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胚胎期吗啡暴露影响日龄小鸡成瘾行为的中间纹状体GABA能突触机制
其他题名The impairment of striatal inhibitory transmission caused by prenatal morphine exposure underlies the morphine-altered psychomotor activity in day-old chicks
尚文
2018-12
摘要

研究背景及目的:胚胎期吗啡暴露对子代奖赏相关神经系统的长期改变可能导致其成瘾易感性的变化,然而何种神经递质系统参与子代成瘾行为的改变尚未可知。研究提示,纹状体内y_氨基丁酸(y-aminobutyric acid, GABA)能突触传递介导成瘾物质相关的精神运动兴奋性及奖赏效应,其可能作为胚胎期吗啡暴露影响子代成瘾易感性的潜在靶点。吗啡能够通过作用于阿片受体抑制GABA释放,而GABA递质在胚胎期对神经发育尤其是GABA能神经轴突的发育起到重要的促进作用,因此我们假设胚胎期吗啡暴露可能通过干扰GABA对GABA能神经突触发育的营养作用,令子代纹状体抑制性突触传递受损,进而使其介导的子代成瘾行为发生改变。

研究方法:我们首先探究了胚胎期吗啡暴露对吗啡诱导子代日龄小鸡精神运动兴奋性的作用。选取胚胎期5-8 ( embryonic period 5-8 , ES-8)和E13-16的鸡胚进行吗啡暴露(1 mg/kg,在子代小鸡出生后第三天进行吗啡注射后的运动测试,观察吗啡诱导的精神运动兴奋性。24小时后,处死小鸡并取脑。分别运用全细胞膜片钳记录和免疫荧光染色法探索子代小鸡中间纹状体(medial striatum,MSt) GABA能神经突触传递功能和谷氨酸脱竣酶( glutamate decarboxylase, GAD65/67阳性的GABA能神经元轴突末梢。最后,我们在ES-8或E13-16吗啡暴露10分钟后补充GABA递质(10 mg/kg,观察是否能够翻转子代的神经及行为异常。

研究结果:ES-8而非E13-16吗啡暴露产生了对吗啡初期镇静效果的去抑制作用。对于GABA能突触传递功能,ES-8吗啡暴露使子代日龄小鸡MSt神经元上记录的微小抑制性突触后电流(miniature inhibitory postsynaptic currents,mIPSC)的频率和幅度均下降,而E13-16吗啡暴露仅降低其幅度而非频率。同时,ES-8而非E13-16吗啡暴露使子代日龄小鸡MSt中GAD阳性的GABA能突触末梢数量显著减少。在ES-8吗啡暴露后补充GABA,发现ES-8吗啡暴露所引发的神经及行为异常均被翻转。

研究结论:我们的结果提示,胚胎早期吗啡暴露导致的子代纹状体GABA能神经突触功能及结构的损伤可能是子代成瘾易感性变化的主要原因之一,吗啡暴露导致的GABA释放减少可能是其神经机制。

其他摘要

Background and purpose: Prenatal morphine exposure (PME) changes addiction susceptibility in offspring which may be an outcome of permanent alterations of neural systems. However, which system plays a crucial role is not well known. GABAergic synaptic transmission within the striatum has implied in regulating drug-associated psychomotor activities and reward effect, meanwhile, GABA transmitter has a positive role in neural development, especially GABAergic axon branching. Since morphine exposure decreases GABA concentration in developing neonatal brain, we hypothesized that PME could disrupt inhibitory synapse formation in the striatum by attenuating GABA release during embryogenesis, which underlies the morphine-altered psychomotor activity in offspring.

Method: We first explored the effect of PME on psychomotor activities to morphine in day-old chicks. Breeding eggs were exposed to morphine (1 mg/kg) during embryonic period 5-8 (ES-8) or E13-16. Locomotor activity test was conducted to observe morphine-induced psychomotor activities in chicks on postnatal day 3. Then,chicks were executed and brains were collected. The function of GABAergic transmission, the number of glutamate decarboxylase (GAD) 65/67-positive GABAergic synapse terminals in chick medial striatum (MSt) were examined by whole cell patch-clamp recording and immunohistochemistry, respectively. Secondly, we clarified whether GABA supply after morphine exposure in embryo could rescue neural and behavioral abnormalities. GABA (10 mg/kg) was administered 10 min after morphine injection during ES-8 or E13-16.

Results: PME during ES一8 but not E13-16 blocked morphine-induced decrease of psychomotor activity in chicks. For GABAergic transmission, PME during ES-8 reduced both frequency and amplitude of miniature inhibitory postsynaptic currents (mIPSCs) in MSt, E13-16 PME only decreased amplitude of mIPSCs but not frequency. The significant loss of GAD-positive puncta in MSt was observed during ES-8 but not E13-16 PME. Furthermore, neural and behavioral alterations caused by were recovered by exogenous GABA supplying to embryos after morphine exposure during ES-8.

Conclusion: Our data indicate that PME during early embryonic stage leads to impairment of GABAergic transmission and synapse structure in striatum, which may relate to addiction susceptibility alteration in offspring. Trophic effect of GABA on GABAergic axon branching during neural development may associate with these pathological changes by PME.

关键词胚胎期吗啡暴露 精神运动兴奋性 中间纹状体 Y_氨基丁酸 GABA能突触传递
学位类型硕士
语种中文
学位名称理学硕士
学位专业健康心理学
学位授予单位中国科学院心理研究所
学位授予地点中国科学院心理研究所
文献类型学位论文
条目标识符http://ir.psych.ac.cn/handle/311026/30075
专题健康与遗传心理学研究室
推荐引用方式
GB/T 7714
尚文. 胚胎期吗啡暴露影响日龄小鸡成瘾行为的中间纹状体GABA能突触机制[D]. 中国科学院心理研究所. 中国科学院心理研究所,2018.
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