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吗啡诱发的强迫性觅药动机及其与中脑神经元活性改变的关系研究
其他题名Morphine induced compulsive drug-seeking behavior and its relationship with the activity of midbrain neurons
彭永华
学位类型硕士
导师郑希耕
2010-05
学位授予单位中国科学院研究生院
学位授予地点北京
学位专业心理学
关键词吗啡 强迫性用药 免疫组化 酪氨酸羟化酶 Fos蛋白
摘要美国精神疾病诊断手册(第四版)认为强迫性用药行为是药物成瘾最重要的诊断标准。以往研究提示累加大剂量用药前处理的大鼠能够表现出强迫性觅药和用药行为特征,而觅药动机不受用药环境限制是强迫性觅药用药的行为重要标准之一。有研究提出只有当动物的觅药用药行为不受用药环境的限制时才能说是形成了药物成瘾,而且以往研究发现强迫性觅药用药行为伴随有中脑多巴胺通路尤其是黒质-纹状体多巴胺通路神经可塑性改变。 本研究采用累加大剂量和固定小剂量吗啡前处理,以戒断后大鼠行为敏感化表达是否受用药环境限制为强迫性觅药指标,从行为层面上明确不同前处理方式下大鼠是否可形成具有强迫性觅药或非强迫性觅药行为特征。在神经机制层面上采用双重标记免疫组化技术检测大鼠中脑腹侧被盖区(Ventral tegmental area, VTA)与黑质(Substantia nigra, SN)脑区内神经元活动,考察具有吗啡强迫性觅药行为特征的大鼠中脑神经元活性的改变。酪氨酸羟化酶(Tyrosine hydroxylase, TH)是脑内多巴胺合成的限速酶,分布于细胞浆和神经元突触,通常用于标记特定脑区的多巴胺能神经元;而细胞核内Fos蛋白的表达是神经元活动的标志。通过对TH和Fos蛋白双重标记免疫组化手段能够检测中脑多巴胺能神经元和非多巴胺能神经元的活动情况。 本研究发现: (1) 累加大剂量吗啡长期用药大鼠行为敏感化的表达不受用药环境的限制,不论是在新颖环境还是在吗啡用药非匹配(unpair)环境中,吗啡点燃后大鼠仍然有行为敏感化的表达。 (2) 固定小剂量吗啡长期用药大鼠行为敏感化的表达受用药环境的调控,大鼠只在用药匹配环境中点燃有行为敏感化的表达,而在非用药环境中点燃大鼠没有行为敏感化的表达。 (3) 免疫组化结果显示累加大剂量吗啡前处理大鼠戒断点燃后中脑多巴胺能神经元的活性没有显著改变,而黒质网状部(Substantia nigra pars reticulate, SNr)外侧部(Lateral)神经元Fos蛋白表达有显著增高。 总之,累加大剂量吗啡长期用药训练动物戒断后药物点燃能具有非情境依赖的行为敏感化表达,该用药模式训练的动物具有强迫性觅药行为特征,而且SNr外侧部神经元活性的改变可能参与强迫性觅药用药。
其他摘要According to the United State Diagnostic and Statistical Manual Mental Disorders DSM-IV, compulsive drug-taking behavior is one of the most important diagnostic criterias in drug addiction. Previous studies suggest that the rats received escalated high-dose drug pretreatment perform compulsive drug-taking behavior, which is measured by abnormally enhanced drug-seeking motivation, continued drug seeking and taking despite adverse consequences, as well as compulsive drug-seeking motivation. Continued drug-seeking behavior even when the drug is known to be unavailable is one of the most important behavioral indicators of compulsive drug-seeking motivation. One could become drug-addictive when the drug-seeking motivation is no longer limited by the drug-paired environment. And compulsive drug-taking behavior is accompanied by the neuroplasticity change of mesolimbic dopamine pathway and nigro-striatal pathway. The present study would probe (1) whether rats pretreated with escalati high-dose or fixed low-dose morphine could express non-context-specific behavioral sensitization when exposed to morphine challenge after 1-week abstinence period; (2) By double labeling immunohistochemistry of Tyrosine hydroxylase (TH) and Fos protein, we disclose the plasticity of neuronal activity in ventral tegmental area and substantia nigra of rats response to morphine challenge after pretreated with morphine or saline. TH is limiting enzyme in dopamine synthesis which is distributed in the cytoplasm and neuronal synapses. It is usually used to label dopaminergic neurons in specific brain regions. Fos protein is a sign of neuronal activity which expresses in the nucleus. Double labeling immunohistochemistry of TH and Fos protein can detect the activity of dopaminergic and nondopaminergic neurons in ventral tegmental area and substantia nigra which may underline the neural mechanism of drug addiction. The main findings are described as bellows: (1) After pretreated by escalated high-dose morphine, rats could express behavioral sensitization without limitation of drug-paired environment. The sensitized behavior could be express in a novelty environment and could not be inhibited by the distinct morphine-unpaired environment. (2) If pretreated by fixed low-dose morphine, rats could just express the behavioral sensitization in morphine-paired environment and the sensitized behavior would be inhibited in the distinct morphine-unpaired environment. (3) The results of immunohistochemistry showed that the activity of dopaminergic neurons in midbrain hadn’t significant change in all groups after morphine challenge, while Fos protein expression in the lateral substantia nigra pars reticulate is significantly higher in the escalated high-dose morphine pretreated rats. In conclusion, pretreatment with escalated high-dose morphine could make rats become compulsive drug-seeking. And the neuroplasticity change of the lateral substantia nigra pars reticulate and it’s neural pathway may involved in the neural mechanisms in compulsive drug-seeking.
学科领域医学心理学
语种中文
文献类型学位论文
条目标识符http://ir.psych.ac.cn/handle/311026/20323
专题健康与遗传心理学研究室
作者单位中国科学院心理研究所
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彭永华. 吗啡诱发的强迫性觅药动机及其与中脑神经元活性改变的关系研究[D]. 北京. 中国科学院研究生院,2010.
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