Intrahippocampal Norleucine¹-Angiotensin IV mitigates scopolamine-induced spatial working memory deficits

Depletion of cholinergic neurons in the hippocampus has been implicated in memory impairment and Alzheimer's Disease (AD). The brain angiotensin AT₄ receptor is co-localized with cholinergic neurons, and the AT₄ receptor has also been implicated in cognitive processing. The current investigation used the spatial win-shift version of the radial arm maze to determine the involvement of AT₄ receptors in spatial working memory formation. We initially established that intrahippocampal scopolamine significantly impaired the spatial working memory performance of Sprague-Dawley rats in the radial arm maze. We also demonstrated that subsequent intrahippocampal infusions of Norleucine¹-Angiotensin IV (Nle¹-AngIV) significantly prevented the scopolamine-induced deficit. Consistent with previously published data on long-term spatial memory, our findings suggest that activation of AT₄ receptors can compensate for impaired spatial working memory resulting from compromised muscarinic acetylcholine receptor function. We further demonstrate that the hippocampus is a site of action for Nle¹-AngIV-mediated cognitive improvement.