title: A Methionine-Induced Animal Model of Schizophrenia: Face and Predictive Validity.
abstract: BACKGROUND
  Modulating the methylation process induces broad biochemical changes, some of which may be involved in schizophrenia. Methylation is in particular central to epigenesis, which is also recognized as a factor in the etiology of schizophrenia. Because methionine administration to patients with schizophrenia has been reported to exacerbate their psychotic symptoms and because mice treated with methionine exhibited social deficits and prepulse inhibition impairment, we investigated whether methionine administration could lead to behavioral changes that reflect schizophrenic symptoms in mice.
  
  
  METHODS
  l-Methionine was administered to mice twice a day for 7 days.
  
  
  RESULTS
  We found that this treatment induces behavioral responses that reflect the 3 types of schizophrenia-like symptoms (positive, negative, or cognitive deficits) as monitored in a battery of behavioral assays (locomotion, stereotypy, social interaction, forced swimming, prepulse inhibition, novel object recognition, and inhibitory avoidance). Moreover, these responses were differentially reversed by typical haloperidol and atypical clozapine antipsychotics in ways that parallel their effects in schizophrenics.
  
  
  CONCLUSIONS
  We thus propose the l-methionine treatment as an animal model recapitulating several symptoms of schizophrenia. We have established the face and predictive validity for this model. Our model relies on an essential natural amino acid and on an intervention that is relatively simple and time effective and may offer an additional tool for assessing novel antipsychotics.
authors.affiliation: Departments of Pharmacology (Ms L. Wang, Dr Alachkar, Ms Sanathara, Dr Belluzzi, Dr Z. Wang, and Dr Civelli), Pharmaceutical Sciences (Dr Civelli), and Developmental and Cell Biology (Dr Civelli), School of Medicine, University of California, Irvine.CA.
authors.forename: Lien
authors.initials: L
authors.lastname: Wang
authors.affiliation: Departments of Pharmacology (Ms L. Wang, Dr Alachkar, Ms Sanathara, Dr Belluzzi, Dr Z. Wang, and Dr Civelli), Pharmaceutical Sciences (Dr Civelli), and Developmental and Cell Biology (Dr Civelli), School of Medicine, University of California, Irvine.CA.
authors.forename: Amal
authors.initials: A
authors.lastname: Alachkar
authors.affiliation: Departments of Pharmacology (Ms L. Wang, Dr Alachkar, Ms Sanathara, Dr Belluzzi, Dr Z. Wang, and Dr Civelli), Pharmaceutical Sciences (Dr Civelli), and Developmental and Cell Biology (Dr Civelli), School of Medicine, University of California, Irvine.CA.
authors.forename: Nayna
authors.initials: N
authors.lastname: Sanathara
authors.affiliation: Departments of Pharmacology (Ms L. Wang, Dr Alachkar, Ms Sanathara, Dr Belluzzi, Dr Z. Wang, and Dr Civelli), Pharmaceutical Sciences (Dr Civelli), and Developmental and Cell Biology (Dr Civelli), School of Medicine, University of California, Irvine.CA.
authors.forename: James D
authors.initials: JD
authors.lastname: Belluzzi
authors.affiliation: Departments of Pharmacology (Ms L. Wang, Dr Alachkar, Ms Sanathara, Dr Belluzzi, Dr Z. Wang, and Dr Civelli), Pharmaceutical Sciences (Dr Civelli), and Developmental and Cell Biology (Dr Civelli), School of Medicine, University of California, Irvine.CA.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Departments of Pharmacology (Ms L. Wang, Dr Alachkar, Ms Sanathara, Dr Belluzzi, Dr Z. Wang, and Dr Civelli), Pharmaceutical Sciences (Dr Civelli), and Developmental and Cell Biology (Dr Civelli), School of Medicine, University of California, Irvine.CA. ocivelli@uci.edu.
authors.forename: Olivier
authors.initials: O
authors.lastname: Civelli
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects; D003024:Clozapine / Q000494:pharmacology; D003863:Depression / Q000188:drug therapy / Q000503:physiopathology; D004195:Disease Models, Animal; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D008715:Methionine; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects; D021641:Recognition, Psychology / Q000187:drug effects; D012559:Schizophrenia / Q000188:drug therapy / Q000503:physiopathology; D012565:Schizophrenic Psychology; D055139:Sensory Gating / Q000187:drug effects; D012919:Social Behavior; D013239:Stereotyped Behavior / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D014150:Antipsychotic Agents; D008715:Methionine; D003024:Clozapine; D006220:Haloperidol
keywords: Schizophrenia; face validity; methionine; mouse model; predictive validity