The effects of novel, selective 5-hydroxytryptamine (5-HT)4 receptor ligands in rat spatial navigation

Activation of central 5-hydroxytryptamine (5-HT4) receptors may enhance cognitive performance. In the present study, the effects of two novel, potent and selective 5-HT4 receptor agonists, RS 67333 (1-(4-amino-5-chloro-2-methoxyphenyl)-3-(1-n-burtl-4-piperidinyl)- 1-propanone) and RS 67506 (1-(4-amino- 5-chloro-2-methoxyphenyl)-3-[1-[2-[(methylsulfonyl)amino]ethyl]-4- piperidinyl]-1-propanone), were studied in a rat model of spatial learning and memory; the Morris water maze. RS 67333 (0.1, 10 and 1000 micrograms/kg, intraperitoneally (i.p.)), a highly potent, selective and hydrophobic 5-HT4 receptor agonist, reversed the decrements in cognitive performance induced by atropine (30 mg/kg, i.p.). By contrast, no effect was seen to RS 67506 (0.1, 10 and 1000 micrograms/kg, i.p.), a hydrophilic 5-HT4 receptor agonist, of equivalent potency and selectivity to RS 67333. This differential effect may reflect the enhanced ability of RS 67333 to enter the CNS, with respect to RS 67506. The ameliorative actions of RS 67333 on cognitive dysfunction were abolished by prior treatment with a selective 5-HT4 receptor antagonist, RS 67532 [1-(4-amino-5-chloro-2-(3, 5-dimethoxy benzyloxyphenyl)-5-(1-piperidinyl)-1-pentanone; 1 mg/kg, i.p.]. When given alone, or in naive rats, RS 67532 (0.1, 10 and 1000 micrograms/kg, i.p.), was without effect. None of the compounds tested affected the swim speed at any of the doses used. In separate locomotor studies, RS 67532 reduced activity at 1 and 10 mg/kg, i.p., although no effect was seen with RS 67333 or RS 67506 (0.01-10 mg/kg, i.p.). These data suggest that RS 67333 reversed the cognitive deficit induced by atropine and support a role of 5-HT4 receptors in rat spatial learning and memory.