Involvement of the AT1 receptor subtype in the effects of angiotensin IV and LVV-haemorphin 7 on hippocampal neurotransmitter levels and spatial working memory.
Intracerebroventricular (i.c.v.) administration of angiotensin IV (Ang IV) or Leu-Val-Val-haemorphin 7 (LVV-H7) improves memory performance in normal rats and reverses memory deficits in rat models for cognitive impairment. These memory effects were believed to be mediated via the putative 'AT4 receptor'. However, this binding site was identified as insulin-regulated aminopeptidase (IRAP). Correspondingly, Ang IV and LVV-H7 were characterised as IRAP inhibitors. This study investigates whether and how IRAP may be involved in the central effects of Ang IV and LVV-H7. We determined the effects of i.c.v. administration of Ang IV or LVV-H7 on hippocampal neurotransmitter levels using microdialysis in rats. We observed that Ang IV modulates hippocampal acetylcholine levels, whereas LVV-H7 does not. This discrepancy was reflected in the observation that Ang IV binds with micromolar affinity to the AT1 receptor whereas no binding affinity was observed for LVV-H7. Correspondingly, we demonstrated that the AT1 receptor is involved in the effects of Ang IV on hippocampal neurotransmitter levels and on spatial working memory in a plus maze spontaneous alternation task. However, the AT1 receptor was not involved in the spatial memory facilitating effect of LVV-H7. Finally, we demonstrated that Ang IV did not diffuse to the hippocampus following i.c.v. injection, suggesting an extrahippocampal site of action. We propose that AT1 receptors are implicated in the neurochemical and cognitive effects of Ang IV, whereas LVV-H7 may mediate its effects via IRAP.
De Bundel
Dimitri
D
Research Group Experimental Pharmacology, Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information, Vrije Universiteit Brussel, Brussels, Belgium.
Demaegdt
Heidi
H
Lahoutte
Tony
T
Caveliers
Vicky
V
Kersemans
Ken
K
Ceulemans
Ann-Gaelle
AG
Vauquelin
Georges
G
Clinckers
Ralph
R
Vanderheyden
Patrick
P
Michotte
Yvette
Y
Smolders
Ilse
I
D000804:Angiotensin II / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006454:Hemoglobins / Q000008:administration & dosage*; D006624:Hippocampus / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D007276:Injections, Intraventricular / Q000379:methods; D007456:Iodine Isotopes / Q000493:pharmacokinetics; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008570:Memory, Short-Term / Q000187:drug effects*; D017551:Microdialysis / Q000379:methods; D018377:Neurotransmitter Agents / Q000378:metabolism*; D010446:Peptide Fragments / Q000008:administration & dosage*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology*; D013028:Space Perception / Q000187:drug effects; D014018:Tissue Distribution / Q000187:drug effects; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods
D006454:Hemoglobins; D007456:Iodine Isotopes; D018377:Neurotransmitter Agents; D010446:Peptide Fragments; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; C012877:angiotensin II, des-Asp(1)-des-Arg(2)-Ile(5)-; C074309:LVV-hemorphin-7