Psychopharmacology

, Volume 209, Issue 4, pp 303–311

Angiotensin IV elevates oxytocin levels in the rat amygdala and produces anxiolytic-like activity through subsequent oxytocin receptor activation

  • Chad E. Beyer
  • Jason M. Dwyer
  • Brian J. Platt
  • Sarah Neal
  • Bin Luo
  • Huai-Ping Ling
  • Qian Lin
  • Robert J. Mark
  • Sharon Rosenzweig-Lipson
  • Lee E. Schechter
Original Investigation

Abstract

Introduction

The effects of angiotensin (Ang) IV result from binding to a constitutively active metallopeptidase known as the AT4 receptor (or oxytocinase/insulin-regulated membrane aminopeptidase). While in vitro evidence indicates that Ang IV inhibits the peptidase activity of AT4 receptors, leading to increases in the concentrations of several peptides, including oxytocin, the consequence of inhibiting AT4 peptidase activity in vivo remains unresolved.

Discussion

Microdialysis coupled to immunoassay techniques revealed that systemic and intra-amygdala injection of Nle-Ang IV, a metabolically stable derivative of Ang IV, significantly elevated extracellular levels of oxytocin in the rat amygdala. Based on earlier reports describing the anxiolytic-like effects of oxytocin, we investigated whether disrupting AT4 peptidase activity would yield similar responses. In the mouse four-plate test, acute treatment with either Nle-Ang IV or LVV-hemorphin-7, a related AT4 receptor ligand, elicited significant increases in the number of punished crossings. These behavioral responses were comparable to the anxiolytic-like effects of oxytocin and to the standard anxiolytic agent, chlordiazepoxide. Cotreatment with either the AT4 receptor antagonist, divalinal, or the selective oxytocin receptor antagonist, WAY-162720, reversed the anxiolytic-like effects of Nle-Ang IV, while combining ineffective doses of Nle-Ang IV and oxytocin increased the number of punished crossings in this assay. Conversely, Nle-Ang IV and LVV-hemorphin-7 were inactive in the mouse tail suspension test of antidepressant activity. These findings represent the first in vivo demonstration of the peptidase activity of AT4 receptors, confirm the anxiolytic-like properties of Ang IV, and reveal a unique and previously uncharacterized relationship between AT4 and oxytocin receptor systems.

