偏向激动中枢CCK系统在甲基苯丙胺成瘾及神经损伤防治中的应用研究

METH具有较强的成瘾性，长期滥用可导致行为、精神和认知功能异常。本课题组前期研究结果提示CCK-8具备潜力作为METH滥用防治药物进行开发。但是，由于CCK-8是CCK受体的非特异性激动剂，在发挥功能的同时也会产生副作用。近年研究发现，G蛋白偶联受体还存在偏向激动信号，如形成受体异源二聚体或与非G蛋白调控因子beta-arrestin直接作用，呈现更高的信号特异性和多样性，使得偏向激动配体的副作用比天然配体少得多。中枢CCK系统是否也存在偏向性信号途径并发挥特殊功能尚不明确。本项目旨在明确激动中枢CCK系统对METH成瘾及神经损伤过程的干预作用及其相关副作用，阐明中枢CCK系统是否存在受体异源二聚化和 beta-arrestin介导的非G蛋白偶联偏向性信号并发挥何种功能，以期为偏向激动中枢CCK系统应用于METH滥用防治提供理论依据。

METH is a strong addictive drug. Long-term abuse of METH can cause behavioral, psychological, and cognitive function disorders. Our preliminary studies suggested that CCK-8 had the potential to be developed as a METH-abuse prevention drug. However, we found that CCK-8 treatment had side effects while functioning, as it is a non-specific agonist of CCK receptor. Recent studies have revealed that G-protein-coupled receptors have biased-agonism signaling, such as forming receptor heterodimer or directly reacting with the non-G-protein regulatory factor beta-arrestin. The biased-agonism signaling presents higher signal specificity and diversity, so that the side effects of the biased agonism ligands are much smaller than natural ligands. However, it remains unclear whether the central nervous CCK system has biased-agonism signal pathway and play special functions. This project aims to clear the intervention effect and the related side effects of the central nervous CCK system agonism on METH-induced addiction and nerve damages. It will also be explored whether the receptor heterodimerization and beta-arrestin-mediated biased-agonism signaling play roles in the central nervous CCK system and what function it has. We are looking forward to providing theoretical basis for the application of the central nervous CCK system biased-agonism in METH-abuse prevention and treatment.