A wealth of neuropharmacological data demonstrates that oxytocin (OT) actions in the mammalian forebrain support a wide variety of affiliative behaviors and repress aggressive behaviors. Based on that literature, it was expected that reproductive and affiliative behaviors would be vastly decreased and aggression markedly increased in OT gene knockout (OTKO) mice. The initial publications reporting the behaviors of these mice did not include such phenotypes. Here, we compared single-unit activities recorded from the ventromedial hypothalamus in tissue slices of male and female OTKO mice and their wild-type littermate to test two hypotheses about OT functional genomics. First, we proposed that in OTKO mice, a very similar 9-amino-acid neuropeptide, arginine vasopressin (a likely gene duplication product), can ‘cross over’ and compensate for the lack of OT. This hypothesis was confirmed in both males and females. Further, we proposed that because of the lifelong absence of OT in OTKO, OT receptors would be more sensitive to OT in the knockout animals. We tested this idea in males and found that it was correct. Thus, an answer to the ‘OTKO paradox’ is put forth, with implications for OT-sensitive behaviors in a variety of species.

Pedersen CA, Caldwell JD, Peterson G, Walker CH, Mason GA: Oxytocin activation of maternal behavior in the rat. Ann N Y Acad Sci 1992;652:58–69.
Carter CS, DeVries AC, Taymans SE, Roberts RL, Williams JR, Getz LL: Peptides, steroids, and pair bonding. Ann N Y Acad Sci 1997;807:260–272.
Argiolas A, Gessa GL: Central functions of oxytocin. Neurosci Biobehav Rev 1991;15:217–231.
Argiolas A: Neuropeptides and sexual behaviour. Neurosci Biobehav Rev 1999;23:1127–1142.
Johns JM, Noonan LR, Zimmerman LI, et al: Chronic cocaine treatment alters social/aggressive behavior in Sprague-Dawley rat dams and in their prenatally exposed offspring. Ann N Y Acad Sci 1998;846:399–404.
McCarthy MM, Kleopoulos SP, Mobbs CV, Pfaff DW: Infusion of antisense oligodeoxynucleotides to the oxytocin receptor in the ventromedial hypothalamus reduces estrogen-induced sexual receptivity and oxytocin receptor binding in the female rat. Neuroendocrinology 1994;59:432–440.
Engelmann M, Ebner K, Wotjak CT, Landgraf R: Endogenous oxytocin is involved in short-term olfactory memory in female rats. Behav Brain Res 1998;90:89–94.
Carter CS, DeVries AC, Getz LL: Physiological substrates of mammalian monogamy: The prairie vole model. Neurosci Biobehav Rev 1995;19:303–314.
Witt DM, Carter CS, Walton DM: Central and peripheral effects of oxytocin administration in prairie voles (Microtus ochrogaster). Pharmacol Biochem Behav 1990;37:63–69.
Gimpl G, Fahrenholz F: The oxytocin receptor system: Structure, function, and regulation. Physiol Rev 2001;81:629–683.
Gainer H, Wray S: Oxytocin and vasopressin. From genes to peptides. Ann N Y Acad Sci 1992;652:14–28.
Nishimori K, Young LJ, Guo Q, Wang Z, Insel TR, Matzuk MM: Oxytocin is required for nursing but is not essential for parturition or reproductive behavior. Proc Natl Acad Sci USA 1996;93:11699–11704.
Young WS 3rd, Shepard E, Amico J, et al: Deficiency in mouse oxytocin prevents milk ejection, but not fertility or parturition. J Neuroendocrinol 1996;8:847–853.
Gross GA, Imamura T, Luedke C, et al: Opposing actions of prostaglandins and oxytocin determine the onset of murine labor. Proc Natl Acad Sci USA 1998;95:11875–11879.
Bussolati G, Cassoni P: Editorial: The oxytocin/oxytocin receptor system – Expect the unexpected. Endocrinology 2001;142:1377–1379.
Young WS 3rd, Gainer H: Transgenesis and the study of expression, cellular targeting and function of oxytocin, vasopression and their receptors. Neuroendocrinology 2003;78:185–203.
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.
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 USA 2003;100:6192–6197.
Tribollet E, Dubois-Dauphin M, Dreifuss JJ, Barberis C, Jard S: Oxytocin receptors in the central nervous system. Distribution, development, and species differences. Ann N Y Acad Sci 1992;652:29–38.
