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The Journal of Neuroscience, September 26, 2007, 27(39):10578-10587; doi:10.1523/JNEUROSCI.2444-07.2007

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Behavioral/Systems/Cognitive
Broad-Spectrum Efficacy across Cognitive Domains by {alpha}7 Nicotinic Acetylcholine Receptor Agonism Correlates with Activation of ERK1/2 and CREB Phosphorylation Pathways

Robert S. Bitner,1 William H. Bunnelle,1 David J. Anderson,1 Clark A. Briggs,1 Jerry Buccafusco,2 Peter Curzon,1 Michael W. Decker,1 Jennifer M. Frost,1 Jens Halvard Gronlien,1 Earl Gubbins,1 Jinhe Li,1 John Malysz,1 Stella Markosyan,1 Kennan Marsh,1 Michael D. Meyer,1 Arthur L. Nikkel,1 Richard J. Radek,1 Holly M. Robb,1 Daniel Timmermann,3 James P. Sullivan,1 and Murali Gopalakrishnan1

1Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064, 2Alzheimer's Research Center, Medical College of Georgia, Augusta, Georgia 30912, and 3NeuroSearch A/S, DK-2750 Ballerup, Denmark

Correspondence should be addressed to Dr. Robert S. Bitner, Department R4N5, Building AP9A, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064. Email: robert.s.bitner{at}abbott.com

The {alpha}7 nicotinic acetylcholine receptor (nAChR) plays an important role in cognitive processes and may represent a drug target for treating cognitive deficits in neurodegenerative and psychiatric disorders. In the present study, we used a novel {alpha}7 nAChR-selective agonist, 2-methyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole (A-582941) to interrogate cognitive efficacy, as well as examine potential cellular mechanisms of cognition. Exhibiting high affinity to native rat (Ki = 10.8 nM) and human (Ki = 16.7 nM) {alpha}7 nAChRs, A-582941 enhanced cognitive performance in behavioral assays including the monkey delayed matching-to-sample, rat social recognition, and mouse inhibitory avoidance models that capture domains of working memory, short-term recognition memory, and long-term memory consolidation, respectively. In addition, A-582941 normalized sensory gating deficits induced by the {alpha}7 nAChR antagonist methyllycaconitine in rats, and in DBA/2 mice that exhibit a natural sensory gating deficit. Examination of signaling pathways known to be involved in cognitive function revealed that {alpha}7 nAChR agonism increased extracellular-signal regulated kinase 1/2 (ERK1/2) phosphorylation in PC12 cells. Furthermore, increases in ERK1/2 and cAMP response element-binding protein (CREB) phosphorylation were observed in mouse cingulate cortex and/or hippocampus after acute A-582941 administration producing plasma concentrations in the range of {alpha}7 binding affinities and behavioral efficacious doses. The MEK inhibitor SL327 completely blocked {alpha}7 agonist-evoked ERK1/2 phosphorylation. Our results demonstrate that {alpha}7 nAChR agonism can lead to broad-spectrum efficacy in animal models at doses that enhance ERK1/2 and CREB phosphorylation/activation and may represent a mechanism that offers potential to improve cognitive deficits associated with neurodegenerative and psychiatric diseases, such as Alzheimer's disease and schizophrenia.

Key words: nicotinic acetylcholine receptor; {alpha}7 agonist; cognitive domains; ERK1/2; CREB; phosphorylation

Received May 29, 2007; revised July 30, 2007; accepted Aug. 13, 2007.

Correspondence should be addressed to Dr. Robert S. Bitner, Department R4N5, Building AP9A, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064. Email: robert.s.bitner{at}abbott.com


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[3H]A-585539 [(1S,4S)-2,2-Dimethyl-5-(6-phenylpyridazin-3-yl)-5-aza-2-azoniabicyclo[2.2.1]heptane], a Novel High-Affinity {alpha}7 Neuronal Nicotinic Receptor Agonist: Radioligand Binding Characterization to Rat and Human Brain
J. Pharmacol. Exp. Ther., January 1, 2008; 324(1): 179 - 187.
[Abstract] [Full Text] [PDF]


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