The International Journal of Neuropsychopharmacology

Research Article

The potent M1 receptor allosteric agonist GSK1034702 improves episodic memory in humans in the nicotine abstinence model of cognitive dysfunction

Pradeep J. Nathana1a2 c1, Jeannette Watsona3, Jesper Lunda3, Ceri H. Daviesa4, Gary Petersa1, Chris M. Doddsa1, Bridget Swirskia1, Philip Lawrencea1, Graham D. Bentleya1, Barry V. O'Neilla1, Jon Robertsona5, Stephen Watsona3, Gareth A. Jonesa3, Paul Maruffa6, Rodney J. Crofta7, Marc Laruellea3 and Edward T. Bullmorea1a2

a1 Medicines Discovery and Development, GlaxoSmithKline Clinical Unit, Cambridge, UK

a2 Brain Mapping Unit, Department of Psychiatry, University of Cambridge, Cambridge, UK

a3 Neuroscience Centre for Excellence in Drug Discovery, GlaxoSmithKline, UK

a4 Neural Pathways Discovery Performance Unit, GSK Research and Development, Singapore

a5 Discovery Biometrics, GlaxoSmithKline, UK

a6 Cogstate Ltd, Australia

a7 School of Psychology, University of Wollongong, Australia

Abstract

Episodic memory deficits are a core feature of neurodegenerative disorders. Muscarinic M1 receptors play a critical role in modulating learning and memory and are highly expressed in the hippocampus. We examined the effect of GSK1034702, a potent M1 receptor allosteric agonist, on cognitive function, and in particular episodic memory, in healthy smokers using the nicotine abstinence model of cognitive dysfunction. The study utilized a randomized, double-blind, placebo-controlled, cross-over design in which 20 male nicotine abstained smokers were tested following single doses of placebo, 4 and 8 mg GSK1034702. Compared to the baseline (nicotine on-state), nicotine abstinence showed statistical significance in reducing immediate (p=0.019) and delayed (p=0.02) recall. GSK1034702 (8 mg) significantly attenuated (i.e. improved) immediate recall (p=0.014) but not delayed recall. None of the other cognitive domains was modulated by either nicotine abstinence or GSK1034702. These findings suggest that stimulating M1 receptor mediated neurotransmission in humans with GSK1034702 improves memory encoding potentially by modulating hippocampal function. Hence, selective M1 receptor allosteric agonists may have therapeutic benefits in disorders of impaired learning including Alzheimer's disease.

(Received November 03 2011)

(Reviewed December 19 2011)

(Revised June 13 2012)

(Accepted June 19 2012)

(Online publication August 29 2012)

Key words

  • Alzheimer's disease;
  • cognition;
  • episodic memory;
  • hippocampus;
  • M1 agonist;
  • M1 receptor

Correspondence

c1 Address for correspondence: Professor P. J. Nathan, GSK Clinical Unit Cambridge, Addenbrooke's Centre for Clinical Investigations, Cambridge Biomedical Campus, Cambridge CB2 2GG, UK. Tel.: +44 1223 296081 Fax: +44 1223 296108 Email: pradeep.j.nathan@gsk.com