Prenatal exposure to the CB1 receptor agonist WIN 55,212-2 causes learning disruption associated with impaired cortical NMDA receptor function and emotional reactivity changes in rat offspring
Prenatal exposure to the CB1 receptor agonist WIN 55,212-2 causes learning disruption associated with impaired cortical NMDA receptor function and emotional reactivity changes in rat offspring
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DOI：
10.1093/cercor/bhi076
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发表时间：
2005-12-01
期刊：
影响因子：
3.7
通讯作者：
Ferraro, L
中科院分区：
文献类型：
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作者：
Antonelli, T;Tomasini, MC;Ferraro, L
本研究的目的是研究产前暴露于大麻素CB 1受体激动剂WIN 55，212 -2（WIN），每日剂量无明显的毒性和/或总体畸形体征（0.5 mg/kg，妊娠第5-20天），是否会影响大鼠后代的皮质神经递质能神经传递、学习和情绪反应。基础和K+-诱发的细胞外谷氨酸水平显着较低的皮质细胞培养物中获得的幼崽暴露于WIN在妊娠期间相对于从新生儿出生的车辆处理的母鼠的培养物中测量。从新生儿出生的车辆处理的母鼠的皮质细胞培养物中加入NMDA浓度依赖性增加谷氨酸水平，这是不存在的细胞培养物中获得的WIN-exposed幼崽。暴露于WINs的大鼠在归巢（10-12天龄）和主动回避测试（80天龄）中的表现也较差，并且分离诱导的超声波发射率下降（10天龄）。最后，产前暴露于WIN诱导皮质神经元数量减少。这些发现（i）为产前暴露于WIN后新生大鼠的皮质多巴胺能神经传递和行为缺陷提供了证据;（ii）表明皮质多巴胺能神经传递、NMDA受体活性的降低和神经元发育的改变可能至少部分地导致了在后代中观察到的学习缺陷和情绪反应性降低。
The aim of this study was to investigate whether prenatal exposure to the cannabinoid CB1 receptor agonist WIN 55,212-2 (WIN) at a daily dose devoid of overt signs of toxicity and/or gross malformations (0.5 mg/kg, gestation days 5-20), influences cortical glutamatergic neurotransmission, learning and emotional reactivity in rat offspring. Basal and K+-evoked extracellular glutamate levels were significantly lower in cortical cell cultures obtained from pups exposed to WIN during gestation with respect to those measured in cultures obtained from neonates born from vehicle-treated dams. The addition of NMDA to cortical cell cultures from neonates born from vehicle-treated dams concentration-dependently increased glutamate levels, and this was absent in cell cultures obtained from WIN-exposed pups. WIN-exposed rats also revealed a poorer performance in homing (10-12 days of age) and active avoidance tests (80 days of age) as well as a decrease in the rate of separation-induced ultrasonic emission (10 days of age). Finally, prenatal exposure to WIN induced a reduction in the number of cortical neuronal population. These findings (i) provide evidence for a deficit in cortical glutamatergic neurotransmission and behaviour in the rat neonate following prenatal exposure to WIN; and (ii) suggest that the reduction in cortical glutamatergic neurotransmission, NMDA receptor activity and alterations in neuronal development might underlie, at least in part, the learning deficit and decreased emotional reactivity observed in the offspring.