Résumé
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
∼
30
nM) and highly selective (
K
i
>
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 EC
50
∼
1--10
nM. VRX-03011 had no effect on contractile properties in guinea pig ileum or colon preparations with an EC
50
>
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.