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Psychopharmacology

, Volume 206, Issue 3, pp 415–427 | Cite as

Cognitive enhancing effects of ghrelin receptor agonists

  • Zeenat AtchaEmail author
  • Woei-Shin Chen
  • Agnes B. Ong
  • Fong-Kuan Wong
  • Aveline Neo
  • Edward R. Browne
  • Jason Witherington
  • Darrel J. Pemberton
Original Investigation

Abstract

Rationale

Ghrelin, the endogenous ligand for the growth hormone secretagogue receptor, has been shown to play a role in multiple physiological processes including appetite regulation, metabolism and, more recently, dendritic spine architecture, long-term potentiation and cognition.

Objective

The objective of this study was to determine the effects of two structurally non-peptide ghrelin receptor agonists (GSK894490A and CP-464709-18) on rodent cognition.

Methods

All experiments were performed in male Lister hooded rats. Effects of the test compounds on rat cognitive performance was determined using the novel object recognition test, a modified water maze paradigm and a scopolamine-induced deficit in cued fear conditioning. These tests were chosen as they each probe a relatively independent cognitive domain and therefore potentially have differing underlying neural substrates.

Results

Both compounds significantly improved performance in the novel object recognition and modified water maze tests but were unable to attenuate a scopolamine deficit in cued fear conditioning.

Conclusions

These results demonstrate that the small-molecule ghrelin receptor agonists profiled here readily cross the blood/brain barrier and elicit pro-cognitive effects in recognition and spatial learning and memory tests. Based on these observations, the central ghrelin receptor would appear to be a chemically tractable receptor and perhaps should be considered as a new drug target for therapeutic approaches to treat diseases affecting cognition.

Keywords

Ghrelin Growth hormone secretagogue receptor Novel object recognition Atlantis water maze Scopolamine fear conditioning Rodent cognition Alzheimer’s disease Schizophrenia 

Notes

Acknowledgements

The authors would like to thank Paul F Chapman from GlaxoSmithKline Centre for Cognition and Neurodegeneration, Singapore for his advice with regards to the manuscript and Simon Bate and Andrew Lloyd from the GSK Discovery Statistics Department for their advice with respect to the statistical analysis of these data.

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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Zeenat Atcha
    • 1
    Email author
  • Woei-Shin Chen
    • 1
  • Agnes B. Ong
    • 1
  • Fong-Kuan Wong
    • 1
  • Aveline Neo
    • 1
  • Edward R. Browne
    • 1
  • Jason Witherington
    • 2
  • Darrel J. Pemberton
    • 1
    • 3
  1. 1.GlaxoSmithKline R&D ChinaCentre for Cognition and Neurodegeneration ResearchSingaporeSingapore
  2. 2.Department of Medicinal Chemistry, Immunoinflammation CEDDGlaxoSmithKline Medicines Research CentreHertfordshireUK
  3. 3.Neurosciences DivisionJohnson and Johnson PRDBeerseBelgium

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