Abstract：
Maternal immune activation (MIA) during pregnancy is known to increase the risk of development of schizophrenia in the offspring. Sex steroid hormone analogues have been proposed as potential antipsychotic treatments but the mechanisms of action involved remain unclear. Estrogen has been shown to alter N-methyl-d-aspartate (NMDA) receptor binding in the brain. We therefore studied the effect of chronic treatment with 17β-estradiol, its isomer, 17α-estradiol, and the selective estrogen receptor modulator, raloxifene, on MIA-induced psychosis-like behaviour and the effect of the NMDA receptor antagonist, MK-801. Pregnant rats were treated with saline or the viral mimetic, poly(I:C), on gestational day 15. Adult female offspring were tested for changes in baseline prepulse inhibition (PPI) and the effects of acute treatment with MK-801 on PPI and locomotor activity. Poly(I:C) offspring had significantly lower baseline PPI compared to control offspring, and this effect was prevented by 17β-estradiol and raloxifene, but not 17α-estradiol. MK-801 reduced PPI in control offspring but had no effect in poly(I:C) offspring treated with vehicle. Chronic treatment with 17β-estradiol and raloxifene restored the effect of MK-801 on PPI. There were no effects of MIA or estrogenic treatment on MK-801 induced locomotor hyperactivity. These results show that MIA affects baseline PPI as well as NMDA receptor-mediated regulation of PPI in female rats, and strengthen the view that estrogenic treatment may have antipsychotic effects.
摘要：
已知怀孕期间的母体免疫激活（MIA）会增加后代患精神分裂症的风险。性类固醇激素类似物已被提议作为潜在的抗精神病药物治疗，但所涉及的作用机制尚不清楚。已显示雌激素改变大脑中N-甲基-d-天冬氨酸（NMDA）受体的结合。因此，我们研究了17β-雌二醇慢性治疗的效果，它的异构体，17α-雌二醇，和选择性雌激素受体调节剂，雷洛昔芬,对MIA诱导的精神病样行为和NMDA受体拮抗剂的影响，MK-801.妊娠大鼠用生理盐水或病毒模拟物治疗，聚（I：C），在妊娠第15天。测试了成年雌性后代的基线前脉冲抑制（PPI）的变化以及MK-801急性治疗对PPI和运动活动的影响。与对照后代相比，Poly（I：C）后代的基线PPI显着降低，17β-雌二醇和雷洛昔芬阻止了这种作用，但不是17α-雌二醇.MK-801在对照后代中降低PPI,但在用载体处理的聚(I:C)后代中没有作用。17β-雌二醇和雷洛昔芬的慢性治疗恢复了MK-801对PPI的作用。MIA或雌激素治疗对MK-801诱导的运动过度没有影响。这些结果表明，在雌性大鼠中，MIA影响基线PPI以及NMDA受体介导的PPI调节，并加强了雌激素治疗可能具有抗精神病作用的观点。
