral, immunohistochemical and lesion study in male rats. Horm Behav. 2016;83:23–38.
Hicks C, Ramos L, Reekie T, Misagh GH, Narlawar R, Kassiou M, et al. Body temperature and cardiac changes induced by peripherally administered oxytocin, vasopressin and the non-peptide oxytocin receptor agonist WAY 267,464: a biotelemetry study in rats. Br J Pharmacol. 2014;171:2868–87.
Klenerova V, Krejci I, Sida P, Hlinak Z, Hynie S. Oxytocin and carbetocin effects on spontaneous behavior of male rats: modulation by oxytocin receptor antagonists. Neuro Endocrinol Lett. 2009;30:335–42.
Manning M, Misicka A, Olma A, Bankowski K, Stoev S, Chini B, et al. Oxytocin and vasopressin agonists and antagonists as research tools and potential therapeutics. J Neuroendocrinol. 2012;24:609–28.
Ramos L, Hicks C, Kevin R, Caminer A, Narlawar R, Kassiou M, et al. Acute pro-social effects of oxytocin and vasopressin when given alone or in combination with 3,4-methylenedioxymethamphetamine in rats: involvement of the V1A receptor. Neuropsychopharmacology. 2013;38:2249–59.
Smith AL, Freeman SM, Voll RJ, Young LJ, Goodman MM. Carbon-11 N-methyl alkylation of L-368,899 and in vivo PET imaging investigations for neural oxytocin receptors. Bioorg Med Chem Lett. 2013;23:902–6.
Boulet NP, Cloutier CJ, Ossenkopp KP, Kavaliers M. Oxytocin, social factors, and the expression of conditioned disgust (anticipatory nausea) in male rats. Behav Pharmacol. 2016;27:718–25.
Blitzer DS, Wells TE, Hawley WR. Administration of an oxytocin receptor antagonist attenuates sexual motivation in male rats. Horm Behav. 2017;94:33–9.
Bull EJ, Hutson PH, Fone KC. Reduced social interaction following 3,4-methylenedioxymethamphetamine is not associated with enhanced 5-HT2C receptor responsivity. Neuropharmacology. 2003;44:439–48.
Brenes JC, Lackinger M, Hoglinger GU, Schratt G, Schwarting RK, Wohr M. Differential effects of social and physical environmental enrichment on brain plasticity, cognition, and ultrasonic communication in rats. J Comp Neurol. 2016;524:1586–607.
Paxinos G, Watson C. The rat brain in stereotaxis coordinates. New York, NY: Academic Press; 1986.
Brudzynski SM. Pharmacology of ultrasonic vocalizations in adult rats: significance, call classification and neural substrate. Curr Neuropharmacol. 2015;13:180–92.
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.
Ludwig M, Leng G. Dendritic peptide release and peptide-dependent behaviours. Nat Rev Neurosci. 2006;7:126–36.
Calcagnoli F, Kreutzmann JC, de Boer SF, Althaus M, Koolhaas JM. Acute and repeated intranasal oxytocin administration exerts anti-aggressive and pro-affiliative effects in male rats. Psychoneuroendocrinology. 2015;51:112–21.
Lukas M, Toth I, Reber SO, Slattery DA, Veenema AH, Neumann ID. The neuropeptide oxytocin facilitates pro-social behavior and prevents social avoidance in rats and mice. Neuropsychopharmacology. 2011;36:2159–68.
Witt DM, Winslow JT, Insel TR. Enhanced social interactions in rats following chronic, centrally infused oxytocin. Pharmacol Biochem Behav. 1992;43:855–61.
Gibson CM, Penn DL, Smedley KL, Leserman J, Elliott T, Pedersen CA. A pilot six-week randomized controlled trial of oxytocin on social cognition and social skills in schizophrenia. Schizophr Res. 2014;156:261–5.
Kosfeld M, Heinrichs M, Zak PJ, Fischbacher U, Fehr E. Oxytocin increases trust in humans. Nature. 2005;435:673–6.
Shin NY, Park HY, Jung WH, Park JW, Yun JY, Jang JH, et al. Effects of oxytocin on neural response to facial expressions in patients with schizophrenia. Neuropsychopharmacology. 2015;40:1919–27.
