鸡胚吗啡用药对学习记忆和成瘾易感性的影响及其受体机制

Prenatal morphine exposure affects neural development of fetus by impairing learning and memory, and increasing susceptibility to morphine abuse. Because nervous systems have different developmental characteristics during different developmental stages, administration of morphine at different stages also has different effects on learning, memory, and susceptibility to morphine. Due to the precise developmental processes of neurotransmitter systems in chick embryo’s brain, and unique superiority of chick embryo model, the purpose of the present studies was to explore critical periods correlated to the memory impairment and the increasing susceptibility to morphine, via one-trial passive avoidance and conditioned place preference as behavior models. Then the possible roles of mu and delta opioid receptors as the possible mechanism were analyzed. Experiment 1 showed that injecting low dose of morphine (1 mg/kg) during the period embryonic 5 to 8 significantly impaired the function of learning and memory, worse than any other periods of the same treatment. Experiment 2 showed that injecting low dose of morphine during the period embryonic 17 to 20 significantly increased the susceptibility to morphine in the new-born chicks. The affected chicks acquired the morphine conditioned place preference more quickly, and maintained it much longer. Experiment 3 showed that during E5-8, injecting delta receptor antagonist naltrindole reversed the learning and memory impairment caused by morphine while delta receptor agonist DPDPE impaired learning and partial memory function. On the other hand, mu opioid receptors had little effect. As for E17-20, given naloxonazine can reverse the increases of susceptibility to morphine, and the mu receptor agonist DAGO cause the increases of susceptibility to morphine. Delta receptors have no effect. The above results demonstrated that prenatal morphine expousure at different developmental periods of chick embryo caused different influences on memory and susceptibility to morphine. That is, E5-8 is the critical period correlate to memory impairment; and E17-20 is the critical period correlate to susceptibility to morphine. Delta receptors were critical in learning and memory impairment while mu receptors in susceptibility.

孕期吗啡滥用影响子代神经发育过程，表现为学习记忆功能的受损和成瘾易感性的增加，严重危害子代身心健康。由于在胚胎期不同发育阶段神经发育特点不同，吗啡对学习记忆和成瘾易感性的影响可能存在敏感的时间窗口。为了探讨吗啡作用下与学习记忆功能损害和成瘾易感性增强密切相关的胚胎发育关键期，及其阿片受体机制，研究利用鸡胚脑内神经递质系统具有较清晰的时间发生特点，和小鸡在学习记忆与成瘾机制研究中的优点，使用雏鸡的一次性被动回避模型和吗啡条件性位置偏爱（CPP）模型做为行为测量模型，通过在鸡胚不同发育阶段进行吗啡干预，分别考察了与学习记忆功能损害和成瘾易感性增强密切相关的胚胎发育关键期。并进一步在胚胎期使用选择性mu和delta受体激动剂和拮抗剂进行干预，探讨学习记忆和成瘾易感性关键期产生的阿片受体机制。研究结果发现：经过对鸡胚发育不同时间段的吗啡给药，胚胎期（E）发育E5-8阶段给予吗啡的小鸡学习记忆受损最为严重，表现为学习和记忆功能的严重下降；而E17-20时段吗啡给药的小鸡更容易获得吗啡CPP且保持时间更长。E5-8阶段给予delta受体拮抗剂natrindole能够翻转吗啡对学习和记忆的损害作用，并且给予delta受体激动剂DPDPE也损害学习和部分记忆功能，mu受体作用不大。E17-20阶段拮抗mu受体能够抑制成瘾易感性的增加，激动mu受体可以增加小鸡的成瘾易感性，delta受体没有明显作用。研究结果表明鸡胚发育不同阶段给予吗啡对小鸡学习记忆和成瘾易感性的影响不同，E5-8是损害学习记忆的关键期，E17-20是成瘾易感性增加的关键期。delta受体在学习记忆关键期中具有重要作用，而mu受体主要介导了成瘾易感性关键期的产生。