RATIONALE AND OBJECTIVES: In rats, 5-hydroxytryptamine(6) (5-HT(6)) receptor antagonists improve learning and memory, but the effects of agonists are poorly defined. This study investigated the effects of 5-HT(6) receptor agonists and antagonists on a rodent model of recognition memory. METHODS: Selective 5-HT(6) receptor agonists and antagonists were administered either alone, after a scopolamine-induced impairment, or combined with sub-effective doses of the acetylcholinesterase inhibitor, donepezil, or the glutamate NMDA receptor antagonist, memantine, in a novel object discrimination paradigm in adult rats. RESULTS: After a 4-h inter-trial delay to induce natural forgetting, vehicle-treated rats spent an equivalent time exploring novel and familiar objects during the choice trial. The 5-HT(6) receptor agonists, E-6801 (1.25-10 mg/kg i.p.) and EMD-386088 (5-10 mg/kg i.p.), and antagonists, SB-271046 and Ro 04-6790 (5 and 10 mg/kg), along with donepezil (0.1-3 mg/kg) and memantine (5-20 mg/kg) all produced significant and mostly dose-dependent increases in novel object exploration, indicative of memory enhancement. Furthermore, sub-effective doses of E-6801 (1 mg/kg) when co-administered with either SB-271046 (3 mg/kg), donepezil (0.1 mg/kg) or memantine (5 mg/kg), and EMD-386088 (2 mg/kg) co-administered with SB-271046 (3 mg/kg) also significantly enhanced object-recognition memory. Additionally, using a 1-min inter-trial delay, E-6801 (2.5 and 5 mg/kg) was as effective as donepezil (0.3 and 1 mg/kg) in reversing a scopolamine-induced (0.5 mg/kg) impairment in object recognition. CONCLUSIONS: This is the first study to demonstrate that E-6801, a potent 5-HT(6) receptor agonist, improves recognition memory by combined modulation of cholinergic and glutamatergic neurotransmission.
RATIONALE AND OBJECTIVES: In rats, 5-hydroxytryptamine(6) (5-HT(6)) receptor antagonists improve learning and memory, but the effects of agonists are poorly defined. This study investigated the effects of 5-HT(6) receptor agonists and antagonists on a rodent model of recognition memory. METHODS: Selective 5-HT(6) receptor agonists and antagonists were administered either alone, after a scopolamine-induced impairment, or combined with sub-effective doses of the acetylcholinesterase inhibitor, donepezil, or the glutamate NMDA receptor antagonist, memantine, in a novel object discrimination paradigm in adult rats. RESULTS: After a 4-h inter-trial delay to induce natural forgetting, vehicle-treated rats spent an equivalent time exploring novel and familiar objects during the choice trial. The 5-HT(6) receptor agonists, E-6801 (1.25-10 mg/kg i.p.) and EMD-386088 (5-10 mg/kg i.p.), and antagonists, SB-271046 and Ro 04-6790 (5 and 10 mg/kg), along with donepezil (0.1-3 mg/kg) and memantine (5-20 mg/kg) all produced significant and mostly dose-dependent increases in novel object exploration, indicative of memory enhancement. Furthermore, sub-effective doses of E-6801 (1 mg/kg) when co-administered with either SB-271046 (3 mg/kg), donepezil (0.1 mg/kg) or memantine (5 mg/kg), and EMD-386088 (2 mg/kg) co-administered with SB-271046 (3 mg/kg) also significantly enhanced object-recognition memory. Additionally, using a 1-min inter-trial delay, E-6801 (2.5 and 5 mg/kg) was as effective as donepezil (0.3 and 1 mg/kg) in reversing a scopolamine-induced (0.5 mg/kg) impairment in object recognition. CONCLUSIONS: This is the first study to demonstrate that E-6801, a potent 5-HT(6) receptor agonist, improves recognition memory by combined modulation of cholinergic and glutamatergic neurotransmission.
Authors: R Kohen; M A Metcalf; N Khan; T Druck; K Huebner; J E Lachowicz; H Y Meltzer; D R Sibley; B L Roth; M W Hamblin Journal: J Neurochem Date: 1996-01 Impact factor: 5.372
Authors: Mark D Lindner; Donald B Hodges; John B Hogan; Anitra F Orie; Jason A Corsa; Donna M Barten; Craig Polson; Barbara J Robertson; Valerie L Guss; Kevin W Gillman; John E Starrett; Valentin K Gribkoff Journal: J Pharmacol Exp Ther Date: 2003-09-15 Impact factor: 4.030
Authors: M Ruat; E Traiffort; J M Arrang; J Tardivel-Lacombe; J Diaz; R Leurs; J C Schwartz Journal: Biochem Biophys Res Commun Date: 1993-05-28 Impact factor: 3.575
Authors: Eric G Mohler; Phillip M Baker; Kimberly S Gannon; Simon S Jones; Sharon Shacham; John A Sweeney; Michael E Ragozzino Journal: Psychopharmacology (Berl) Date: 2011-10-12 Impact factor: 4.530