Angiotensin IV elevates oxytocin levels in the rat amygdala and produces anxiolytic-like activity through subsequent oxytocin receptor activation
- First Online:
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.
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.
KeywordsAT4 receptors Nle-angiotensin IV LVV-hemorphin-7 Divalinal Oxytocin Anxiety
- 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
- 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
- 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
- Paxinos G, Watson C (1986) Rat brain in stereotactic coordinates. Academic, San DiegoGoogle Scholar
- 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
- 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