CCK受体不同亚型及敏感度在吗啡依赖及其慢性神经损伤过程中的作用研究

It is very hard to stop abusing due to psychological addiction for drug abusers, which is an important reason for the increasing number of drug addicts. We found that CCK-8 played a regulative effect on morphine dependence and relapse, and possessed neuroprotective function as well. There are two subtypes of CCK receptor, which were recently termed type-1 and type-2. Because the sensitivity of subtypes of CCK receptor is different, distinct doses of CCK-8 played various roles in the process of morphine dependence and relapse. However, due to the lack of commercialization of high selectivity for specific ligands, and CCK1 and CCK2 receptors usually co-expressed in the same tissue or cell, their exact effect is not able to be determined. Therefore, the present study aims to explore the role of different CCK receptor subtype and sensitivity in process of morphine dependence and chronic neurological damage, and to build an experimental celluar model by liposomal transfection technology, in which CCK1 and CCK2 receptor were stably expressed alone or together. Furthermore, we propose to clear the effect of exogenous CCK-8, via CCK1 and CCK2 receptor, on morphine dependence and its central rewarding effect, learning and memory processes, as well as the change of DA, Glu and GABA neurotransmitter in related brain areas by utilizing behavioral observation and microdialysis in vivo, and provide systematic and reliable theoretical base for the application of CCK-8 in prevention and treatment of morphine dependence and relapse.

吸毒者"心瘾"难除，是吸毒人数不断增加的重要原因。我们研究发现CCK-8对吗啡依赖及复吸过程有显著的调节作用，且具有神经保护功能。CCK主要存在CCK1和CCK2受体亚型，因其敏感度不同，使不同剂量的CCK-8在吗啡依赖及复吸过程发挥着不同功能。但由于缺少商品化高选择性专一配体，且CCK1和CCK2受体常共存于同一组织或细胞中，使其各自究竟发挥什么作用无法确定。因此，本研究将通过脂质体转染技术建立CCK1或CCK2受体单独或共同稳定表达的细胞实验模型，以系统研究CCK受体不同亚型和敏感度对吗啡依赖及其慢性神经损伤的调控作用；并在整体水平采用行为学及微透析技术观察外源性CCK-8如何通过CCK1或CCK2受体参与吗啡依赖及其中枢奖赏效应、学习记忆过程的影响，并检测相关脑区DA、Glu、GABA等神经递质的变化，为CCK-8在吗啡依赖和复吸防治方面的实际应用提供系统、可靠的理论依据。

面对严峻的禁毒形势和庞大的毒品滥用群体，开发有效的戒毒药物具有深刻的现实意义和社会价值。我们发现八肽胆囊收缩素（CCK-8）对吗啡依赖过程具有显著的干预作用，但其具体机制尚不明确。本项目拟建立一种CCK1、CCK2受体与阿片受体共同稳定表达的细胞实验模型，为CCK-8 在吗啡成瘾方面的理论研究提供技术手段；考察不同剂量CCK-8对吗啡慢性处理的干预作用，进一步完善CCK-8作为戒毒药物的初步确证性研究；明确CCK受体不同亚型以及受体不同敏感状态对吗啡慢性处理是否具有不同的调控作用，揭示不同剂量CCK-8干预吗啡成瘾及慢性神经损伤过程与CCK受体作用模式的关系。经过4年的研究，上述研究任务均已完成，我们首先明确了CCK-8可以有效干预吗啡成瘾过程，抑制戒断后的焦虑样行为及慢性吗啡处理诱导的认知功能损伤；成功建立了一种CCK1、CCK2受体与阿片受体共同稳定表达的细胞实验模型，明确了外源性CCK-8在调控吗啡慢性处理的过程中CCK受体的不同亚型以及受体的不同敏感状态的作用。本项目首次揭示了CCK-8的在调控吗啡成瘾过程中的不同功能与CCK受体不同亚型的作用模式相关，完善了对外源性CCK-8 调控吗啡成瘾的药理学评价及其机制研究，为药物成瘾的防治提供了新的靶点，同时拓展了对CCK生物学功能的认识，具有重要的学术价值和理论意义。