Contributions of the brain angiotensin IV-AT(4) receptor subtype system tospatial learning

The development of navigational strategies to solve spatial problems appear s to be dependent on an intact hippocampal formation. The circular water ma ze task requires the animal to use extramaze spatial cues to locate a pedes tal positioned just below the surface of the water. Presently, we investiga ted the role of a recently discovered brain angiotensin receptor subtype (A T(4)) in the acquisition of this spatial learning task. The AT(4) receptor subtype is activated by angiotensin IV (AngIV) rather than angiotensins II or III, as documented for the AT(1) and AT(2) receptor subtypes, and is hea vily distributed in the CA(1)-CA(3) fields of the hippocampus. Chronic intr acerebroventricular infusion of a newly synthesized AT(4) agonist (Norleuci ne(1)-AngIV) via osmotic pump facilitated the rate of acquisition to solve this task, whereas treatment with an AT(4) receptor antagonist (Divalinal) significantly interfered with the acquisition of successful search strategi es. Animals prepared with bilateral knife cuts of the perforant path, a maj or afferent hippocampal fiber bundle originating in the entorhinal cortex, displayed deficits in solving this task. This performance deficit could be reversed with acute intracerebroventricular infusion of a second AT(4) rece ptor agonist (Norleucinal). These results suggest that the brain AngIV-AT(4 ) system plays a role in the formation of spatial search strategies and mem ories. Further, application of an AT(4) receptor agonist compensated for sp atial memory deficits in performance accompanying perforant path knife cuts . Possible mechanisms underlying this compensatory effect are discussed.