Elsevier

Regulatory Peptides

Volume 74, Issues 2–3, 30 June 1998, Pages 97-103
Regulatory Peptides

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

https://doi.org/10.1016/S0167-0115(98)00028-7Get rights and content

Abstract

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, Nle1-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.

Introduction

Alzheimer's disease (AD) is characterized by a progressive deterioration of cognitive processing, especially associative (e.g. identification of people, places, and events) and spatial (location in one's environment) memories. Accompanying these dysfunctions is a marked and dramatic depletion of central cholinergic neurons primarily in structures concerned with cognitive processing 1, 2, 3, 4. These brain structures include the nucleus basalis of Meynert (NBM), septal nuclei, temporal cortices, and the CA1 region of the hippocampus. Within these structures, choline acetyltransferase (ChAT), a marker for cholinergic activity, is depleted by up to 90% [5]. Animal models prepared with ibotenic acid or electrolytic lesions to the septal nuclei and the nucleus basalis magnocellularis (non-primate mammalian equivalent of NBM), show a disruption of performance in associative and spatial learning paradigms 6, 7. Based upon loss of cholinergic neurotransmission in AD patients, pharmacological blockade of the cholinergic system has often been used to create an animal model of AD. Specifically, the muscarinic receptor antagonist, scopolamine hydrobromide (scop), induces learning and memory deficits when administered peripherally or centrally 8, 9, 10, 11.

Our laboratory has recently discovered a new angiotensin receptor subtype, termed AT4 [12], that selectively binds the hexapeptide angiotensin II (3–8) (Ang IV: Val-Tyr-Ile-His-Pro-Phe) 13, 14. A role in learning and memory has been postulated for the AT4 receptor based upon several observations. (1) There are high concentrations of AT4 receptor sites in areas of rat and guinea pig brain classically associated with cognition, including the hippocampus and neocortex [15], and the hippocampus, neocortex, and NBM in the monkey [16]. (2) Central administration of Ang IV has been shown to facilitate retention of a passive avoidance-conditioning task while an AT4 antagonist disrupts this process 17, 18. And (3), icv application of Ang IV selectively activates c-Fos in pyramidal and granular cells of the hippocampus suggesting that these cells, which are vital to cognitive function, are responsive to AT4 agonists [19]. Given the short half-life of native Ang IV, our laboratory deemed it useful to synthesize a metabolically stable analog, with high affinity for the AT4 receptor (Kd=3×10−12 M) and low affinity for the AT1/AT2 receptors [20]. This was accomplished with the synthesis of norleucine1-Ang IV (Nle1-Ang IV).

The circular water-maze task has been utilized as a measure of spatial memory and is sensitive to the cognitive disruption induced by scop [21]. Thus, the present study tested the effects of Nle1-Ang IV on spatial learning and memory in scop treated animals. We hypothesized that scop-induced deficits in acquisition of the circular water-maze task would be reversed by central administration of Nle1-Ang IV.

Section snippets

Animals and surgery

Twenty-four female Sprague-Dawley rats (Charles River derived; 250–350 g) were housed individually in an AAALAC-approved vivarium maintained at 22±1°C, with an alternating 12:12 h light/dark cycle initiated at 0700 h. All animals had ad libitum access to water and Purina laboratory rat chow. Food was removed the night before surgery. Each animal was anesthetized with Equithesin (3.5 mg/kg pentobarbital IP, Jensen-Salsbury laboratory), and an intracerebroventricular (icv) guide cannula (PE 60,

Results

Fig. 1A shows the mean (±SEM) latencies to find the submerged platform during acquisition training. The scop-treated animals that subsequently received aCSF performed poorly as compared with members of the control group (aCSF followed by aCSF); however, the scop-treated rats that received Nle1-Ang IV attained the low latencies achieved by the controls. Specifically, a 3 (groups)×8 (days) ANOVA revealed a groups effect (F2,19=6.12, P<0.01); a days effect (F7,133=25.12, P<0.001); and a

