VRX-03011, a novel 5-HT(4) agonist, enhances memory and hippocampal acetylcholine efflux.
Neuropharmacology 2007 Jun 30; 53(4):563-73
Mohler E EG, Shacham S S, Noiman S S, Lezoualc'h F F, Robert S S, Gastineau M M, Rutkowski J J, Marantz Y Y, Dumuis A A, Bockaert J J, Gold P PE, Ragozzino M ME
Department of Psychology, University of Illinois at Chicago. Chicago, IL 60607, USA; Department of Psychology, University of Illinois Urbana–Champaign, Champaign, IL 68210, USA.
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-HT(4) agonist, that is both potent (K(i) approximately 30nM) and highly selective (K(i)>5muM for all other 5-HT receptors tested). In separate experiments, rats received VRX-03011 (0.1-10mg/kg i.p.) 30min prior to spontaneous alternation testing in a no-delay or a 30-s delay condition. VRX-03011 (1, 5 and 10mg/kg, but not 0.1mg/kg) significantly enhanced delayed spontaneous alternation performance while none of the doses enhanced performance in the no-delay test. VRX-03011 (1 and 5mg/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 (sAPPalpha) with an EC(50) approximately 1--10nM. VRX-03011 had no effect on contractile properties in guinea pig ileum or colon preparations with an EC(50)>10muM and did not alter rat intestinal transit at doses up to 10mg/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.