Zuckerman Lee, Rehavi Moshe, Nachman Rachel, Weiner Ina
Department of Psychology, Tel Aviv University, Tel Aviv, Israel.
Neuropsychopharmacology. 2003 Oct;28(10):1778-89. doi: 10.1038/sj.npp.1300248.
Prenatal exposure to infection is associated with increased liability to schizophrenia, and it is believed that such an association is mediated by the maternal immune response, in particular, the proinflammatory cytokines released by the maternal immune system, which may disrupt fetal brain development. Impaired capacity to ignore irrelevant stimuli is one of the central deficits in schizophrenia, and is manifested, among others, in loss of latent inhibition (LI), a phenomenon whereby repeated inconsequential pre-exposure to a stimulus impairs its subsequent capacity to signal significant consequences. We tested the effects of prenatal immune activation induced by peripheral administration of the synthetic cytokine releaser polyriboinosinic-polyribocytidilic acid (poly I : C) to pregnant dams, on LI in juvenile and adult offspring. Consistent with the characteristic maturational delay of schizophrenia, prenatal immune activation did not affect LI in the juvenile offspring, but led to LI disruption in adulthood. Both haloperidol (0.1 mg/kg) and clozapine (5 mg/kg) reinstated LI in the adult offspring. In addition, prenatal immune activation led to a postpubertal emergence of increased sensitivity to the locomotor-stimulating effects of amphetamine and increased in vitro striatal dopamine release, as well as to morphological alterations in the hippocampus and the entorhinal cortex in the adult offspring, consistent with the well-documented mesolimbic dopaminergic and temporolimbic pathology in schizophrenia. These results suggest that prenatal poly I : C administration may provide a neurodevelopmental model of schizophrenia that reproduces a putative inducing factor; mimics the temporal course as well as some central abnormalities of the disorder; and predicts responsiveness to antipsychotic drugs. Neuropsychopharmacology (2003) 28, 1778-1789. advance online publication, 16 July 2003; doi:10.1038/sj.npp.1300248
产前暴露于感染与精神分裂症易感性增加有关，据信这种关联是由母体免疫反应介导的，特别是母体免疫系统释放的促炎细胞因子，这可能会扰乱胎儿大脑发育。忽视无关刺激的能力受损是精神分裂症的核心缺陷之一，尤其表现为潜伏抑制（LI）丧失，即对某一刺激的反复无关前暴露会损害其随后发出重要后果信号的能力。我们测试了对怀孕母鼠外周给予合成细胞因子释放剂聚肌苷酸-聚胞苷酸（poly I : C）诱导的产前免疫激活对幼年和成年后代LI的影响。与精神分裂症典型的成熟延迟一致，产前免疫激活并未影响幼年后代的LI，但导致成年期LI破坏。氟哌啶醇（0.1 mg/kg）和氯氮平（5 mg/kg）均可使成年后代的LI恢复。此外，产前免疫激活导致青春期后对苯丙胺的运动刺激作用敏感性增加、体外纹状体多巴胺释放增加，以及成年后代海马体和内嗅皮质出现形态学改变，这与精神分裂症中充分记录的中脑边缘多巴胺能和颞叶边缘病理学一致。这些结果表明，产前给予poly I : C可能提供一种精神分裂症的神经发育模型，该模型再现了一种假定的诱发因素；模拟了该疾病的时间进程以及一些核心异常；并预测了对抗精神病药物的反应性。《神经精神药理学》（2003年）28卷，1778 - 1789页。2003年7月16日在线优先发表；doi:10.1038/sj.npp.1300248