Keywords

AT4 receptors Nle-angiotensin IV LVV-hemorphin-7 Divalinal Oxytocin Anxiety 

References

  1. Albiston AL, Mustafa T, McDowall SG, Mendelsohn FAO, Lee J, Chai SY (2003) AT(4) receptor is insulin-regulated membrane aminopeptidase: potential mechanisms of memory enhancement. Trends Endocrinol Metab 14:72–77CrossRefPubMedGoogle Scholar
  2. Arletti R, Bertolini A (1987) Oxytocin acts as an antidepressant in two animal models of depression. Life Sci 41:1725–1730CrossRefPubMedGoogle Scholar
  3. Aron C, Simon P, Larousse C, Boissier JR (1971) Evaluation of a rapid technique for detecting minor tranquilizers. Neuropharmacology 10:459–469CrossRefPubMedGoogle Scholar
  4. 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
  5. Chai SY, Bastias MA, Clune EF, Matsacos DJ, Mustafa T, Lee JH, McDowall SG, Paxinos G, Mendelsohn FA, Albiston AL (2000) Distribution of angiotensin IV binding sites (AT4 receptor) in the human forebrain, midbrain and pons as visualised by in vitro receptor autoradiography. J Chem Neuroanat 20:339–348CrossRefPubMedGoogle Scholar
  6. Chai SY, Fernando R, Peck G, Ye SY, Mendelsohn FAO, Jenkins TA, Albiston AL (2004) The angiotensin IV/AT(4) receptor. Cell Mol Life Sci 61:2728–2737CrossRefPubMedGoogle Scholar
  7. Cryan JF, Mombereau C, Vassout A (2005) The tail suspension test as a model for assessing antidepressant activity: review of pharmacological and genetic studies in mice. Neurosci Biobehav Rev 29:571–625CrossRefPubMedGoogle Scholar
  8. Ferguson JN, Aldag JM, Insel TR, Young LJ (2001) Oxytocin in the medial amygdala is essential for social recognition in the mouse. J Neurosci 21:8278–8285PubMedGoogle Scholar
  9. Gard PR, Daw P, Mashhour ZS, Tran P (2007) Interactions of angiotensin IV and oxytocin on behaviour in mice. J Renin Angiotensin Aldosterone Syst 8:133–138CrossRefPubMedGoogle Scholar
  10. Herbst JJ, Ross SA, Scott HM, Bobin SA, Morris NJ, Lienhard GE, Keller SR (1997) Insulin stimulates cell surface aminopeptidase activity toward vasopressin in adipocytes. Am J Physiol 272:E600–E606PubMedGoogle Scholar
  11. Keller SR, Scott HM, Mastick CC, Aebersold R, Lienhard GE (1995) Cloning and characterization of a novel insulin-regulated membrane aminopeptidase from Glut4 vesicles. J Biol Chem 270:23612–23618CrossRefPubMedGoogle Scholar
  12. Kirsch P, Esslinger C, Chen Q, Mier D, Lis S, Siddhanti S, Gruppe H, Mattay VS, Gallhofer B, Meyer-Lindenberg A (2005) Oxytocin modulates neural circuitry for social cognition and fear in humans. J Neurosci 25:11489–11493CrossRefPubMedGoogle Scholar
  13. Kosfeld M, Heinrichs M, Zak PJ, Fischbacher U, Fehr E (2005) Oxytocin increases trust in humans. Nature 435:673–676CrossRefPubMedGoogle Scholar
  14. Kovacs GL, De Wied D (1994) Peptidergic modulation of learning and memory processes. Pharmacol Rev 46:269–291PubMedGoogle Scholar
  15. Krebs LT, Kramar EA, Hanesworth JM, Sardinia MF, Ball AE, Wright JW, Harding JW (1996) Characterization of the binding properties and physiological action of divalinal-angiotensin IV, a putative AT4 receptor antagonist. Regul Pept 67:123–130CrossRefPubMedGoogle Scholar
  16. Lee J, Albiston AL, Allen AM, Mendelsohn FA, Ping SE, Barrett GL, Murphy M, Morris MJ, McDowall SG, Chai SY (2004) Effect of I.C.V. injection of AT4 receptor ligands, NLE1-angiotensin IV and LVV-hemorphin 7, on spatial learning in rats. Neuroscience 124:341–349CrossRefPubMedGoogle Scholar
  17. Lee PR, Brady DL, Shapiro RA, Dorsa DM, Koenig JI (2007) Prenatal stress generates deficits in rat social behavior: reversal by oxytocin. Brain Res 1156:152–167Google Scholar
  18. Matsumoto H, Rogi T, Yamashiro K, Kodama S, Tsuruoka N, Hattori A, Takio K, Mizutani S, Tsujimoto M (2000) Characterization of a recombinant soluble form of human placental leucine aminopeptidase/oxytocinase expressed in Chinese hamster ovary cells. Eur J Biochem 267:46–52CrossRefPubMedGoogle Scholar
