BIMU 1 and RS 67333, two 5-HT4 receptor agonists, modulate spontaneous alternation deficits induced by scopolamine in the mouse.
The present study was conducted to determine the effects of two potent 5-HT4 receptor agonists, BIMU 1 (1 (3-ethyl-2,3-dihydro-N-[endo-8-methyl-8-azabicyclo (3.2.1)-oct-3-yl]-2-oxo-1H) benzimidazole-1-carboxamide hydrochloride; 1, 3, 10 mg/kg, i.p.) and RS 67333 (1-(4-amino-5-chloro-2-methoxyphenyl)-3-(1-n-butyl-4-piperidinyl)-1-propanone; 0.25, 0.5, 1 mg/kg, i.p.) on the learning impairment induced by the muscarinic acetylcholine receptor antagonist, scopolamine (1 mg/kg) in mice. Working memory was examined by observing spontaneous alternation behavior in the Y-maze test. Both BIMU 1 (10 mg/kg) and RS 67333 (1 mg/kg) prevented the scopolamine-induced alternation deficits, whereas no effect could be evidenced on locomotor or emotional indices. The reversal actions of BIMU 1 and RS 67333 on this cognitive dysfunction were abolished by the selective 5-HT4 receptor antagonist GR 125487 (1-[2-[(methyl sulfonyl)-amino]-ethyl]-4-piperidinyl-methyl-5-fluoro-2-methoxy-1H-indole-3-carboxylate; 10 mg/kg, i.p.). When given alone at the same doses, none of the three serotonergic agents had any measurable effect. These results demonstrate the ability of 5-HT4 receptor agonists to reverse spontaneous working memory deficits and further confirm the therapeutic potential of such ligands in the treatment of cognitive alterations that associate short-term working memory disorders and cholinergic hypofunction.
Laboratoire de Pharmacologie, Centre d'Etudes et de Recherche sur le Médicament de Normandie, UFR des Sciences Pharmaceutiques, Université de Caen, 1 rue Vaubénard, 14032 Caen, France.
Véronique
V
Lelong
Laurent
L
Lhonneur
François
F
Dauphin
Michel
M
Boulouard
D000814:Aniline Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D008297:Male; D008568:Memory / Q000187:drug effects* / Q000502:physiology; D008569:Memory Disorders / Q000139:chemically induced / Q000517:prevention & control*; D051379:Mice; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D044422:Receptors, Serotonin, 5-HT4 / Q000502:physiology; D012601:Scopolamine / Q000037:antagonists & inhibitors / Q000633:toxicity; D058828:Serotonin 5-HT4 Receptor Agonists
D000814:Aniline Compounds; D001562:Benzimidazoles; D019086:Bridged Bicyclo Compounds, Heterocyclic; D010880:Piperidines; D058828:Serotonin 5-HT4 Receptor Agonists; C070187:(endo-N-8-methyl-8-azabicyclo(3.2.1)oct-3-yl)-2,3-dihydro-3-ethyl-2-oxo-1H-benzimidazol-1-carboxamide; D044422:Receptors, Serotonin, 5-HT4; C107826:RS 67333; D012601:Scopolamine