5-HT4 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-HT4 receptors. The present study was conducted to determine the effect of BIMU1, a mixed 5-HT4 agonist/5-HT3 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 micrograms/kg injected intraperitoneally), a 5-HT3 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-HT4 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-HT4 receptors, since we determined a brain concentration of GR 125487 equal to 3.8 x 10(-7) M after the intraperitoneal injection of 10 mg/kg of this drug. This GR 125487 concentration is certainly sufficient to occupy all the 5-HT4 brain receptors (Kd = 10(-10) M) but not to occupy 5-HT3 receptors (Kd > 10(-6) M). The 5-HT4 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.
Letty
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Laboratoire de Médecine Expérimentale, Inserm U 249, CNRS 9008, Institut de Biologie, Montpellier, France.
Child
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Dumuis
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Pantaloni
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Bockaert
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Rondouin
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D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008570:Memory, Short-Term / Q000187:drug effects / Q000502:physiology*; D018721:Muscarinic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology*; D012702:Serotonin Antagonists / Q000378:metabolism / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000378:metabolism / Q000494:pharmacology; D012903:Smell / Q000187:drug effects / Q000502:physiology*; D012919:Social Behavior; D013449:Sulfonamides / Q000378:metabolism / Q000494:pharmacology
D001562:Benzimidazoles; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007211:Indoles; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013449:Sulfonamides; C070187:(endo-N-8-methyl-8-azabicyclo(3.2.1)oct-3-yl)-2,3-dihydro-3-ethyl-2-oxo-1H-benzimidazol-1-carboxamide; C070189:(endo-N-8-methyl-8-azabicyclo-(3.2.1)oct-3-yl)-2,3-dihydro-3-isopropyl-2-oxo-1H-benzimidazol-1-carboxamide; C082871:GR 113808