Broad-spectrum efficacy across cognitive domains by alpha7 nicotinic acetylcholine receptor agonism correlates with activation of ERK1/2 and CREB phosphorylation pathways

J Neurosci. 2007 Sep 26;27(39):10578-87. doi: 10.1523/JNEUROSCI.2444-07.2007.


The alpha7 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 alpha7 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) alpha7 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 alpha7 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 alpha7 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 alpha7 binding affinities and behavioral efficacious doses. The MEK inhibitor SL327 completely blocked alpha7 agonist-evoked ERK1/2 phosphorylation. Our results demonstrate that alpha7 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.

MeSH terms

  • Aminoacetonitrile / analogs & derivatives
  • Aminoacetonitrile / pharmacology
  • Animals
  • Central Nervous System Agents / pharmacology*
  • Cognition / drug effects
  • Cognition / physiology
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Humans
  • Learning / drug effects
  • Learning / physiology
  • Macaca mulatta
  • Male
  • Mental Processes / drug effects*
  • Mental Processes / physiology
  • Mice
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Phosphorylation
  • Pyridazines / pharmacology
  • Pyrroles / pharmacology
  • Rats
  • Receptors, Nicotinic*
  • Signal Transduction
  • Treatment Outcome
  • Xenopus
  • alpha7 Nicotinic Acetylcholine Receptor


  • A-582941
  • Central Nervous System Agents
  • Chrna7 protein, human
  • Chrna7 protein, mouse
  • Chrna7 protein, rat
  • Cyclic AMP Response Element-Binding Protein
  • Pyridazines
  • Pyrroles
  • Receptors, Nicotinic
  • SL 327
  • alpha7 Nicotinic Acetylcholine Receptor
  • Aminoacetonitrile
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3