Arletti R, Bertolini A. Oxytocin stimulates lordosis behavior in female rats. Neuropeptides. 1985;6:247–53.
Iovino M, Giagulli VA, Licchelli B, Iovino E, Guastamacchia E, Triggiani V. Synaptic inputs of neural afferent pathways to vasopressin- and oxytocin-secreting neurons of supraoptic and paraventricular hypothalamic nuclei. Endocr Metab Immune Disord Drug Targets. 2016;16:276–87.
Falke N. Oxytocin stimulates oxytocin release from isolated nerve terminals of rat neural lobes. Neuropeptides. 1989;14:269–74.
Ferris CF, Yee JR, Kenkel WM, Dumais KM, Moore K, Veenema AH, et al. Distinct BOLD activation profiles following central and peripheral oxytocin administration in awake rats. Front Behav Neurosci. 2015;9:245.
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;38:1985–93.
Boccia ML, Goursaud AP, Bachevalier J, Anderson KD, Pedersen CA. Peripherally administered non-peptide oxytocin antagonist, L368,899, accumulates in limbic brain areas: a new pharmacological tool for the study of social motivation in non-human primates. Horm Behav. 2007;52:344–51.
Romero-Fernandez W, Borroto-Escuela DO, Agnati LF, Fuxe K. Evidence for the existence of dopamine D2-oxytocin receptor heteromers in the ventral and dorsal striatum with facilitatory receptor-receptor interactions. Mol Psychiatry. 2013;18:849–50.
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;58:38–43.
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;15:448–63.
Kovacs GL, Sarnyai Z, Barbarczi E, Szabo G, Telegdy G. The role of oxytocin-dopamine interactions in cocaine-induced locomotor hyperactivity. Neuropharmacology. 1990;29:365–8.
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 Schmiede Arch Pharmacol. 2008;376:441–8.
Brannan T, Martinez-Tica J, Yahr MD. Changes in body temperature markedly affect striatal dopamine release and metabolism: an in vivo study. J Neural Transm Gen Sect. 1992;89:193–6.
Takahata R, Moghaddam B. Activation of glutamate neurotransmission in the prefrontal cortex sustains the motoric and dopaminergic effects of phencyclidine. Neuropsychopharmacology. 2003;28:1117–24.
Del Arco A, Segovia G, Mora F. Blockade of NMDA receptors in the prefrontal cortex increases dopamine and acetylcholine release in the nucleus accumbens and motor activity. Psychopharmacol (Berl). 2008;201:325–38.
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;17:758–69.
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.
Caldwell HK, Stephens SL, Young WS 3rd. Oxytocin as a natural antipsychotic: a study using oxytocin knockout mice. Mol Psychiatry. 2009;14:190–6.
Uvnas-Moberg K, Hillegaart V, Alster P, Ahlenius S. Effects of 5-HT agonists, selective for different receptor subtypes, on oxytocin, CCK, gastrin and somatostatin plasma levels in the rat. Neuropharmacology. 1996;35:1635–40.
Emiliano AB, Cruz T, Pannoni V, Fudge JL. The interface of oxytocin-labeled cells and serotonin transporter-containing fibers in the primate hypothalamus: a substrate for SSRIs therapeutic effects? Neuropsychopharmacology. 2007;32:977–88.
Arakawa H. Involvement of serotonin and oxytocin in neural mechanism regulating amicable social signal in male mice: Implication for impaired recognition of amicable cues in BALB/c strain. Behav Neurosci. 2017;131:176–91.
Thompson MR, Callaghan PD, Hunt GE, Cornish JL, McGregor IS. A role for oxytocin and 5-HT(1A) receptors in the prosocial effects of 3,4 methylenedioxymethamphetamine (“ecstasy. Neuroscience. 2007;146:509–14.
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:e27237.
Huang H, Michetti C, Busnelli M, Manago F, Sannino S, Scheggia D, et al. Chronic and acute intranasal oxytocin produce divergent social effects in mice. Neuropsychopharmacology. 2014;39:1102–14.
