Differential modulation of the 5-HT(4) receptor agonists and antagonist on rat learning and memory

Recent data suggest that activation of 5-HT(4) receptors may modulate cognitive processes such as learning and memory. In the present study, the effects of two potent and selective 5-HT(4) agonists, RS 17017 [1-(4-amino-5-chloro-2-methoxyphenyl)-5- (piperidin-1-yl)-1-pentanone hydrochloride] and RS 67333 [1(4-amino-5-chloro-2-methoxyphenyl)-3- (1-n-butyl-4-piperidinyl)-1-propanone], were studied in an olfactory associative discrimination task. The implication of 5-HT(4) receptors in the associative discriminative task was suggested by the following observation. Injection of a selective 5-HT(4) receptor antagonist RS 67532 [1-(4-amino-5-chloro-2-(3, 5-dimethoxybenzyloxyphenyl)-5-(1-piperidinyl)-1-pentanone; 1 mg/kg: i.p.] before the third training session induced a consistent deficit in associative memory during the following training sessions. This deficit was absent when the antagonist was injected together with either a specific hydrophilic 5-HT(4) (RS 17017, 1 mg/kg) or a specific hydrophobic (RS 67333, 1 mg/kg) 5-HT(4) receptor agonist. RS 67333 was more potent than RS 17017. This difference in potency certainly reflects a difference in their capacity to enter into the brain. This is also likely to be the reason why, injected alone, the hydrophobic 5-HT(4) agonist (RS 67333) but not the hydrophilic 5-HT(4) agonist (RS 17017) improved learning and memory performance.