Effect of I.C.V. injection of AT4 receptor ligands, NLE1-angiotensin IV and LVV-hemorphin 7, on spatial learning in rats

doi:10.1016/j.neuroscience.2003.12.006

Neuroscience

Volume 124, Issue 2, 2004, Pages 341-349

https://doi.org/10.1016/j.neuroscience.2003.12.006 Get rights and content

Abstract

Central administration of angiotensin IV (Ang IV) or its analogues enhance performance of rats in passive avoidance and spatial memory paradigms. The purpose of this study was to examine the effect of a single bolus injection of two distinct AT₄ ligands, Nle¹-Ang IV or LVV-haemorphin-7, on spatial learning in the Barnes circular maze. Mean number of days for rats treated with either Nle¹-Ang IV or LVV-haemorphin-7 to achieve learner criterion is significantly reduced compared with controls (P<0.001 and P<0.05 respectively). This is due to enhanced ability of the peptide-treated rats to adopt a spatial strategy for finding the escape hatch. In all three measures of learning performance, (1) the number of errors made, (2) the distance travelled and (3) the latency in finding the escape hatch, rats treated with either 100 pmol or 1 nmol of Nle¹-Ang IV or 100 pmol LVV-haemorphin-7 performed significantly better than the control groups. As early as the first day of testing, the rats treated with the lower dose of Nle¹-Ang IV or LVV-haemorphin-7 made fewer errors (P<0.01 and P<0.05 respectively) and travelled shorter distances (P<0.05 for both groups) than the control animals. The enhanced spatial learning induced by Nle¹-Ang IV (100 pmol) was attenuated by the co-administration of the AT₄ receptor antagonist, divalinal-Ang IV (10 nmol). Thus, administration of AT₄ ligands results in an immediate potentiation of learning, which may be associated with facilitation of synaptic transmission and/or enhancement of acetylcholine release.

Section snippets

Materials

Nle¹-Ang IV (Nle-Tyr-Ile-His-Pro-Phe; Auspep, Parkville, Australia), LVV-haemorphin-7 (Leu-Val-Val-Tyr-Pro-Trp-Thr-Gln-Arg-Phe; Mimotopes, Clayton, Australia) and divalinal Ang-IV (H-Val-(R)-Tyr-Val-(R)-His-Pro-Phe-OH; Auspep) were dissolved in artificial cerebrospinal fluid (aCSF) and stored as 1 mM stock solutions at −20 °C. Stock solutions were thawed and diluted with vehicle on the day of the experiment.

Animals and surgery

Male Sprague–Dawley rats (230–280 g) aged 6–8 weeks were housed individually in an

I.c.v. injection of Nle¹-Ang IV or LVV-haemorphin-7 enhances spatial learning in the barnes maze

All rats treated with a single dose of 100 pmol Nle¹-Ang IV or LVV-haemorphin-7 injected into the lateral cerebral ventricles, 5 min prior to the first trial on day 1, reached learner criterion 3–4 days earlier than the control group. The percentage of animals in each of the treatment groups achieving learner criterion on any given day is plotted as learning curves in Fig. 1. The groups of animals receiving 100 pmol Nle¹-Ang IV and 100 pmol LVV-hermophin-7 all (100%) achieved learner criterion

Central administration of AT₄ ligands enhances learning in the Barnes maze

The present study demonstrates that a single bolus injection of two distinct peptides, Nle¹-Ang IV and LVV-haemorphin-7, enhanced learning in the Barnes circular maze. Whilst it took up to 8 days for all of the control rats to achieve learner criterion, rats treated with either AT₄ ligand all learnt by day 5. This shows that two distinct AT₄ ligands can enhance performance in spatial learning, clearly demonstrating that the effect is specifically mediated by the AT₄ receptor.

The beneficial

Conclusion

The current study has shown for the first time that a single i.c.v. injection of an AT₄ ligand/IRAP inhibitor, either Nle¹-Ang IV or LVV-haemorphin-7, significantly improves acquisition and/or consolidation of spatial memory in normal rats. This effect of the AT₄ ligands is powerful, immediate and prolonged. This could be associated with immediate, short-term events such as enhanced neurotransmitter release and/or synaptic efficacy. In the light of the recent discovery that the AT₄ receptor is