Maternal immune activation and repeated maternal separation alter offspring conditioned avoidance response learning and antipsychotic response in male rats.

Previous work shows that repeated administration of several commonly used antipsychotic drugs, such as olanzapine (OLZ) over several days, induces an enhanced disruption of conditioned avoidance response (CAR) (termed antipsychotic sensitization) in normal adolescent and adult rats. However, it is unclear whether the same phenomenon can also be demonstrated in rat models of schizophrenia. The present study investigated OLZ sensitization in a combined maternal immune activation (MIA) and repeated maternal separation (RMS) model of schizophrenia. Sprague-Dawley male rats were first subjected to an early prenatal exposure to polyinosinic:polycytidylic acid (PolyI:C) on gestation days 13 (4 mg/kg, iv) and 15 (6 mg/kg, iv). They were then repeatedly separated from their mothers for 3 h daily during the first two weeks of postpartum. After they became adolescent (on postnatal day, PND 43), acute and OLZ sensitization effects in the CAR model was assessed. Adolescent MIA rats showed an impaired acquisition of conditioned avoidance response, but displayed a normal acute OLZ-induced avoidance suppression and OLZ sensitization effect. In adulthood (PND 81), MIA rats again showed an impairment in the acquisition of CAR. However, they showed a reduced response to OLZ (1.0 mg/kg; sc) treatment during the repeated drug test days, indicating a disruption of the induction of OLZ sensitization. In the OLZ sensitization challenge test, both MIA and control rats exhibited a robust and similar sensitization effect. In both adolescence and adulthood, RMS alone had no effect on any of the behavioral outcomes, and combined MIA-RMS even abolished the MIA alone-induced disruption of avoidance acquisition and the induction of OLZ sensitization. These results indicate that MIA disrupts associative learning and may reduce antipsychotic efficacy in the early stage of OLZ treatment. RMS does not appear to affect associative learning and behavioral responses to OLZ, and may possibly attenuate MIA-induced deficits. Our findings demonstrate that OLZ sensitization is a robust phenomenon but its magnitude can be altered by early MIA.

先前的研究表明，连续数天重复给予几种常用的抗精神病药物，如奥氮平（OLZ），会在正常的青春期和成年大鼠中导致条件性回避反应（CAR）的破坏增强（称为抗精神病药致敏）。然而，尚不清楚在精神分裂症大鼠模型中是否也能出现相同的现象。本研究在一种母体免疫激活（MIA）和重复母体分离（RMS）相结合的精神分裂症模型中研究了奥氮平致敏作用。首先让斯普拉格 - 道利雄性大鼠在妊娠第13天（4mg/kg，静脉注射）和第15天（6mg/kg，静脉注射）早期产前暴露于聚肌苷酸 - 聚胞苷酸（PolyI:C）。然后在产后的前两周每天将它们与母亲重复分离3小时。在它们进入青春期（出生后第43天，PND 43）后，评估CAR模型中的急性和奥氮平致敏效应。青春期MIA大鼠表现出条件性回避反应的习得受损，但显示出正常的急性奥氮平诱导的回避抑制和奥氮平致敏效应。在成年期（PND 81），MIA大鼠再次表现出CAR习得受损。然而，在重复给药测试期间，它们对奥氮平（1.0mg/kg；皮下注射）治疗的反应降低，表明奥氮平致敏的诱导受到破坏。在奥氮平致敏激发试验中，MIA大鼠和对照大鼠都表现出强烈且相似的致敏效应。在青春期和成年期，单独的RMS对任何行为结果都没有影响，并且MIA - RMS联合甚至消除了单独MIA诱导的回避习得破坏和奥氮平致敏的诱导。这些结果表明，MIA会破坏联想学习，并可能降低奥氮平治疗早期的抗精神病疗效。RMS似乎不影响联想学习和对奥氮平的行为反应，并且可能减轻MIA诱导的缺陷。我们的研究结果表明，奥氮平致敏是一种强烈的现象，但其程度可因早期MIA而改变。