title: A two-hit model of suicide-trait-related behaviors in the context of a schizophrenia-like phenotype: Distinct effects of lithium chloride and clozapine.
abstract: Schizophrenia patients show a high rate of premature mortality due to suicide. The pathophysiological mechanisms of these suicidal behaviors in schizophrenia do not appear to involve serotonergic neurotransmission as found in the general population. Our aim was to develop an in vivo model of schizophrenia presenting suicide-trait-related behaviors such as aggressiveness, impulsivity, anxiety and helplessness. We opted for a two-hit model: C57BL/6 dams were injected with polyI:C on gestational day 12. The pups were submitted to social isolation for 4weeks after weaning. During the last week of social isolation and 30min before behavioral testing, the mice received vehicle, lithium chloride or clozapine. Lithium chloride is well known for its suicide preventive effects in the non-schizophrenic population, while clozapine is the antipsychotic with the best-established suicide preventive effect. The two-hit model induced several schizophrenia-related and suicide-trait-related behaviors in male, but not female, mice. Additionally, lithium chloride improved prepulse inhibition, aggressiveness, impulsivity and anxiety-like behavior in socially isolated mice only, whereas clozapine prevented behavioral abnormalities mainly in mice prenatally exposed to polyI:C and submitted to isolated rearing. The distinct effects of lithium chloride and clozapine suggested that mice prenatally exposed to polyI:C and submitted to social isolation presented a distinct phenotype from that of mice submitted to social isolation only. Because diagnosing suicidal risk in patients is a challenge for psychiatrists given the lack of specific clinical predictors, our in vivo model could help in gaining a better understanding of the mechanisms underlying suicidal behavior in the context of schizophrenia.
authors.affiliation: Department of Physiology and Biophysics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 12(e) avenue Nord, Sherbrooke, QC J1H 5N4, Canada.
authors.forename: Jessica
authors.initials: J
authors.lastname: Deslauriers
authors.affiliation: Department of Physiology and Biophysics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 12(e) avenue Nord, Sherbrooke, QC J1H 5N4, Canada.
authors.forename: Karine
authors.initials: K
authors.lastname: Belleville
authors.affiliation: Department of Physiology and Biophysics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 12(e) avenue Nord, Sherbrooke, QC J1H 5N4, Canada.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Beaudet
authors.affiliation: Department of Physiology and Biophysics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 12(e) avenue Nord, Sherbrooke, QC J1H 5N4, Canada.
authors.forename: Philippe
authors.initials: P
authors.lastname: Sarret
authors.affiliation: Department of Physiology and Biophysics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 12(e) avenue Nord, Sherbrooke, QC J1H 5N4, Canada; Department of Psychiatry, Centre Hospitalier Universitaire de Sherbrooke, 580 Bowen Sud, Sherbrooke, QC J1G 2E8, Canada. Electronic address: Sylvain.Grignon@USherbrooke.ca.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Grignon
mesh_terms: D000374:Aggression / Q000187:drug effects; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001007:Anxiety; D003024:Clozapine / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D018021:Lithium Chloride / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D012559:Schizophrenia / Q000188:drug therapy; D012565:Schizophrenic Psychology; D012934:Social Isolation; D059020:Suicidal Ideation; D000092864:Suicide Prevention
chemical_list: D014150:Antipsychotic Agents; D018021:Lithium Chloride; D003024:Clozapine
keywords: Clozapine; Lithium; Schizophrenia; Social isolation; Suicide