title: The selective 5-HT6 receptor antagonist SLV has putative cognitive- and social interaction enhancing properties in rodent models of cognitive impairment.
abstract: In the present study, our aim was to investigate whether the novel highly selective 5-hydroxytryptamine6 (5-HT6) receptor antagonist SLV can ameliorate impairments in cognition and social interaction with potential relevance for both schizophrenia and Alzheimer's disease (AD). SLV sub-chronically - treated Wistar rats reared in isolation showed significantly enhanced prepulse inhibition (PPI) and object recognition performance when compared to vehicle - treated rats. In the isolated rats, also a significant reduction in expression of hippocampal neural cell adhesion molecule polysialylation (NCAM-PSA) was found which was ameliorated following treatment with SLV (30mg/kg). The social engagement deficit in rats exposed in utero (on gestational day 12.5) to valproic acid (VPA) was reversed by treatment with SLV (30mg/kg). SLV (20 and 30mg/kg, p.o.) fully reversed MK-801 - induced deficits in the ORT and also scopolamine - induced deficits in both the Object Recognition Task (ORT) and Object Location Task (OLT) in Wistar rats. In addition, a combination of sub-optimal doses of SLV and donepezil attenuated scopolamine-induced ORT deficits. Furthermore, SLV (10mg/kg, p.o.) reversed spontaneous alternation deficits in the T-maze induced by MK-801 administration in Swiss mice and in aged C57Bl/6J mice. SLV additionally improved T-Maze spatial learning and passive avoidance learning in Sprague-Dawley rats with amyoid-beta (Aβ) injections into the hippocampus. In contrast, no benefits were found with SLV or the tested reference compounds (donepezil and RVT-101) on cognitive performance of 12months old Tg2576 mice. Also, in the social recognition task, an absence of cognitive enhancing properties was observed with SLV on "normal forgetting" in Wistar rats. Finally, analysis of spontaneous inhibitory postsynaptic currents (sIPSCs) frequency recorded from pyramidal cells revealed a reduction in the presence of 1μM of SLV. In conclusion, SLV was investigated in several rodent animal models and found to be effective at a least effective dose (LED) of 20mg/kg and 10mg/kg (p.o.) in the rat and the mouse, respectively.
authors.affiliation: Abbott Healthcare Products BV (formerly Solvay Pharmaceuticals), C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands. Electronic address: natasja.debruin@gmail.com.
authors.forename: N M W J
authors.initials: NMWJ
authors.lastname: de Bruin
authors.affiliation: Abbott Healthcare Products BV (formerly Solvay Pharmaceuticals), C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: van Loevezijn
authors.affiliation: AbbVie Deutschland GmbH & Co. KG, Dept. of Pharmacology, Knollstr., 67061 Ludwigshafen, Germany.
authors.forename: K M
authors.initials: KM
authors.lastname: Wicke
authors.affiliation: Abbott Healthcare Products BV (formerly Solvay Pharmaceuticals), C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: de Haan
authors.affiliation: Abbott Healthcare Products BV (formerly Solvay Pharmaceuticals), C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Venhorst
authors.affiliation: Abbott Healthcare Products BV (formerly Solvay Pharmaceuticals), C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands.
authors.forename: J H M
authors.initials: JHM
authors.lastname: Lange
authors.affiliation: Abbott Healthcare Products BV (formerly Solvay Pharmaceuticals), C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands.
authors.forename: L
authors.initials: L
authors.lastname: de Groote
authors.affiliation: Abbott Healthcare Products BV (formerly Solvay Pharmaceuticals), C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands.
authors.forename: M A W
authors.initials: MAW
authors.lastname: van der Neut
authors.affiliation: Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, PO Box 616, 6200 MD Maastricht, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Prickaerts
authors.affiliation: Neurofit SAS, Bioparc, Parc d'Innovation, Boulevard Sebastien Brant, 67400 Illkirch, France.
authors.forename: E
authors.initials: E
authors.lastname: Andriambeloson
authors.affiliation: Berand Ltd., NovaUCD, Belfield Innovation Park, University College Dublin, Dublin 4, Ireland.
authors.forename: A G
authors.initials: AG
authors.lastname: Foley
authors.affiliation: Abbott Healthcare Products BV (formerly Solvay Pharmaceuticals), C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: van Drimmelen
authors.affiliation: Abbott Healthcare Products BV (formerly Solvay Pharmaceuticals), C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: van der Wetering
authors.affiliation: Abbott Healthcare Products BV (formerly Solvay Pharmaceuticals), C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands.
authors.forename: C G
authors.initials: CG
authors.lastname: Kruse
mesh_terms: D000367:Age Factors; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D060825:Cognitive Dysfunction / Q000188:drug therapy*; D005260:Female; D006624:Hippocampus / Q000187:drug effects*; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects*; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000188:drug therapy*; D065808:Prepulse Inhibition / Q000187:drug effects*; D017966:Pyramidal Cells / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011985:Receptors, Serotonin; D021641:Recognition, Psychology / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D012938:Social Perception
chemical_list: D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C097216:serotonin 6 receptor
keywords: 5-Hydroxytryptamine(6) (5-HT(6)); Cognition; Social behavior