A role for the angiotensin AT4 receptor subtype in overcoming scopolamine-induced spatial memory deficits.

There is increasing interest in the role of the brain angiotensin AT4 receptor subtype in cognitive processing. This receptor subtype is activated by angiotensin IV (AngIV), is heavily distributed in the mammalian hippocampus, neocortex, and cerebellum, and has been linked with a learning and memory function. The present investigation utilized intracerebroventricular (i.c.v.)-infused scopolamine hydrobromide (scop), a muscarinic receptor antagonist, to disrupt acquisition of the circular water maze task of spatial memory. All animals received 2 days of training trials (five trials/day) using a visible platform in an effort to preclude subsequent confounding by scopolamine-induced sensory and/or motor impairments. In the first experiment, i.c.v.-infused scopolamine (70 nmol) was followed by 0, 10, 100, or 1000 pmol i.c.v. doses of Nle(1)-AngIV in separate groups of rats. Results indicated that each dose of Nle(1)-AngIV improved the poor acquisition of this task induced by scopolamine treatment. However, the 100- and 1000-pmol doses were most effective with respect to latency and distance to find the submerged pedestal. A second experiment demonstrated that treatment with a specific AT4 receptor antagonist, Nle(1), Leual(3)-AngIV (1000 pmol), blocked the ability of Nle(1)-AngIV (100 pmol) to improve the performance of scopolamine-compromised rats. These results support the notion that hippocampal AT4 receptors are involved in spatial memory processing, and that activation of these binding sites can overcome the disruption of spatial memory accompanying treatment with a muscarinic receptor antagonist.

Contributions of the brain angiotensin IV-AT4 receptor subtype system to spatial learning.

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.

Attenuation of scopolamine-induced spatial learning impairments by an angiotensin IV analog.

Recently, a receptor for the angiotensin II(3-8) (Ang IV) hexapeptide, was discovered in the hippocampus, suggesting a possible role in learning. The present study utilized intracerebroventricularly (icv) infused scopolamine hydrobromide (scop) to disrupt spatial learning in the circular water maze, followed by the Ang IV analog norleucine1-Ang IV (Nle1-Ang IV), to restore normal performance. Rats were icv pretreated with either scop or artificial cerebrospinal fluid (aCSF) followed by either icv injected Nle1-Ang IV or aCSF, and then behaviourally tested. During acquisition training, each animal's latency to locate the platform, path distance, speed, and efficiency ratios were measured. A probe trial was conducted on the final day of training and the time spent in the target quadrant and the number of crossings over the former location of the platform (annulus crossings) were observed. The results indicate that those animals treated with scop followed by aCSF performed poorly during acquisition training as compared with controls. In contrast, those animals that received scop followed by Nle1-Ang IV attained equivalent latencies, distances, and efficiency ratios to find the platform as those achieved by controls. There were no observed differences in swimming speed, thus arguing against drug-induced motor impairment. During the probe trial, animals treated with scop followed by aCSF spent less time in the target quadrant and made fewer annulus crossings as compared to controls, while the scop, Nle'-Ang IV treated animals performed equivalently to controls. These results suggest that Nle1-Ang IV acts to counteract the disruption of spatial learning induced by scopolamine.

Effects of LY231617 and angiotensin IV on ischemia-induced deficits in circular water maze and passive avoidance performance in rats.

The antioxidant LY231617 has previously been shown to offer significant protection against postischemic cell death in the hippocampus and corpus striatum of rats. The present results extend this observation by demonstrating a concomitant protection against the spatial memory deficits that accompany damage to the hippocampus, as measured by the circular water maze task. These animals were further tested for changes in associative memory by employing a passive avoidance conditioning task. No deficits in passive avoidance conditioning were measured among the 4-vessel occlusion animals treated with LY231617 or vehicle. However, the intracerebroventricular injection of angiotensin IV (Ang IV) immediately prior to foot-shock conditioning improved retention of the conditioned response during the subsequent 2-day period. These results suggest that LY231617 can offer considerable protection against global ischemia-induced cell death in the hippocampus with resulting preservation of spatial memory abilities. In addition, untreated animals that suffered cell losses in the hippocampus remained capable of responding to the facilitory effect of centrally administered Ang IV on a non-spatial memory task. The hypothesized mechanisms of the protection characteristics of LY231617, and the nootropic effect of Ang IV, are discussed.