Barberis C, Audigier S, Durroux T, Elands J, Schmidt A, Jard S: Pharmacology of oxytocin and vasopressin receptors in the central and peripheral nervous system. Ann N Y Acad Sci 1992;652:39–45.
Chini B, Mouillac B, Balestre MN, et al: Two aromatic residues regulate the response of the human oxytocin receptor to the partial agonist arginine vasopressin. FEBS Lett 1996;397:201–206.
Chen YL, Shepherd C, Spinelli W, Lai FM: Oxytocin and vasopressin constrict rat isolated uterine resistance arteries by activating vasopressin V1A receptors. Eur J Pharmacol 1999;376:45–51.
Kow LM, Pfaff DW: Suprachiasmatic neurons in tissue slices from ovariectomized rats: Electrophysiological and neuropharmacological characterization and the effects of estrogen treatment. Brain Res 1984;297:275–286.
Kow LM, Commons KG, Ogawa S, Pfaff DW: Potentiation of the excitatory action of NMDA in ventrolateral periaqueductal gray by the mu-opioid receptor agonist, DAMGO. Brain Res 2002;935:87–102.
Kow LM, Johnson AE, Ogawa S, Pfaff DW: Electrophysiological actions of oxytocin on hypothalamic neurons in vitro: Neuropharmacological characterization and effects of ovarian steroids. Neuroendocrinology 1991;54:526–535.
Kow LM, Weesner GD, Pfaff DW: Alpha 1-adrenergic agonists act on the ventromedial hypothalamus to cause neuronal excitation and lordosis facilitation: Electrophysiological and behavioral evidence. Brain Res 1992;588:237–245.
Kow LM, Pfaff DW: Transmitter and peptide actions on hypothalamic neurons in vitro: Implications for lordosis. Brain Res Bull 1988;20:857–861.
Kow LM, Pfaff DW: Vasopressin excites ventromedial hypothalamic glucose-responsive neurons in vitro. Physiol Behav 1986;37:153–158.
Schumacher M, Coirini H, Pfaff DW, McEwen BS: Behavioral effects of progesterone associated with rapid modulation of oxytocin receptors. Science 1990;250:691–694.
Schumacher M, Coirini H, Flanagan LM, Frankfurt M, Pfaff DW, McEwen BS: Ovarian steroid modulation of oxytocin receptor binding in the ventromedial hypothalamus. Ann N Y Acad Sci 1992;652:374–386.
Schumacher M, Coirini H, Johnson AE, et al: The oxytocin receptor: A target for steroid hormones. Regul Pept 1993;45:115–119.
Engelmann M, Wotjak CT, Ebner K, Landgraf R: Behavioural impact of intraseptally released vasopressin and oxytocin in rats. Exp Physiol 2000;85(spec No):125S–130S.
Kow LM, Ragnauth A, Brewer C, Ogawa S, Pfaff DW: Arginine vasopressin (AVP) stimulates oxytocin responsive neurons in the hypothalamus of oxytocin (OT) gene knockout (OTKO) mice (No 90.3). Soc Neurosci Abst 2001;27:249.
Robinson DA, Wei F, Wang GD, et al: Oxytocin mediates stress-induced analgesia in adult mice. J Physiol 2002;540:593–606.
Van Kesteren RE, Smit AB, De Lange RP, et al: Structural and functional evolution of the vasopressin/oxytocin superfamily: Vasopressin-related conopressin is the only member present in Lymnaea, and is involved in the control of sexual behavior. J Neurosci 1995;15:5989–5998.
Hokfelt T: Neuropeptides in perspective: The last ten years. Neuron 1991;7:867–879.
Mohr E, Meyerhof W, Richter D: Vasopressin and oxytocin: Molecular biology and evolution of the peptide hormones and their receptors. Vitam Horm 1995;51:235–266.
Kimura T, Makino Y, Saji F, et al: Molecular characterization of a cloned human oxytocin receptor. Eur J Endocrinol 1994;131:385–390.
Harmon AC, Huhman KL, Moore TO, Albers HE: Oxytocin inhibits aggression in female Syrian hamsters. J Neuroendocrinol 2002;14:963–969.
