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The Journal of Neuroscience, May 15, 1999, 19(10):3952-3961

Contributions of the Brain Angiotensin IV-AT₄ Receptor Subtype System to Spatial Learning

John W. Wright^{1, 2, 3}, LeighAnn Stubley⁴, Eric S. Pederson³, Enikö A. Kramár³, Jodi M. Hanesworth², and Joseph W. Harding^{1, 2, 3}

Departments of ¹ Psychology, ²  Veterinary and Comparative Anatomy, Pharmacology, and Physiology, and ³ Program in Neuroscience, Washington State University, Pullman, Washington 99164, and ⁴ Center for Neurobiology of Aging, University of Florida, Gainesville, Florida 32610

The development of navigational strategies to solve spatial problems appears to be dependent on an intact hippocampal formation. The circular water maze task requires the animal to use extramaze spatial cues to locate a pedestal positioned just below the surface of the water. Presently, we investigated the role of a recently discovered brain angiotensin receptor subtype (AT₄) in the acquisition of this spatial learning task. The AT₄ receptor subtype is activated by angiotensin IV (AngIV) rather than angiotensins II or III, as documented for the AT₁ and AT₂ receptor subtypes, and is heavily distributed in the CA₁-CA₃ fields of the hippocampus. Chronic intracerebroventricular infusion of a newly synthesized AT₄ agonist (Norleucine¹-AngIV) via osmotic pump facilitated the rate of acquisition to solve this task, whereas treatment with an AT₄ receptor antagonist (Divalinal) significantly interfered with the acquisition of successful search strategies. Animals prepared with bilateral knife cuts of the perforant path, a major 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 AT₄ receptor agonist (Norleucinal). These results suggest that the brain AngIV-AT₄ system plays a role in the formation of spatial search strategies and memories. Further, application of an AT₄ receptor agonist compensated for spatial memory deficits in performance accompanying perforant path knife cuts. Possible mechanisms underlying this compensatory effect are discussed.

Key words: spatial memory; hippocampus; perforant path knife cuts; angiotensin IV analogs; AT₄ receptor; circular water maze

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Copyright © 1999 Society for Neuroscience  0270-6474/99/19103952-10$05.00/0

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