title: Effects of 5-HT6 antagonists, Ro-4368554 and SB-258585, in tests used for the detection of cognitive enhancement and antipsychotic-like activity.
abstract: 5-Hydroxytryptamine 6 (5-HT6) receptors are involved in learning and memory processes and are discussed as promising targets for the treatment of cognitive impairment in central nervous system disorders. A number of 5-HT6 antagonists are currently in the clinical development for schizophrenia and Alzheimer's disease (AD). There is some discrepancy regarding cognitive efficacy in subjects, and only limited data are available on the role of the 5-HT6 receptor in animal models of psychosis. The aim of this study was to investigate the efficacy of the selective 5-HT6 antagonists, Ro-4368554 (1-10 mg/kg, intraperitoneally) and SB-258585 (3-30 mg/kg, intraperitoneally), in animal models for schizophrenia and AD. Both compounds showed cognition-enhancing effects in object recognition, whereas only SB-258585 was able to prevent the scopolamine-induced deficit in the Morris water-maze test. Neither Ro-4368554 nor SB-258585 prevented scopolamine-induced impairment in contextual fear conditioning. Similarly, both compounds were ineffective on MK-801-induced deficits in contextual fear conditioning and spatial working memory. Ro-4368554, but not SB-258585 reversed the apomorphine-induced deficit in prepulse inhibition. Amphetamine-induced hyperlocomotion was not affected by either compound. Taken together, the overall efficacy of Ro-4368554 and SB-258585 in animal models for AD and schizophrenia is rather limited. These data show moderate efficacy in some models for AD but do not support the therapeutic potential of 5-HT6 antagonists for schizophrenia.
authors.affiliation: Departments of In vivo Pharmacology bIn vitro Pharmacology, Merz Pharmaceuticals GmbH, Frankfurt, Germany. andreas.gravius@merz.de
authors.forename: Andreas
authors.initials: A
authors.lastname: Gravius
authors.forename: Judit
authors.initials: J
authors.lastname: Laszy
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Pietraszek
authors.forename: Katalin
authors.initials: K
authors.lastname: Sághy
authors.forename: Jens
authors.initials: J
authors.lastname: Nagel
authors.forename: Caroline
authors.initials: C
authors.lastname: Chambon
authors.forename: Nico
authors.initials: N
authors.lastname: Wegener
authors.forename: Barbara
authors.initials: B
authors.lastname: Valastro
authors.forename: Wojciech
authors.initials: W
authors.lastname: Danysz
authors.forename: István
authors.initials: I
authors.lastname: Gyertyán
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000503:physiopathology; D000661:Amphetamine / Q000633:toxicity; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005239:Fear / Q000187:drug effects; D006948:Hyperkinesis / Q000139:chemically induced; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects*; D012559:Schizophrenia / Q000188:drug therapy / Q000503:physiopathology; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D007211:Indoles; D010879:Piperazines; D011985:Receptors, Serotonin; C507242:Ro4368554; C418570:SB 258585; D012702:Serotonin Antagonists; D013449:Sulfonamides; C097216:serotonin 6 receptor; D000661:Amphetamine