5-HT sub(4) receptors improve social olfactory memory in the rat

Serotonin (5-HT) is involved in a large variety of physiological functions and it appears now that it could play a role in cognitive processes through the activation of 5-HT sub(4) receptors. The present study was conducted to determine the effect of BIMU1, a mixed 5-HT sub(4) agonist/5-HT sub(3) antagonist on social olfactory recognition in rats; a behaviour test which has previously been shown to access short-term memory and to be sensitive to cholinergic drugs. This test is based on the investigation of an unfamiliar juvenile by an adult rat during two distinct 5-min presentations. At a 30-min delay after each presentation adults recognized the juvenile, whereas after a 2-hr delay all the adults had forgotten it. When administered intraperitoneally immediately after the first presentation, BIMU1 (10 mg/kg) enhanced short-term memory (i.e. recognition of the juvenile after a 2-hr delay). Ondansetron (10 and 100 mu g/kg injected intraperitoneally), a 5-HT sub(3) antagonist, had no significant effect on this form of memory. The effect of BIMU1 was antagonized by intraperitoneal injection of GR 125487, a very selective and potent 5-HT sub(4) antagonist. The antagonistic effect was obtained at 1 and 10 mg/kg of GR 125487, but not at 0.1 mg/kg. It is certainly a specific effect on brain 5-HT sub(4) receptors, since we determined a brain concentration of GR 125487 equal to 3.8 x 10 super(-7) M after the intraperitoneal injection of 10 mg/kg of this drag. This GR 125487 concentration is certainly sufficient to occupy all the 5-HT sub(4) brain receptors (K sub(d) = 10 super(-10) M) but not to occupy 5-HT sub(3) receptors (K sub(d) > 10 super(-6) M). The 5-HT sub(4) specificity of the blockade by GR 125487 is further demonstrated by the fact that a 10-fold lower dose of GR 125487 (1 mg/kg) is also effective to inhibit the BIMU1 effect.