Psychopharmacology

, Volume 185, Issue 2, pp 218–225 | Cite as

Anxiolytic-like activity of oxytocin in male mice: behavioral and autonomic evidence, therapeutic implications

  • Robert H. Ring
  • Jessica E. Malberg
  • Lisa Potestio
  • Julia Ping
  • Steve Boikess
  • Bin Luo
  • Lee E. Schechter
  • Stacey Rizzo
  • Zia Rahman
  • Sharon Rosenzweig-Lipson
Original Investigation

Abstract

Rationale

Oxytocin (OT) acts as a neuromodulator/neurotransmitter within the central nervous system (CNS) and regulates a diverse range of CNS functions. Notably, evidence from studies in females has revealed an important role for OT in regulating anxiety behavior.

Objectives

The objective of this study was to examine the effects of OT on both behavioral and autonomic parameters of the anxiety response in male mice using three pharmacologically validated preclinical models of anxiety: the four-plate test (FPT), elevated zero maze (EZM), and stress-induced hyperthermia (SIH).

Results

In the FPT, both peripherally (3–30 mg/kg i.p.) and centrally (1–10 μg i.c.v.) administered OT produced dose-dependent increases in punished crossings, indicating an anxiolytic-like effect. The effects of centrally administered OT in the FPT were blocked with peripheral administration of a brain-penetrant OT receptor (OTR) antagonist WAY-162720 (30 mg/kg i.p.), and the effects of peripherally administered OT were blocked with central administration of a non-penetrant OTR antagonist L-371,257, suggesting OT acts centrally. In the EZM, centrally administered OT (0.1–1.0 μg, i.c.v.) produced significant increases in the percentage time spent in the open quadrants of the maze, comparable to alprazolam (0.5–1.0 μg, i.c.v.). In SIH, OT (1–10 mg/kg i.p.) dose-dependently attenuated stress-induced increases in core body temperature, comparable to the reference anxiolytic chlordiazepoxide (CDP) (10 mg/kg i.p.).

Conclusions

These results provide specific behavioral and autonomic evidence of anxiolytic-like effects for oxytocin in males and, together with previously reported observations in females, suggest the potential utility of OTR agonism as a therapeutically relevant mechanism of action for novel anxiolytics in both sexes.

Keywords

Oxytocin Vasopressin Anxiety Stress Depression Hyperthermia Autonomic Anxiolytic Benzodiazepine 

