title: Dissociable effects of NR2A and NR2B NMDA receptor antagonism on cognitive flexibility but not pattern separation.
abstract: BACKGROUND
  N-methyl-D-aspartate (NMDA) receptors play crucial roles in learning and memory, but the role of each NMDA receptor subtype in a specific cognitive process is unclear. Non-selective blockers of NMDA receptor are used to model the cognitive impairment in schizophrenia and Alzheimer's disease. Counter-intuitively selective NR2A and 2B NMDA receptor antagonists are thought to have pro-cognitive properties. These seemingly contrasting findings might in part be the result of different compounds and behavioral measures used across studies.
  
  
  OBJECTIVE
  We compared the effect of NVP-AAM077 (NR2A antagonist), CP 101-606 (NR2B antagonist), and MK-801 (non-selective antagonist) in a series of touch screen tasks that can be used to measure spatial cognition and cognitive flexibility.
  
  
  METHODS
  NVP-AAM077, CP 101-606, and MK-801 were administered prior to testing, in adult male Lister-hooded rats trained in tasks of location discrimination, paired associate learning (PAL), and trial unique non-match to location (TUNL).
  
  
  RESULTS
  Results showed that MK-801 impaired performance on all the tasks. In contrast, CP 101-606 only impaired reversal learning in location discrimination and had minimal effect on working memory in TUNL and caused a modest improvement in accuracy in PAL and acquisition of a spatial discrimination. NVP-AAM077 had little effect on performance across tasks, although these data allude to a potential enhancement of acquisition of a spatial location and impairments in spatial reversal learning in a separation-dependent manner.
  
  
  CONCLUSIONS
  These data demonstrated that non-selective NMDA antagonism will disrupt numerous aspects of cognitive function. However, selective antagonism is capable of impairing or enhancing cognitive function in a task-dependent fashion.
authors.affiliation: Janssen Research & Development, Turnhoutseweg 30, 2340, Beerse, Belgium. gkumar_discovery@yahoo.com.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Kumar
authors.affiliation: Janssen Research & Development, Turnhoutseweg 30, 2340, Beerse, Belgium.
authors.forename: Joseph
authors.initials: J
authors.lastname: Olley
authors.affiliation: Janssen Research & Development, Turnhoutseweg 30, 2340, Beerse, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: Steckler
authors.affiliation: Janssen Research & Development, Turnhoutseweg 30, 2340, Beerse, Belgium.
authors.forename: John
authors.initials: J
authors.lastname: Talpos
mesh_terms: D000818:Animals; D001245:Association Learning / Q000187:drug effects; D003071:Cognition / Q000187:drug effects*; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D008297:Male; D010880:Piperidines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D065852:Spatial Memory / Q000187:drug effects
chemical_list: C498554:5-(alpha-methyl-4-bromobenzylamino)phosphonomethyl-1,4-dihydroquinoxaline-2,3-dione; D018691:Excitatory Amino Acid Antagonists; C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; D010880:Piperidines; D011810:Quinoxalines; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; C095106:traxoprodil mesylate
keywords: CP 101-606; Location discrimination; MK-801; NR2A antagonist; NR2B antagonist; NVP-AAM077; Paired associate learning; Spatial discrimination; TUNL; Touch screen