VRX-03011, a novel 5-HT4 agonist, enhances memory and hippocampal acetylcholine efflux

Eric G. Mohler, Sharon Shacham, Silvia Noiman, Frank Lezoualc'h, Sylvain Robert, Monique Gastineau, Joseph Rutkowski, Yael Marantz, Aline Dumuis, Joel Bockaert, Paul E. Gold, Michael E. Ragozzino

Research output: Contribution to journalArticle

80 Scopus citations

Abstract

Recent evidence suggests that 5-hydroxytryptamine (5-HT)4 receptor activity enhances cognition and provides neuroprotection. Here we report the effects of VRX-03011, a novel partial 5-HT4 agonist, that is both potent (Ki ∼ 30 nM) and highly selective (Ki > 5 μM for all other 5-HT receptors tested). In separate experiments, rats received VRX-03011 (0.1-10 mg/kg i.p.) 30 min prior to spontaneous alternation testing in a no-delay or a 30-s delay condition. VRX-03011 (1, 5 and 10 mg/kg, but not 0.1 mg/kg) significantly enhanced delayed spontaneous alternation performance while none of the doses enhanced performance in the no-delay test. VRX-03011 (1 and 5 mg/kg) concomitantly enhanced hippocampal acetylcholine output and delayed spontaneous alternation scores compared to that of vehicle controls, but had no effect on hippocampal acetylcholine release under a resting condition. Moreover, suboptimal doses of VRX-03011 and the acetylcholinesterase inhibitor galanthamine combined to enhance memory. VRX-03011 also regulated amyloid precursor protein (APP) metabolism by inducing a concentration-dependent increase in the non-amyloidogenic soluble form of APP (sAPPα) with an EC50 ∼ 1--10 nM. VRX-03011 had no effect on contractile properties in guinea pig ileum or colon preparations with an EC50 > 10 μM and did not alter rat intestinal transit at doses up to 10 mg/kg. These findings suggest that VRX-03011 may represent a novel treatment for Alzheimer's disease that reduces cognitive impairments and provides neuroprotection without gastrointestinal side effects.

Original languageEnglish (US)
Pages (from-to)563-573
Number of pages11
JournalNeuropharmacology
Volume53
Issue number4
DOIs
StatePublished - Sep 2007
Externally publishedYes

Keywords

  • 5-HT
  • Acetylcholine
  • Alzheimer's disease
  • Behavior
  • Hippocampus
  • Memory
  • Microdialysis
  • Serotonin

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

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    Mohler, E. G., Shacham, S., Noiman, S., Lezoualc'h, F., Robert, S., Gastineau, M., Rutkowski, J., Marantz, Y., Dumuis, A., Bockaert, J., Gold, P. E., & Ragozzino, M. E. (2007). VRX-03011, a novel 5-HT4 agonist, enhances memory and hippocampal acetylcholine efflux. Neuropharmacology, 53(4), 563-573. https://doi.org/10.1016/j.neuropharm.2007.06.016