Ferris CF, Foote KB, Meltser HM, Plenby MG, Smith KL, Insel TR: Oxytocin in the amygdala facilitates maternal aggression. Ann N Y Acad Sci 1992;652:456–457.
Cushing BS, Carter CS: Prior exposure to oxytocin mimics the effects of social contact and facilitates sexual behaviour in females. J Neuroendocrinol 1999;11:765–769.
DeVries AC, Young WS 3rd, Nelson RJ: Reduced aggressive behaviour in mice with targeted disruption of the oxytocin gene. J Neuroendocrinol 1997;9:363–368.
Winslow JT, Hearn EF, Ferguson J, Young LJ, Matzuk MM, Insel TR: Infant vocalization, adult aggression, and fear behavior of an oxytocin null mutant mouse. Horm Behav 2000;37:145–155.
Pedersen CA, Ascher JA, Monroe YL, Prange AJ Jr: Oxytocin induces maternal behavior in virgin female rats. Science 1982;216:648–650.
Winslow JT, Insel TR: The social deficits of the oxytocin knockout mouse. Neuropeptides 2002;36:221–229.
Insel TR, Winslow JT, Wang Z, Young LJ: Oxytocin, vasopressin, and the neuroendocrine basis of pair bond formation. Adv Exp Med Biol 1998;449:215–224.
Young LJ: Oxytocin and vasopressin as candidate genes for psychiatric disorders: Lessons from animal models. Am J Med Genet 2001;105:53–54.
Russell JA, Leng G, Douglas AJ: The magnocellular oxytocin system, the fount of maternity: Adaptations in pregnancy. Front Neuroendocrinol 2003;24:27–61.
Caldwell JD, Hruby VJ, Hill P, Prange AJ Jr, Pedersen CA: Is oxytocin-induced grooming mediated by uterine-like receptors? Neuropeptides 1986;8:77–86.
Imamura T, Luedke CE, Vogt SK, Muglia LJ: Oxytocin modulates the onset of murine parturition by competing ovarian and uterine effects. Am J Physiol Regul Integr Comp Physiol 2000;279:R1061–R1067.
Armstrong WE, Stern JE, Teruyama R: Plasticity in the electrophysiological properties of oxytocin neurons. Microsc Res Tech 2002;56:73–80.
Dudek FE, Tasker JG, Wuarin JP: Intrinsic and synaptic mechanisms of hypothalamic neurons studied with slice and explant preparations. J Neurosci Methods 1989;28:59–69.
Renaud LP, Allen AM, Cunningham JT, et al: Synaptic and neurotransmitter regulation of activity in mammalian hypothalamic magnocellular neurosecretory cells. Prog Brain Res 1992;92:277–288.
Douglas AJ, Russell JA: Endogenous opioid regulation of oxytocin and ACTH secretion during pregnancy and parturition. Prog Brain Res 2001;133:67–82.
Ragnauth A, Moy V, Brewer C, Kow LM, Ogawa S, Pfaff DW: Female oxytocin gene knockout (OTKO) mice in a semi-natural environment (SNE) exhibit altered aggressive behaviors (No 746.1). Soc Neurosci Abst 2001;27:1981.
Taylor SE, Klein LC, Lewis BP, Gruenewald TL, Gurung RA, Updegraff JA: Biobehavioral responses to stress in females: Tend-and-befriend, not fight-or-flight. Psychol Rev 2000;107:411–429.
Grossman JB, Carter A, Volkmar FR: Social behavior in autism. Ann N Y Acad Sci 1997;807:440–454.
Lord C, Cook EH, Leventhal BL, Amaral DG: Autism spectrum disorders. Neuron 2000;28:355–363.
McCracken JT, McGough J, Shah B, et al: Risperidone in children with autism and serious behavioral problems. N Engl J Med 2002;347:314–321.
Modahl C, Green L, Fein D, et al: Plasma oxytocin levels in autistic children. Biol Psychiatry 1998;43:270–277.
Leboyer M, Bouvard MP, Launay JM, et al: Brief report: A double-blind study of naltrexone in infantile autism. J Autism Dev Disord 1992;22:309–319.
Wotjak CT, Ganster J, Kohl G, Holsboer F, Landgraf R, Engelmann M: Dissociated central and peripheral release of vasopressin, but not oxytocin, in response to repeated swim stress: New insights into the secretory capacities of peptidergic neurons. Neuroscience 1998;85:1209–1222.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.