Discussion

Although the brain renin–angiotensin system has been implicated in cognitive processes, results from human and animal studies have been inconclusive. Specifically, it has been reported that humans given angiotensin converting enzyme (ACE) inhibitors to control hypertension, also reveal enhanced cognitive performance and `feelings of well being' 23, 24, 25. In agreement with these reports, administration of ACE inhibitors to naive, aged, and scopolamine-treated rodents has been shown to

Acknowledgements

The authors wish to thank Korrie Foley and Ryan Nielson for their assistance in collecting these data. This research was supported by funds provided by Hedral Therapeutics, the Edward E. and Lucille I. Laing Endowment, and Washington State University.

References (59)

  • J.J. Braszko et al.

    Angiotensin II(3-8)-hexapeptide affects motor activity, performance of passive avoidance and a conditioned avoidance response in rats

    Neuroscience

    (1988)
  • J.W. Wright et al.

    The angiotensin IV system: functional implications

    Frontiers in Neuronedocrinology

    (1995)
  • K.A. Roberts et al.

    Autoradiographic identification of brain angiotensin IV binding sites and differential c-Fos expression following intracerebroventricular injection of angiotensin II and IV in rats

    Brain Res

    (1995)
  • M.F. Sardinia et al.

    AT4 receptor structure-binding relationship: N-terminal-modified angiotensin IV analogues

    Peptides

    (1994)
  • B. Costall et al.

    The effects of ACE inhibitors captopril and 5Q29,852 in rodent tests of cognition

    Pharmacol Biochem Behav

    (1989)
  • J.J. Braszko et al.

    Psychotropic effects of angiotensin II and III in rats: locomotor and exploratory vs. cognitive behaviour

    Behav Brain Res

    (1987)
  • J.J. Braszko et al.

    Effect of angiotensin II and saralasin on motor activity and the passive avoidance behavior of rats

    Peptides

    (1988)
  • D.I. Yonkov et al.

    Cholinergic influence on memory facilitation induced by angiotensin II in rats

    Neuropeptides

    (1990)
  • J.W. Wright et al.

    Brain angiotensin receptor subtypes AT1, AT2, and AT4 and their functions

    Regul Pept

    (1995)
  • M.K. Sim

    Degradation of angiotensin I in the endothelium and smooth muscle of the rat aorta

    Biochem Pharmacol

    (1993)
  • R.B. Messing et al.

    Naloxone enhancement of memory

    Behav Neural Biol

    (1979)
  • J.N. Crawley et al.

    Co-existence of galanin and acetylcholine: is galanin involved in memory processes and dementia?

    Trends Neurosci

    (1989)
  • J.A. Nagel et al.

    Enhanced inhibitory avoidance leaming produced by post-trial injections of substance P into the basal forebrain

    Behav Neural Biol

    (1988)
  • J.M. Barnes et al.

    Angiotensin II inhibits acetylcholine release from human temporal cortex: implications for cognition

    Brain Res

    (1990)
  • N.M. Barnes et al.

    Angiotensin converting enzyme density is increased in temporal cortex from patients with Alzheimer's disease

    Eur J Pharmacol

    (1991)
  • G.S. Zubenko et al.

    Cerebrospinal fluid levels of angiotensin-converting enzyme in Alzheimer's disease, Parkinson's disease and progressive supranuclear palsy

    Brain Res

    (1985)
  • J.W. Wright et al.

    Brain angiotensin receptor subtypes in the control of physiological and behavioral responses

    Neurosci Biobehav Rev

    (1994)
  • M.J. Wayner et al.

    Role of angiotensin II and AT1 receptors in hippocampal LTP

    Pharmacol Biochem Behav

    (1993)
  • J.B. Denny et al.

    Angiotensin II blocks hippocampal long-term potentiation

    Brain Res

    (1991)
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