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

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.