Angiotensin IV elevates oxytocin levels in the rat amygdala and produces anxiolytic-like activity through subsequent oxytocin receptor activation.
BACKGROUND
The effects of angiotensin (Ang) IV result from binding to a constitutively active metallopeptidase known as the AT(4) receptor (or oxytocinase/insulin-regulated membrane aminopeptidase). While in vitro evidence indicates that Ang IV inhibits the peptidase activity of AT(4) receptors, leading to increases in the concentrations of several peptides, including oxytocin, the consequence of inhibiting AT(4) peptidase activity in vivo remains unresolved.


CONCLUSIONS
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 AT(4) 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 AT(4) 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 AT(4) 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 AT(4) receptors, confirm the anxiolytic-like properties of Ang IV, and reveal a unique and previously uncharacterized relationship between AT(4) and oxytocin receptor systems.
Pfizer Global Research and Development CN8000, Princeton, NJ, 08543-8000, USA. chad.beyer@lohocla.com
Chad E
CE
Beyer
Jason M
JM
Dwyer
Brian J
BJ
Platt
Sarah
S
Neal
Bin
B
Luo
Huai-Ping
HP
Ling
Qian
Q
Lin
Robert J
RJ
Mark
Sharon
S
Rosenzweig-Lipson
Lee E
LE
Schechter
D000679:Amygdala / Q000187:drug effects* / Q000378:metabolism; D000804:Angiotensin II / Q000008:administration & dosage / Q000031:analogs & derivatives*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage*; D001007:Anxiety / Q000378:metabolism / Q000517:prevention & control* / Q000523:psychology; D001522:Behavior, Animal / Q000187:drug effects; D003863:Depression / Q000188:drug therapy / Q000378:metabolism / Q000523:psychology; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D006454:Hemoglobins / Q000008:administration & dosage; D007118:Immunoassay; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D007279:Injections, Subcutaneous; D008024:Ligands; D008297:Male; D051379:Mice; D017551:Microdialysis; D010121:Oxytocin / Q000378:metabolism*; D010446:Peptide Fragments / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000819:agonists* / Q000378:metabolism; D018045:Receptors, Oxytocin / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation
C090830:AT4 receptor; D057911:Angiotensin Receptor Antagonists; D014151:Anti-Anxiety Agents; D006454:Hemoglobins; D008024:Ligands; D010446:Peptide Fragments; D011945:Receptors, Angiotensin; D018045:Receptors, Oxytocin; C104765:divalinal-angiotensin IV; D000804:Angiotensin II; C012877:angiotensin II, des-Asp(1)-des-Arg(2)-Ile(5)-; D010121:Oxytocin; C074309:LVV-hemorphin-7