title: Effects of the selective 5-HT(7) receptor antagonist SB-269970 in animal models of psychosis and cognition.
abstract: The 5-hydroxytryptamine7 (5-HT7) receptor is a G-protein coupled receptor for serotonin that has been implicated in the pathophysiology of psychiatric and neurological disorders including anxiety, depression and schizophrenia. A number of studies have attempted to evaluate the potential role of the 5-HT7 receptor in schizophrenia by utilising genetic or pharmacological tools but to date these have provided conflicting results. Here we investigate the effect of a selective 5-HT7 receptor antagonist, SB-269970, in in vivo psychosis and cognition models and relate efficacy to brain exposures of the compound. SB-269970 significantly attenuated amphetamine-induced rearing and circling in rats. A similar effect was observed in an N-methyl d-aspartic acid (NMDA) receptor antagonist driven psychosis model, where SB-269970 significantly reversed phencyclidine-induced hyperlocomotion, rearing and circling; although the effect was not as robust as with the 5-HT2a receptor antagonist positive control, MDL100,907. SB-269970 also attenuated a temporal deficit in novel object recognition (NOR), indicative of an improvement in recognition memory. Pharmacokinetic analysis of plasma and brain samples taken after behavioural testing confirmed that efficacy was achieved at doses and pre-treatment times where receptor occupancy was substantial. These findings highlight the anti-psychotic and pro-cognitive potential of 5-HT7 receptor antagonists and warrant further studies to explore their therapeutic potential in schizophrenia.
authors.affiliation: Schizophrenia and Cognitive Disorders Discovery Performance Unit, Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline Research & Development Ltd, New Frontiers Science Park, Harlow, Essex, CM19 5AW, UK.
authors.forename: Kerry A
authors.initials: KA
authors.lastname: Waters
authors.forename: Tania O
authors.initials: TO
authors.lastname: Stean
authors.forename: Beverley
authors.initials: B
authors.lastname: Hammond
authors.forename: David J
authors.initials: DJ
authors.lastname: Virley
authors.forename: Neil
authors.initials: N
authors.lastname: Upton
authors.forename: James N C
authors.initials: JN
authors.lastname: Kew
authors.forename: Ishrut
authors.initials: I
authors.lastname: Hussain
mesh_terms: D000661:Amphetamine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D021461:Animals, Outbred Strains; D003071:Cognition / Q000187:drug effects*; D004195:Disease Models, Animal; D005464:Fluorobenzenes / Q000494:pharmacology / Q000627:therapeutic use; D008124:Locomotion / Q000187:drug effects; D008297:Male; D010622:Phencyclidine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010636:Phenols / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use; D011618:Psychotic Disorders / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects*; D021641:Recognition, Psychology / Q000187:drug effects; D012702:Serotonin Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C522380:5-HT(7) receptor, rat; D005464:Fluorobenzenes; D010636:Phenols; D010880:Piperidines; D011985:Receptors, Serotonin; C404922:SB 269970; D012702:Serotonin Antagonists; D013449:Sulfonamides; D000661:Amphetamine; C079049:volinanserin; D010622:Phencyclidine