title: Animal models of cognitive dysfunction and negative symptoms of schizophrenia: focus on NMDA receptor antagonism.
abstract: Cognitive deficits in schizophrenia remain an unmet clinical need. Improved understanding of the neuro- and psychopathology of these deficits depends on the availability of carefully validated animal models which will assist the development of novel therapies. There is much evidence that at least some of the pathology and symptomatology (particularly cognitive and negative symptoms) of schizophrenia results from a dysfunction of the glutamatergic system which may be modelled in animals through the use of NMDA receptor antagonists. The current review examines the validity of this model in rodents. We review the ability of acute and sub-chronic treatment with three non-competitive NMDA antagonists; phencyclidine (PCP), ketamine and MK801 (dizocilpine) to produce cognitive deficits of relevance to schizophrenia in rodents and their subsequent reversal by first- and second-generation antipsychotic drugs. Effects of NMDA receptor antagonists on the performance of rodents in behavioural tests assessing the various domains of cognition and negative symptoms are examined: novel object recognition for visual memory, reversal learning and attentional set shifting for problem solving and reasoning, 5-Choice Serial Reaction Time for attention and speed of processing; in addition to effects on social behaviour and neuropathology. The evidence strongly supports the use of NMDA receptor antagonists to model cognitive deficit and negative symptoms of schizophrenia as well as certain pathological disturbances seen in the illness. This will facilitate the evaluation of much-needed novel pharmacological agents for improved therapy of cognitive deficits and negative symptoms in schizophrenia.
authors: The School of Pharmacy, University of Bradford, Bradford, West Yorkshire, BD7 1DP, UK. j.c.neill@brad.ac.uk
authors: Joanna C
authors: JC
authors: Neill
authors: Samuel
authors: S
authors: Barnes
authors: Samantha
authors: S
authors: Cook
authors: Ben
authors: B
authors: Grayson
authors: Nagi F
authors: NF
authors: Idris
authors: Samantha L
authors: SL
authors: McLean
authors: Shikha
authors: S
authors: Snigdha
authors: Lakshmi
authors: L
authors: Rajagopal
authors: Michael K
authors: MK
authors: Harte
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001288:Attention / Q000187:drug effects; D003072:Cognition Disorders / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051381:Rats; D011930:Reaction Time / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D021641:Recognition, Psychology; D012193:Reversal Learning / Q000187:drug effects; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism; D012565:Schizophrenic Psychology; D012919:Social Behavior
chemical_list: D014150:Antipsychotic Agents; D016194:Receptors, N-Methyl-D-Aspartate