  19. 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
  20. Mlynarik M, Zelena D, Bagdy G, Makara GB, Jezova D (2007) Signs of attenuated depression-like behavior in vasopressin deficient Brattleboro rats. Horm Behav 51:395–405CrossRefPubMedGoogle Scholar
  21. Neumann ID, Krömer SA, Toschi N, Ebner K (2000) Brain oxytocin inhibits the (re)activity of the hypothalamo-pituitary–adrenal axis in male rats: involvement of hypothalamic and limbic brain regions. Regul Pept 96:31–38CrossRefPubMedGoogle Scholar
  22. Paxinos G, Watson C (1986) Rat brain in stereotactic coordinates. Academic, San DiegoGoogle Scholar
  23. Popik P, Vetulani J, VanRee JM (1996) Facilitation and attenuation of social recognition in rats by different oxytocin-related peptides. Eur J Pharmacol 308:113–116CrossRefPubMedGoogle Scholar
  24. Ring RH, Malberg JE, Potestio L, Ping J, Boikess S, Luo B, Schechter LE, Rizzo S, Rahman Z, Rosenzweig-Lipson S (2006) Anxiolytic-like activity of oxytocin in male mice: behavioral and autonomic evidence, therapeutic implications. Psychopharmacology (Berl) 185:218–225CrossRefGoogle Scholar
  25. Ring RH, Schechter LE, Leonard SK, Dwyer JM, Platt BJ, Graf R, Grauer S, Pulicicchio C, Resnick L, Rahman Z, Sukoff Rizzo SJ, Luo B, Beyer CE, Logue SF, Marquis KL, Hughes ZA, Rosenzweig-Lipson S (2010) Receptor and behavioral pharmacology of WAY-267464, a non-peptide oxytocin receptor agonist. Neuropharmacology 58:69–77CrossRefPubMedGoogle Scholar
  26. Ripoll N, Hascoët M, Bourin M (2006) The four-plates test: anxiolytic or analgesic paradigm? Prog Neuropsychopharmacol Biol Psychiatry 30:873–880CrossRefPubMedGoogle Scholar
  27. Rush AJ, Zimmerman M, Wisniewski SR, Fava M, Hollon SD, Warden D, Biggs MM, Shores-Wilson K, Shelton RC, Luther JF, Thomas B, Trivedi MH (2005) Comorbid psychiatric disorders in depressed outpatients: demographic and clinical features. J Affect Disord 87:43–55CrossRefPubMedGoogle Scholar
  28. Schechter LE, Lin Q, Smith DL, Zhang G, Shan Q, Platt B, Brandt MR, Dawson LA, Cole D, Bernotas R, Robichaud A, Rosenzweig-Lipson S, Beyer CE (2008) Neuropharmacological profile of novel and selective 5-HT6 receptor agonists: WAY-181187 and WAY-208466. Neuropsychopharmacology 33:1323–1335CrossRefPubMedGoogle Scholar
  29. Sofroniew MV (1983) Morphology of vasopressin and oxytocin neurons and their central vascular projections. Prog Brain Res 60:101–104CrossRefPubMedGoogle Scholar
  30. Steru L, Chermat R, Thierry B, Simon P (1985) The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology (Berl) 85:367–370CrossRefGoogle Scholar
  31. Swanson GN, Hanesworth JM, Sardinia MF, Coleman JK, Wright JW, Hall KL, Miller-Wing AV, Stobb JW, Cook VI, Harding EC et al (1992) Discovery of a distinct binding site for angiotensin II (3–8), a putative angiotensin IV receptor. Regul Pept 40:409–419CrossRefPubMedGoogle Scholar
  32. von Bohlen und Halbach O (2003) Angiotensin IV in the central nervous system. Cell Tissue Res 311:1–9CrossRefGoogle Scholar
  33. 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
  34. Winslow JT, Insel TR (2002) The social deficits of the oxytocin knockout mouse. Neuropeptides 36:221–229CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Chad E. Beyer
    • 1
    • 2
    • 3
  • Jason M. Dwyer
    • 1
  • Brian J. Platt
    • 1
  • Sarah Neal
    • 1
  • Bin Luo
    • 1
  • Huai-Ping Ling
    • 1
  • Qian Lin
    • 1
  • Robert J. Mark
    • 1
  • Sharon Rosenzweig-Lipson
    • 1
  • Lee E. Schechter
    • 1
  1. 1.Pfizer Global Research and Development CN8000PrincetonUSA
  2. 2.Lohocla Research CorporationAuroraUSA
  3. 3.Department of Pharmacology, School of MedicineUniversity of Colorado DenverAuroraUSA

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