Differential modulation of the 5-HT4 receptor agonists and antagonist on rat learning and memory

Recent data suggest that activation of 5-HT4 receptors may modulate cogniti ve processes such as learning and memory. In the present study, the effects of two potent and selective 5-HT4 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-propano ne], were studied in an olfactory associative discrimination task. The impl ication of 5-HT4 receptors in the associative discriminative task was sugge sted by the following observation. Injection of a selective 5-HT4 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 sessi on 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-HT4 (RS 17017, 1 mg/kg) or a specific hydrophobic (RS 67333, 1 mg/kg) 5-HT4 receptor agonist. RS 67333 was more potent than RS 17017. This difference in potency certainly reflect s a difference in their capacity to enter into the brain. This is also like ly to be the reason why, injected alone, the hydrophobic 5-HT4 agonist (RS 67333) but not the hydrophilic 5-HT4 agonist (RS 17017) improved learning a nd memory performance. (C) 2000 Elsevier Science Ltd. All rights reserved.