title: Maternal immune activation leads to age-related behavioral and immunological changes in male rat offspring - the effect of antipsychotic drugs.
abstract: BACKGROUND
  Prenatal immune system disturbances have been postulated to play an important role in pathogenesis of schizophrenia and related disorders. In the present study, we sought to answer the question whether behavioral changes in the neurodevelopmental model of schizophrenia in rats are accompanied by alterations in proliferative activity of splenocytes and pro- and anti-inflammatory cytokine levels. Furthermore, the effects of two antipsychotic drugs on these parameters were determined.
  
  
  METHODS
  Lipopolysaccharide (LPS) was administered subcutaneously to pregnant dams at a dose of 1 mg/kg every second day from the 7(th) day of pregnancy till delivery. Age-dependent behavioral and immunological changes were studied when control and prenatally LPS-pretreated offspring male rats were 30 and 90 days old. Chlorpromazine (10 mg/kg ip) or clozapine (10 mg/kg ip) was administered chronically (21 days) after behavioral verification to 3 months old offspring males. Changes in sensorimotor gating (prepulse inhibition, PPI), mitogen-induced proliferative activity of splenocytes ([(3)H]-thymidine incorporation) and cytokine levels (ELISA) were measured.
  
  
  RESULTS
  Prenatally LPS-pretreated rats showed PPI deficit only at 90 but not at 30 days of age, whereas an enhancement of mitogen-stimulated proliferative activity of splenocytes was observed in both time points. Additionally, the level of proinflammatory cytokines (IL-1β, IL-2, IL-6, TNF-α) in prenatally LPS-pretreated rats was enhanced when they were 30 days old and remained elevated in 90 days old offspring. No changes in IL-10 level were observed. Chronic administration of chlorpromazine or clozapine reduced the deficit in PPI deficit in prenatally LPS-treated rats. In the used model, chlorpromazine normalized both T and B lymphocyte proliferation, whereas clozapine B lymphocyte activity only. Moreover, both antipsychotics modulated the enhanced levels of IL-1β, IL-2 and TNF-α in the offspring of LPS-treated mothers.
  
  
  CONCLUSIONS
  This study indicates that in LPS-evoked model of schizophrenia, peripheral immunological changes are long-lasting and precede behavioral deficit. The disturbances in T cell-mediated immunity as well as cytokine production were attenuated by antipsychotic drug administration.
authors: Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Kraków, Poland. basta@if-pan.krakow.pl
authors: Agnieszka
authors: A
authors: Basta-Kaim
authors: Ewa
authors: E
authors: Szczęsny
authors: Monika
authors: M
authors: Leśkiewicz
authors: Katarzyna
authors: K
authors: Głombik
authors: Joanna
authors: J
authors: Slusarczyk
authors: Bogusława
authors: B
authors: Budziszewska
authors: Magdalena
authors: M
authors: Regulska
authors: Marta
authors: M
authors: Kubera
authors: Wojciech
authors: W
authors: Nowak
authors: Krzysztof
authors: K
authors: Wędzony
authors: Władysław
authors: W
authors: Lasoń
mesh_terms: D000367:Age Factors; D000375:Aging; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002746:Chlorpromazine / Q000494:pharmacology*; D003024:Clozapine / Q000494:pharmacology*; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D018450:Disease Progression; D004334:Drug Administration Schedule; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D018836:Inflammation Mediators / Q000097:blood; D007279:Injections, Subcutaneous; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity*; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D018811:Maternal Exposure; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017208:Rats, Wistar; D013216:Reflex, Startle / Q000187:drug effects; D012559:Schizophrenia / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D012565:Schizophrenic Psychology; D055139:Sensory Gating / Q000187:drug effects; D013154:Spleen / Q000187:drug effects* / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D013997:Time Factors
chemical_list: D014150:Antipsychotic Agents; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D003024:Clozapine; D002746:Chlorpromazine