References

  1. Altemus M (1995) Neuropeptides in anxiety disorders. Effects of lactation. Ann N Y Acad Sci 771:697–707PubMedCrossRefGoogle Scholar
  2. Amico JA, Mantella RC, Vollmer RR, Li X (2004a) Anxiety and stress responses in female oxytocin deficient mice. J Neuroendocrinol 16:319–324PubMedCrossRefGoogle Scholar
  3. Amico JA, Vollmer RR, Karam JR, Lee PR, Li X, Koenig JI, McCarthy MM (2004b) Centrally administered oxytocin elicits exaggerated grooming in oxytocin null mice. Pharmacol Biochem Behav 78:333–339CrossRefPubMedGoogle Scholar
  4. Argiolas A, Gessa GL (1991) Central functions of oxytocin. Neurosci Biobehav Rev 15:217–231PubMedCrossRefGoogle Scholar
  5. Aron C, Simon P, Larousse C, Boissier JR (1971) Evaluation of a rapid technique for detecting minor tranquilizers. Neuropharmacology 10:459–469CrossRefPubMedGoogle Scholar
  6. Bale TL, Davis AM, Auger AP, Dorsa DM, McCarthy MM (2001) CNS region-specific oxytocin receptor expression: importance in regulation of anxiety and sex behavior. J Neurosci 21:2546–2552PubMedGoogle Scholar
  7. Bielsky IF, Young LJ (2004) Oxytocin, vasopressin, and social recognition in mammals. Peptides 25:1565–1574CrossRefPubMedGoogle Scholar
  8. Borsini F, Lecci A, Volterra G, Meli A (1989) A model to measure anticipatory anxiety in mice? Psychopharmacology (Berl) 98:207–211CrossRefGoogle Scholar
  9. Bourin M, Hascoet M, Mansouri B, Colombel MC, Bradwejn J (1992) Comparison of behavioral effects after single and repeated administrations of four benzodiazepines in three mice behavioral models. J Psychiatry Neurosci 17:72–77PubMedGoogle Scholar
  10. DSM-IV-TR (2000) Diagnostic and statistical manual of mental disorders (DSM-IV-TR), 4th edn (text revision). American Psychiatric AssociationGoogle Scholar
  11. Engelmann M, Ebner K, Wotjak CT, Landgraf R (1998) Endogenous oxytocin is involved in short-term olfactory memory in female rats. Behav Brain Res 90:89–94CrossRefPubMedGoogle Scholar
  12. Ermisch A, Barth T, Ruhle HJ, Skopkova J, Hrbas P, Landgraf R (1985) On the blood–brain barrier to peptides: accumulation of labelled vasopressin, DesGlyNH2-vasopressin and oxytocin by brain regions. Endocrinol Exp 19:29–37PubMedGoogle Scholar
  13. Feifel D, Reza T (1999) Oxytocin modulates psychotomimetic-induced deficits in sensorimotor gating. Psychopharmacology (Berl) 141:93–98CrossRefGoogle Scholar
  14. Hascoet M, Bourin M, Colombel MC, Fiocco AJ, Baker GB (2000) Anxiolytic-like effects of antidepressants after acute administration in a four-plate test in mice. Pharmacol Biochem Behav 65:339–344CrossRefPubMedGoogle Scholar
  15. Holst S, Uvnas-Moberg K, Petersson M (2002) Postnatal oxytocin treatment and postnatal stroking of rats reduce blood pressure in adulthood. Auton Neurosci 99:85–90CrossRefPubMedGoogle Scholar
  16. Huber D, Veinante P, Stoop R (2005) Vasopressin and oxytocin excite distinct neuronal populations in the central amygdala. Science 308:245–248CrossRefPubMedGoogle Scholar
  17. Insel TR, Shapiro LE (1992) Oxytocin receptor distribution reflects social organization in monogamous and polygamous voles. Proc Natl Acad Sci U S A 89:5981–5985PubMedCrossRefGoogle Scholar
  18. Jones PM, Robinson IC (1982) Differential clearance of neurophysin and neurohypophysial peptides from the cerebrospinal fluid in conscious guinea pigs. Neuroendocrinology 34:297–302PubMedGoogle Scholar
  19. Kash SF, Tecott LH, Hodge C, Baekkeskov S (1999) Increased anxiety and altered responses to anxiolytics in mice deficient in the 65-kDa isoform of glutamic acid decarboxylase. Proc Natl Acad Sci U S A 96:1698–1703CrossRefPubMedGoogle Scholar
  20. Kruse J (1986) Oxytocin: pharmacology and clinical application. J Fam Pract 23:473–479PubMedGoogle Scholar
  21. Lee C, Rodgers RJ (1990) Antinociceptive effects of elevated plus-maze exposure: influence of opiate receptor manipulations. Psychopharmacology (Berl) 102:507–513CrossRefGoogle Scholar
  22. Mantella RC, Vollmer RR, Li X, Amico JA (2003) Female oxytocin-deficient mice display enhanced anxiety-related behavior. Endocrinology 144:2291–2296CrossRefPubMedGoogle Scholar
  23. McCarthy MM (1990) Oxytocin inhibits infanticide in female house mice (Mus domesticus). Horm Behav 24:365–375CrossRefPubMedGoogle Scholar
  24. McCarthy MM, Kow LM, Pfaff DW (1992) Speculations concerning the physiological significance of central oxytocin in maternal behavior. Ann N Y Acad Sci 652:70–82PubMedCrossRefGoogle Scholar
  25. McCarthy MM, McDonald CH, Brooks PJ, Goldman D (1996) An anxiolytic action of oxytocin is enhanced by estrogen in the mouse. Physiol Behav 60:1209–1215CrossRefPubMedGoogle Scholar
