title: Preclinical assessment of an adjunctive treatment approach for cognitive impairment associated with schizophrenia using the alpha7 nicotinic acetylcholine receptor agonist WYE-103914/SEN34625.
abstract: BACKGROUND
  α7 nicotinic acetylcholine receptor (nAChR) agonists are proposed as candidate agents for the adjunctive treatment of cognitive deficits associated with schizophrenia. Despite the pursuit of such an approach clinically, it is surprising that the preclinical profile of pro-cognitive agents in conjunction with antipsychotic drugs is currently unexplored.
  
  
  OBJECTIVE
  We determined if the memory-enhancing effects of the selective α7 nAChR agonist WYE-103914 were preserved in the presence of the atypical antipsychotic drug risperidone, and if the antipsychotic-like profile of risperidone was preserved in the presence of WYE-103914.
  
  
  METHODS
  Using the rat novel object recognition (NOR) paradigm, the maintenance of memory-enhancing activity of the α7 nAChR agonist WYE-103914 in the presence of risperidone was examined. Similarly, in the standard tests of antipsychotic-like activity, apomorphine-induced climbing (AIC) in mice and conditioned avoidance responding (CAR) in rats, the preservation of antipsychotic-like activity of risperidone was evaluated in the presence of WYE-103914.
  
  
  RESULTS
  WYE-103914 exhibited memory-enhancing activity in rat NOR, and this effect of WYE-103914 was retained in the presence of risperidone. In AIC, the atypical antipsychotic profile of risperidone was not significantly altered by WYE-103914. In contrast, WYE-103914 moderately potentiated the efficacy profile of risperidone in CAR, an effect that did not appear to be convincingly linked to a pharmacokinetic interaction.
  
  
  CONCLUSIONS
  These data underscore the value of a preclinical evaluation of the adjunctive profile of a memory-enhancing agent in combination with antipsychotics and provide further support to augmentation with α7 nAChR agonists to address the cognitive deficits associated with schizophrenia.
authors.affiliation: Neuroscience Research Unit, Pfizer Global Research and Development, 445 Eastern Point Road, MS8220-4220, Groton, CT 06340, USA.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Marquis
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Comery
authors.forename: Flora
authors.initials: F
authors.lastname: Jow
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Navarra
authors.forename: Steven M
authors.initials: SM
authors.lastname: Grauer
authors.forename: Claudine
authors.initials: C
authors.lastname: Pulicicchio
authors.forename: Cody
authors.initials: C
authors.lastname: Kelley
authors.forename: Julie A
authors.initials: JA
authors.lastname: Brennan
authors.forename: Renza
authors.initials: R
authors.lastname: Roncarati
authors.forename: Carla
authors.initials: C
authors.lastname: Scali
authors.forename: Simon
authors.initials: S
authors.lastname: Haydar
authors.forename: Chiara
authors.initials: C
authors.lastname: Ghiron
authors.forename: Georg C
authors.initials: GC
authors.lastname: Terstappen
authors.forename: John
authors.initials: J
authors.lastname: Dunlop
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism; D018967:Risperidone / Q000494:pharmacology*; D012559:Schizophrenia / Q000188:drug therapy* / Q000503:physiopathology; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C550466:1-(6-(4-fluorophenyl)pyridin-3-yl)-3-(4-piperidin-1-ylbutyl)urea; D014150:Antipsychotic Agents; C579166:Chrna7 protein, mouse; C579165:Chrna7 protein, rat; D011725:Pyridines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D014508:Urea; D018967:Risperidone