Central administration of angiotensin IV rapidly enhances novel object recognition among mice

• Published in: Neuropharmacology 2013-07, Vol.70, p.247-253
• Main Authors: Paris, Jason J., Eans, Shainnel O., Mizrachi, Elisa, Reilley, Kate J., Ganno, Michelle L., McLaughlin, Jay P.
• Format: Article
• Language: English
• Subjects: Alanine; Alanine - chemistry; Angiotensin II - administration & dosage; Angiotensin II - analogs & derivatives; Angiotensin II - chemical synthesis; Angiotensin II - pharmacology; Angiotensin II(3–8); Angiotensin Receptor Antagonists - pharmacology; Animals; Cognition; Dose-Response Relationship, Drug; Drug discovery; Infusions, Intraventricular; Learning and memory; Male; Mice; Motor Activity - drug effects; Nootropic Agents - administration & dosage; Nootropic Agents - antagonists & inhibitors; Nootropic Agents - pharmacology; Novel object recognition; Recognition (Psychology) - drug effects; Renin–angiotensin system; Time Factors
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2013.01.025

Angiotensin IV (Val1-Tyr2-Ile3-His4-Pro5-Phe6) has demonstrated potential cognitive-enhancing effects. The present investigation assessed and characterized: (1) dose-dependency of angiotensin IV's cognitive enhancement in a C57BL/6J mouse model of novel object recognition, (2) the time-course for these effects, (3) the identity of residues in the hexapeptide important to these effects and (4) the necessity of actions at angiotensin IV receptors for procognitive activity. Assessment of C57BL/6J mice in a novel object recognition task demonstrated that prior administration of angiotensin IV (0.1, 1.0, or 10.0, but not 0.01 nmol, i.c.v.) significantly enhanced novel object recognition in a dose-dependent manner. These effects were time dependent, with improved novel object recognition observed when angiotensin IV (0.1 nmol, i.c.v.) was administered 10 or 20, but not 30 min prior to the onset of the novel object recognition testing. An alanine scan of the angiotensin IV peptide revealed that replacement of the Val1, Ile3, His4, or Phe6 residues with Ala attenuated peptide-induced improvements in novel object recognition, whereas Tyr2 or Pro5 replacement did not significantly affect performance. Administration of the angiotensin IV receptor antagonist, divalinal-Ang IV (20 nmol, i.c.v.), reduced (but did not abolish) novel object recognition; however, this antagonist completely blocked the procognitive effects of angiotensin IV (0.1 nmol, i.c.v.) in this task. Rotorod testing demonstrated no locomotor effects with any angiotensin IV or divalinal-Ang IV dose tested. These data demonstrate that angiotensin IV produces a rapid enhancement of associative learning and memory performance in a mouse model that was dependent on the angiotensin IV receptor. ► Cognitive-enhancing effects of i.c.v. angiotensin IV (Ang IV) characterized in mice. ► Ang IV dose-dependently (0.1–10 nmol) enhances novel object recognition (NOR). ► Ang IV enhancement of NOR performance occurs rapidly, but of brief duration. ► Ang IV receptor antagonist blocks Ang IV-mediated enhancement of NOR. ► Alanine scan of Ang IV suggests three residues contributing to procognitive core.