  26. Morris M, Callahan MF, Li P, Lucion AB (1995) Central oxytocin mediates stress-induced tachycardia. J Neuroendocrinol 7:455–459PubMedCrossRefGoogle Scholar
  27. Neumann ID (2002) Involvement of the brain oxytocin system in stress coping: interactions with the hypothalamo–pituitary–adrenal axis. Prog Brain Res 139:147–162PubMedCrossRefGoogle Scholar
  28. Neumann ID, Torner L, Wigger A (2000) Brain oxytocin: differential inhibition of neuroendocrine stress responses and anxiety-related behaviour in virgin, pregnant and lactating rats. Neuroscience 95:567–575CrossRefPubMedGoogle Scholar
  29. Numan M, Insel TR (2003) The neurobiology of parental behavior. Springer, Berlin Heidelberg New YorkGoogle Scholar
  30. Oka T, Oka K, Hori T (2001) Mechanisms and mediators of psychological stress-induced rise in core temperature. Psychosom Med 63:476–486PubMedGoogle Scholar
  31. Olivier B, Zethof T, Pattij T, van Boogaert M, van Oorschot R, Leahy C, Oosting R, Bouwknecht A, Veening J, van der Gugten J, Groenink L (2003) Stress-induced hyperthermia and anxiety: pharmacological validation. Eur J Pharmacol 463:117–132CrossRefPubMedGoogle Scholar
  32. Pellow S, Chopin P, File SE, Briley M (1985) Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 14:149–167CrossRefPubMedGoogle Scholar
  33. Ring RH (2005) The central vasopressinergic and oxytocinergic systems as targets for psychiatric drug development neurohypophyseal hormones: from genomics and physiology to disease. American Physiological Society, Steamboat Springs, Colorado, p 162Google Scholar
  34. Robinson DA, Wei F, Wang GD, Li P, Kim SJ, Vogt SK, Muglia LJ, Zhuo M (2002) Oxytocin mediates stress-induced analgesia in adult mice. J Physiol 540:593–606CrossRefPubMedGoogle Scholar
  35. Rodgers RJ, Lee C, Shepherd JK (1992) Effects of diazepam on behavioural and antinociceptive responses to the elevated plus-maze in male mice depend upon treatment regimen and prior maze experience. Psychopharmacology (Berl) 106:102–110CrossRefGoogle Scholar
  36. Shepherd JK, Grewal SS, Fletcher A, Bill DJ, Dourish CT (1994) Behavioural and pharmacological characterisation of the elevated “zero-maze” as an animal model of anxiety. Psychopharmacology (Berl) 116:56–64CrossRefGoogle Scholar
  37. Tsatsaris V, Carbonne B, Cabrol D (2004) Atosiban for preterm labour. Drugs 64:375–382CrossRefPubMedGoogle Scholar
  38. Uvnäs-Moberg K, Widstrom A-M, Nissen E, Bjorvell H (1990) Personality traits in women 4 days postpartum and their correlation with plasma levels of oxytocin and prolactin. J Psychosom Obstet Gynaecol 11:261–273CrossRefGoogle Scholar
  39. Uvnäs-Moberg K, Alster P, Hillegaart V, Ahlenius S (1992) Oxytocin reduces exploratory motor behaviour and shifts the activity towards the centre of the arena in male rats. Acta Physiol Scand 145:429–430PubMedGoogle Scholar
  40. Uvnäs-Moberg K, Ahlenius S. Hillegaart V, Alster P (1994) High doses of oxytocin cause sedation and low doses cause an anxiolytic-like effect in male rats. Pharmacol Biochem Behav 49:101–106CrossRefPubMedGoogle Scholar
  41. Williams PD, Clineschmidt BV, Erb JM, Freidinger RM, Guidotti MT, Lis EV, Pawluczyk JM, Pettibone DJ, Reiss DR, Veber DF et al (1995) 1-(1-[4-[(N-Acetyl-4-piperidinyl)oxy]-2-methoxybenzoyl]piperidin-4- yl)-4H-3,1-benzoxazin-2(1H)-one (L-371,257): a new, orally bioavailable, non-peptide oxytocin antagonist. J Med Chem 38:4634–4636CrossRefPubMedGoogle Scholar
  42. Windle RJ, Shanks N, Lightman SL, Ingram CD (1997) Central oxytocin administration reduces stress-induced corticosterone release and anxiety behavior in rats. Endocrinology 138:2829–2834CrossRefPubMedGoogle Scholar
  43. Windle RJ, Kershaw YM, Shanks N, Wood SA, Lightman SL, Ingram CD (2004) Oxytocin attenuates stress-induced c-fos mRNA expression in specific forebrain regions associated with modulation of hypothalamo–pituitary–adrenal activity. J Neurosci 24:2974–2982CrossRefPubMedGoogle Scholar
  44. Winslow JT, Hearn EF, Ferguson J, Young LJ, Matzuk MM, Insel TR (2000) Infant vocalization, adult aggression, and fear behavior of an oxytocin null mutant mouse. Horm Behav 37:145–155CrossRefPubMedGoogle Scholar
  45. Zethof TJ, Van der Heyden JA, Tolboom JT, Olivier B (1995) Stress-induced hyperthermia as a putative anxiety model. Eur J Pharmacol 294:125–135CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Robert H. Ring
    • 1
  • Jessica E. Malberg
    • 1
  • Lisa Potestio
    • 1
  • Julia Ping
    • 1
  • Steve Boikess
    • 1
  • Bin Luo
    • 1
  • Lee E. Schechter
    • 1
  • Stacey Rizzo
    • 1
  • Zia Rahman
    • 1
  • Sharon Rosenzweig-Lipson
    • 1
  1. 1.Depression and Anxiety Disorders, Discovery NeuroscienceWyeth ResearchPrincetonUSA

Personalised recommendations