Lee PR, Brady DL, Shapiro RA, Dorsa DM, Koenig JI. Social interaction deficits caused by chronic phencyclidine administration are reversed by oxytocin. Neuropsychopharmacology. 2005;30:1883–94.
Song Z, McCann KE, McNeill JKt, Larkin TE 2nd, Huhman KL, Albers HE. Oxytocin induces social communication by activating arginine-vasopressin V1a receptors and not oxytocin receptors. Psychoneuroendocrinology. 2014;50:14–9.
Suraev AS, Bowen MT, Ali SO, Hicks C, Ramos L, McGregor IS. Adolescent exposure to oxytocin, but not the selective oxytocin receptor agonist TGOT, increases social behavior and plasma oxytocin in adulthood. Horm Behav. 2014;65:488–96.
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.
Baracz SJ, Cornish JL. The neurocircuitry involved in oxytocin modulation of methamphetamine addiction. Front Neuroendocrinol. 2016;43:1–18.
Lukas M, Wohr M. Endogenous vasopressin, innate anxiety, and the emission of pro-social 50-kHz ultrasonic vocalizations during social play behavior in juvenile rats. Psychoneuroendocrinology. 2015;56:35–44.
Seffer D, Rippberger H, Schwarting RK, Wohr M. Pro-social 50-kHz ultrasonic communication in rats: post-weaning but not post-adolescent social isolation leads to social impairments-phenotypic rescue by re-socialization. Front Behav Neurosci. 2015;9:102.
Burgdorf J, Wood PL, Kroes RA, Moskal JR, Panksepp J. Neurobiology of 50-kHz ultrasonic vocalizations in rats: electrode mapping, lesion, and pharmacology studies. Behav Brain Res. 2007;182:274–83.
Klein BY, Tamir H, Welch MG. PI3K/Akt responses to oxytocin stimulation in Caco2BB gut cells. J Cell Biochem. 2011;112:3216–26.
Acknowledgements
We thank Clare Spicer for technical assistance. Studies were designed by KCFF and MVK with input from TMB, LJS, and DA. Experimental work was undertaken at the University of Nottingham by SK, KCFF, SW, and AW. The first draft of the manuscript was produced by SK, MVK, and KCFF and all authors contributed to production of the final version.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
We declare that, except for income received from their primary employer, no financial support or compensation has been received from any individual or corporate entity over the past three years for research or professional service and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest. The contribution to this work made by SK, MVK, and KCFF was financially supported by Roche. The University of Nottingham BBSRC DTP provided funding for Adele Edwards and Stuart Williams to perform dose–response studies with oxytocin while on laboratory rotations. LJS, TMB, and DA are employed by Hoffmann-la Roche.
Additional information
Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Rights and permissions
About this article
Cite this article
Kohli, S., King, M.V., Williams, S. et al. Oxytocin attenuates phencyclidine hyperactivity and increases social interaction and nucleus accumben dopamine release in rats. Neuropsychopharmacol 44, 295–305 (2019). https://doi.org/10.1038/s41386-018-0171-0
Received:
Revised:
Accepted:
Published:
Version of record:
Issue date:
DOI: https://doi.org/10.1038/s41386-018-0171-0
This article is cited by
-
Oxytocin attenuates isolation-evoked emotional and social behavioral dysregulation through neural, immune, and microbiota mechanisms
Translational Psychiatry (2026)
-
Tactile stimulation reverses painful stimuli outcomes via PVN-VTA oxytocin circuitry and dopaminergic regulation
Communications Biology (2025)
-
Upregulation of the hypothalamo-neurohypophysial system and activation of vasopressin neurones attenuates hyperalgesia in a neuropathic pain model rat
Scientific Reports (2022)
-
The vagus nerve mediates the suppressing effects of peripherally administered oxytocin on methamphetamine self-administration and seeking in rats
Neuropsychopharmacology (2021)
-
1MeTIQ and olanzapine, despite their neurochemical impact, did not ameliorate performance in fear conditioning and social interaction tests in an MK-801 rat model of schizophrenia
Pharmacological Reports (2021)
