BIMU1 increases associative memory in rats by activating 5-HT4 receptors

Olfactory association learning was used to investigate the involvement of 5-HT4 receptors in learning and long-term memory. The behavioral role of the 5-HT4 receptors was studied by using BIMU1 (3-ethyl-2,3-dihydro-N-[endo-8-methyl-8-azabicyclo(3.2.1)oct-3-yl]-2-oxo -1 H-benzimidazole-1-carboxamide, hydrochloride (Boehringer Ingelheim, Italy); a mixed 5-HT4 agonist/5-HT3 antagonist, and GR125487 (1-[2-[methyl sulphonyl)-amino]ethyl]-4-piperidinyl-methyl 5-fluro-2-methoxy-1H-indole-3- carboxylate; Glaxo Group Research, Hertfordshire, U.K.), a specific 5-HT4 antagonist. The intraperitoneal injections of BIMU1 at 1, 5, and 10 mg/kg were followed by an substantial improvement (> 15% in percentage of correct responses at the dose of 10 mg/kg) in associative memory. Difficulty rapidly reversing behavioral responses to previously learned association, 1 month later indicated that the BIMU1 effect at 10 mg/kg was not transient, but correlated to long-term memory. The effects of BIMU1 are most likely to be mediated by 5-HT4 receptors since they were blocked by GR125487 at 10 mg/kg. These data suggest that activation of 5-HT4 receptors may modulate cognitive processes like learning and memory.