title: An assessment of the effects of serotonin 6 (5-HT6) receptor antagonists in rodent models of learning.
abstract: Antagonists of serotonin 6 (5-HT6) receptors have been reported to enhance cognition in animal models of learning, although this finding has not been universal. We have assessed the therapeutic potential of the specific 5-HT6 receptor antagonists 4-amino-N-(2,6-bis-methylamino-pyrimidin-4-yl)-benzenesulfonamide (Ro 04-6790) and 5-chloro-N-(4-methoxy-3-piperazin-1-yl-phenyl)-3-methyl-2-benzothiophenesulfonamide (SB-271046) in rodent models of cognitive function. Although mice express the 5-HT6 receptor and the function of this receptor has been investigated in mice, all reports of activity with 5-HT6 receptor antagonists have used rat models. In the present study, receptor binding revealed that the pharmacological properties of the mouse receptor are different from the rat and human receptor: Ro 04-6790 does not bind to the mouse 5-HT6 receptor, so all in vivo testing included in the present report was conducted in rats. We replicated previous reports that 5-HT6 receptor antagonists produce a stretching syndrome previously shown to be mediated through cholinergic mechanisms, but Ro 04-6790 and SB-271046 failed to attenuate scopolamine-induced deficits in a test of contextual fear conditioning. We also failed to replicate the significant effects reported previously in both an autoshaping task and in a version of the Morris water maze. The results of our experiments are not consistent with previous reports that suggested that 5-HT6 antagonists might have therapeutic potential for cognitive disorders.
authors.affiliation: Department of Neuroscience, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA. mark.lindner@bms.com
authors.forename: Mark D
authors.initials: MD
authors.lastname: Lindner
authors.forename: Donald B
authors.initials: DB
authors.lastname: Hodges
authors.forename: John B
authors.initials: JB
authors.lastname: Hogan
authors.forename: Anitra F
authors.initials: AF
authors.lastname: Orie
authors.forename: Jason A
authors.initials: JA
authors.lastname: Corsa
authors.forename: Donna M
authors.initials: DM
authors.lastname: Barten
authors.forename: Craig
authors.initials: C
authors.lastname: Polson
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Robertson
authors.forename: Valerie L
authors.initials: VL
authors.lastname: Guss
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Gillman
authors.forename: John E
authors.initials: JE
authors.lastname: Starrett
authors.forename: Valentin K
authors.initials: VK
authors.lastname: Gribkoff
mesh_terms: D000818:Animals; D001665:Binding Sites; D006801:Humans; D007858:Learning / Q000187:drug effects*; D008409:Mastication / Q000187:drug effects; D051379:Mice; D023421:Models, Animal; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*; D015000:Yawning / Q000187:drug effects; D000096926:Benzenesulfonamides
chemical_list: D011743:Pyrimidines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013449:Sulfonamides; D013876:Thiophenes; C114163:Ro 4-6790; D000096926:Benzenesulfonamides; C097216:serotonin 6 receptor; C117443:SB 271046