title: Acute and chronic effects of NMDA receptor antagonists in rodents, relevance to negative symptoms of schizophrenia: a translational link to humans.
abstract: Negative symptoms of schizophrenia remain an unmet clinical need as they are common, persistent, respond poorly to existing treatments and lead to disability. Blunted affect, alogia, asociality, anhedonia and avolition are regarded as key negative symptoms despite DSM-IV-TR specifying a more limited range. The key to development of improved therapies is improved animal models that mimic the human condition in terms of behaviour and pathology and that predict efficacy of novel treatments in patients. Accumulating evidence shows that NMDA receptor (NMDAR) antagonists mimic cognitive deficits of relevance to schizophrenia in animals, along with associated pathological changes. This review examines evidence for the ability of NMDAR antagonists to mimic anhedonia and asociality, two negative symptoms of schizophrenia, in animals. The use of various species, paradigms and treatment regimens are reviewed. We conclude that sub-chronic treatment with NMDAR antagonists, typically PCP, induces social withdrawal in animals but not anhedonia. NMDAR antagonists have further effects in paradigms such as motivational salience that may be useful for mimicking other aspects of negative symptoms but these require further development. Sub-chronic treatment regimens of NMDAR antagonists also have some neurobiological effects of relevance to negative symptoms. It is our view that a sub-chronic treatment regime with NMDAR antagonists, particularly PCP, with animals tested following a wash-out period and in a battery of tests to assess certain behaviours of relevance to negative symptoms and social withdrawal (the animal equivalent of asociality) is valuable. This will enhance our understanding of the psycho and neuropathology of specific negative symptom domains and allow early detection of novel pharmacological targets.
authors.affiliation: Manchester Pharmacy School, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK. Electronic address: Joanna.neill@manchester.ac.uk.
authors.forename: Joanna C
authors.initials: JC
authors.lastname: Neill
authors.affiliation: Manchester Pharmacy School, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Harte
authors.affiliation: Neuroscience and Psychiatry Unit, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Haddad
authors.affiliation: Public Health Wales, Unit 1 Charnwood Court, Heol Billingsley, Parc Nantgarw, Cardiff CF15 7QZ, UK.
authors.forename: Emma S
authors.initials: ES
authors.lastname: Lydall
authors.affiliation: School of Psychology, Cardiff University, Tower Building, Park Place, Cardiff CF10 3AT, UK.
authors.forename: Dominic M
authors.initials: DM
authors.lastname: Dwyer
mesh_terms: D059445:Anhedonia / Q000502:physiology; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012377:Rodentia; D012559:Schizophrenia / Q000188:drug therapy / Q000503:physiopathology*; D012565:Schizophrenic Psychology; D012919:Social Behavior; D057170:Translational Research, Biomedical
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate
keywords: Anhedonia; Animal models; Motivation; NMDA receptor antagonists; Negative symptoms; Schizophrenia; Social withdrawal