VRX-03011, a novel 5-HT4 agonist, enhances memory and hippocampal acetylcholine efflux.
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 30 nM) and highly selective (K(i) > 5 microM 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 (sAPPalpha) with an EC(50) approximately 1--10 nM. VRX-03011 had no effect on contractile properties in guinea pig ileum or colon preparations with an EC(50) > 10 microM 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.
Mohler
Eric G
EG
Department of Psychology, University of Illinois at Chicago, Chicago, IL 60607, USA.
Shacham
Sharon
S
Noiman
Silvia
S
Lezoualc'h
Frank
F
Robert
Sylvain
S
Gastineau
Monique
M
Rutkowski
Joseph
J
Marantz
Yael
Y
Dumuis
Aline
A
Bockaert
Joel
J
Gold
Paul E
PE
Ragozzino
Michael E
ME
D000109:Acetylcholine / Q000502:physiology*; D000818:Animals; D003071:Cognition / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D008024:Ligands; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D023421:Models, Animal; D011728:Pyridones / Q000494:pharmacology*; D051381:Rats; D044422:Receptors, Serotonin, 5-HT4 / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*; D014162:Transfection
C525011:6,7-dihydro-4-hydroxy-7-isopropyl-6-oxo-N-(3-(piperidin-1-yl)propyl)thieno(2,3-b)pyridine-5-carboxamide; D008024:Ligands; D011728:Pyridones; D017366:Serotonin Receptor Agonists; D013876:Thiophenes; D044422:Receptors, Serotonin, 5-HT4; D000109:Acetylcholine