去甲肾上腺素参与吗啡神经适应性改变的中枢机制
其他题名neural mechanism of morphine-induced neuroadaptation with the involvement of noradrenalin
王冬梅
学位类型博士
导师隋南
2007-06-18
学位授予单位中国科学院心理研究所
学位授予地点心理研究所
学位专业基础心理学
关键词神经适应性变化 α受体 内侧前额叶 伏隔核 精神兴奋性 新颖寻求
摘要

    戒断后复吸行为仍然长期存在是药物成瘾临床治疗的难题,长期接触成瘾药物引起的神经适应性变化是强迫性觅药和复吸的神经基础。成瘾药物引起的神经适应性变化一方面使得个体对药物的反应性增加,而另一方面表现为个体对自然奖赏物反应的下降。这两种共存现象应该有部分共同的神经机制,同时药物也应该有其特异性的神经机制。揭示从偶然的可以控制的用药行为到不可控的强迫性觅药过程中发生的神经适应性变化具有重要的理论与实际意义。基于以上假设,为了揭示药物成瘾过程中去甲肾上腺素能a受体在强迫性觅药动机中的作用,本研究以吗啡精神兴奋性的敏化现象为行为模型,通过行为药理学方法探索去甲肾上腺素能a受体参与成瘾过程的神经机制。比较了初次用药和反复用药前额叶皮层和伏隔核的a受体对吗啡精神兴奋性的调节作用,并进一步比较相应脑区的该受体对新颖寻求的影响。
主要结果如下:
    1连续吗啡给药后,大鼠对吗啡诱导的精神运动兴奋性反应增强而对新颖奖赏反应性减弱;
    2前额叶皮质注射a1受体的拮抗剂prazosin能降低未接触过吗啡(naive )的大鼠的精神兴奋性,但不能降低吗啡戒断大鼠的精神兴奋性;同时降低大鼠的新颖寻求行为;
    3前额叶皮层注射a2受体激动剂clonidine能降低naive大鼠以及吗啡戒断大鼠的吗啡精神兴奋性,同时降低吗啡戒断大鼠的新颖寻求行为;
    4伏隔核注射。,受体的拮抗剂prazosin不影响naive大鼠和吗啡戒断大鼠的吗啡精神兴奋性,而也不影响吗啡戒断大鼠的新颖寻求行为;
    5伏隔核注射a2受体的激动剂clonidine降低naive大鼠的吗啡精神兴奋性,但不影响吗啡处理大鼠的精神兴奋性,也不影响吗啡戒断大鼠的新颖寻求。
以上结果表明:
    1反复接触吗啡导致内侧前额叶a1受体功能下调以及伏隔核a2受体功能下调可能是引起强迫性觅药行为的原,因;
    2拮抗内侧前额叶的a1受体加剧了药物戒断后对自然奖赏兴趣的下降;
    3拮抗内侧前额叶a2受体抑制觅药动机的同时,也拮抗了个体对新颖刺激的寻求动机,提示在筛选治疗成瘾的药物时,要尽量减少对自然奖赏的影响,避免产生较大的副作用。

其他摘要

    That relapse still exists even after prolonged withdrawal is a difficult issue in the medical cure of drug addiction. Neuro-adaptation induced by prolonged exposure to addictive drugs is the neural mechanisms of both compulsive drug seeking and relapse.Neuro-adaptation caused by addictive drugs increases the individuals' response to drugs and on the other hand, it reduces the response to natural reward in withdrawn individuals.There must be common neural mechanisms between the co-existing phenomena, and there must also be unique neural mechanisms in the drugs.To reveal the neuro-adaptation arising in the process from random, controllable drug-use to uncontrollable compulsive drug seeking  is of great significance both theoretically and practically.Based on the above hypothesis, in order to reveal the function of alpha adrenergic receptor in compulsive drug-seeking motivation during the process  of  drug  addiction,  using  sensitization  of  morphine-induced psychomotor activity as behavioral model, through the method of behavioral pharmacology, the neural mechanisms of alpha  adrenergic  receptor's involvement in the process of addiction has been studied.The adjustment function caused by alpha receptors in medial prefrontal cortex and nucleus accumbens to morphine-induced psychomotor activity has been compared in tfie period of first use of drugs and in repetitive-use period. Furthermore, the effect on novelty seeking caused by alpha-receptors in relevant brain areas has also been compared.
Major results are as follow:
    1 After prolonged morphine exposure, rats' response to morphine-induced psychomotor activity is strengthened and response to novel object induced reward weakened.
    2 Injection of prazosin in medial prefrontal cortex will block morphine-induced psychomotor activity of naive rats,  however, it will not block hat of morphine-withdrawn rats, but it will block the novelty seeking behavior of morphine-withdrawn rats.
    3 Injection of clonidine in medial prefrontal cortex will block morphine-induced psychomotor effect of both naive rats and morphine-withdrawn rats, and will block the novelty seeking behavior of morphine-withdrawn rats.
    4 Injection of prazosin in nucleus accumbens will not affect the morphine-induced psychomotor effect of either naive rats or morphine-withdrawn rats, nor will it affect the novelty seeking behavior of morphine-withdrawn rats.
    5 Injection of clonidine in nucleus accumbens will block morphine-induced psychomotor  effect  of  naive  rats,  however,  it  will  not  block  that  of morphine-withdrawn rats, nor will it affect the novelty seeking behavior of morphine-withdrawn rats.
These results show:
    1 The weakening of the function of alpha1 receptors in medial prefrontal cortex and alpha2 receptors in nucleus accumbens caused by repetitive exposure to morphine is probably the cause of compulsive drug-seeking activity.
    2 Blocking alpha1 receptors in medial prefrontal cortex accelerates the loss of interest in nafiiral reward after mnrnhine withdrawal.
    3 Blocking alpha2 receptors in medial prefrontal cortex not only restrains drug-seeking motivation, but also blocks the individual's seeking motivation for novelty stimulus, which suggests that, while selecting medicine for curing addiction, it should be considered to reduce the influence on natural reward as much as possible and to avoid major side-effect.

学科领域心理学
页数64
语种中文
文献类型学位论文
条目标识符http://ir.psych.ac.cn/handle/311026/4574
专题中国科学院心理研究所回溯数据库(1956-2010)
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王冬梅. 去甲肾上腺素参与吗啡神经适应性改变的中枢机制[D]. 心理研究所. 中国科学院心理研究所,2007.
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