ORIGINAL INVESTIGATION Cognitive enhancing effects of ghrelin receptor agonists Zeenat Atcha & Woei-Shin Chen & Agnes B. Ong & Fong-Kuan Wong & Aveline Neo & Edward R. Browne & Jason Witherington & Darrel J. Pemberton Received: 11 February 2009 / Accepted: 8 July 2009 / Published online: 4 August 2009 # Springer-Verlag 2009 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 perfor- mance 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 Introduction Ghrelin is an acylated 28-amino acid peptide that was initially isolated from rat stomach and subsequently identified as the endogenous ligand for the growth hormone secretagogue receptor (GHS-R) (Kojima et al. 1999). Whilst ghrelin is predominately synthesised and secreted into the bloodstream by X/A-like cells found in the gastrointestinal oxynitic mucosa (Dornonville de la Cour et al. 2001), small amounts can also be found in other tissues including the placenta, testis, kidney, pituitary, small intestine, lung and brain (for review, see Gualillo et al. 2003). In addition to its potent, dose-related growth hormone releasing effects, ghrelin also significantly stimulates Z. Atcha (*) : W.-S. Chen : A. B. Ong : F.-K. Wong : A. Neo : E. R. Browne : D. J. Pemberton GlaxoSmithKline R&D China, Centre for Cognition and Neurodegeneration Research, Biopolis at One-North, 11 Biopolis Way, The Helios Building, #03-01/02, Singapore 138667, Singapore e-mail: Zeenat.I.Atcha@gsk.com J. Witherington Department of Medicinal Chemistry, Immunoinflammation CEDD, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK Present Address: D. J. Pemberton Neurosciences Division, Johnson and Johnson PRD, Turnhoutseweg 30, 2340 Beerse, Belgium Psychopharmacology (2009) 206:415–427 DOI 10.1007/s00213-009-1620-6