title: A comparison of the effects of ketamine and phencyclidine with other antagonists of the NMDA receptor in rodent assays of attention and working memory.
abstract: BACKGROUND
  N-methyl-D: -Aspartate receptor (NMDAR) antagonists such as ketamine induce cognitive symptoms in man similar to those of schizophrenia and therefore might be useful as models of the disease in animals. However, it is unclear which NMDAR antagonist(s) offer the best means to produce cognitive deficits in attention and working memory and to what extent those deficits can be measured selectively in rats.
  
  
  OBJECTIVE
  The present study systematically compared the effects of eight different NMDAR antagonists-MK-801, phencyclidine, (S)-(+)-ketamine, memantine, SDZ-220,581, Ro 25-6981, CP 101-606 and NVP-AAM077-in rats using standard tests of visual attention, the five-choice serial reaction time task (5CSRT), and working memory, the delayed matching to position task (DMTP).
  
  
  RESULTS
  Drug-induced responses varied qualitatively and quantitatively in both a compound- and a task-dependent manner. Effects were generally confounded by concomitant motor and motivational disruption, although individual doses of phencyclidine for example appeared to impair selectively cognitive functions. Interestingly, GluN2B selective antagonists were unique in their effects; inducing potential performance benefit in the 5CSRT.
  
  
  CONCLUSIONS
  Overall, the opportunity to induce a selective cognitive deficit in attention (5CSRT) or working memory (DMTP) in the rat is limited by both the NMDAR antagonist and the dose range used. The importance of a preclinical focus on ketamine, which is used more frequently in clinical settings, is limited by the extent to which cognitive effects can be both detected and quantified using this exposure regimen within these two operant assays.
authors.affiliation: Lilly Centre for Cognitive Neuroscience, Lilly Research Laboratories, Eli Lilly & Co. Ltd., Erl Wood Manor, Sunninghill Road, Windlesham, Surrey, GU20 6PH, UK.
authors.forename: Janice W
authors.initials: JW
authors.lastname: Smith
authors.forename: Francois
authors.initials: F
authors.lastname: Gastambide
authors.forename: Gary
authors.initials: G
authors.lastname: Gilmour
authors.forename: Sophie
authors.initials: S
authors.lastname: Dix
authors.forename: Julie
authors.initials: J
authors.lastname: Foss
authors.forename: Kirstie
authors.initials: K
authors.lastname: Lloyd
authors.forename: Nadia
authors.initials: N
authors.lastname: Malik
authors.forename: Mark
authors.initials: M
authors.lastname: Tricklebank
mesh_terms: D000818:Animals; D001288:Attention / Q000187:drug effects*; D001522:Behavior, Animal / Q000187:drug effects; D002755:Choice Behavior / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects*; D010622:Phencyclidine / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011930:Reaction Time / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
chemical_list: D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine; D010622:Phencyclidine