CUL3和ARIH1介导的腺苷酸环化酶异源敏化在吗啡依赖发生中的作用研究

批准号:
82003737
项目类别:
青年科学基金项目
资助金额:
24.0 万元
负责人:
丁众
依托单位:
学科分类:
神经精神药物药理
结题年份:
2023
批准年份:
2020
项目状态:
已结题
项目参与者:
丁众
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中文摘要
腺苷酸环化酶(AC)负责催化ATP生成cAMP,其在病理状态下的适应性改变,如AC异源敏化参与了慢性吗啡暴露下cAMP信号通路的增强,进而导致药物依赖的发生。我们前期研究发现,CUL3和ARIH1是AC异源敏化发生的必要分子。有研究报道,CUL3发挥功能通常需要ARIH1的协助。我们进一步研究发现,MLN4924(Neddylation抑制剂,已被证实能阻断AC异源敏化)显著抑制了慢性吗啡暴露小鼠NAc内ARIH1与CUL3的结合以及AC异源敏化,且抑制了小鼠吗啡依赖的发生(包括躯体和精神),但CUL3和ARIH1在吗啡依赖发生中的作用还不清楚。因此,本项目拟应用细胞和动物模型验证以下科学假说:在慢性吗啡暴露下,小鼠NAc内ARIH1与CUL3的结合增多,诱导了AC异源敏化,进而导致了吗啡依赖的发生。该研究将有助于阐明AC异源敏化参与药物依赖发生的机制,为药物依赖的防治提供新思路和新靶点。
英文摘要
One of the best-established molecular mechanisms of addiction is upregulation of the cAMP second messenger pathway. Heterologous sensitization of adenylate cyclase (AC), is characterized by an enhanced responsiveness to drug stimulated cAMP accumulation following persistent activation of Gαi/o-coupled receptors, and this phenomenon was originally proposed to explain tolerance and withdrawal following chronic opiate administration. We recently identified CUL3 and ARIH1 as essential molecules for the development of AC sensitization. In addition, we reported that MLN4924, the neddylation pathway inhibitor, blocked heterologous sensitization of many AC isoforms including AC1, AC2, AC5, and AC6. As one recent study reported that CUL3 and ARIH1 work in unison to regulate substrate ubiquitylation, we later examined the activity of MLN4924 in animal models of morphine dependence. Our results showed that MLN4924 blocked the interaction between CUL3 and ARIH1 as well as the AC sensitization in NAc of mice bearing chronic morphine administration. Furthermore, MLN4924 also attenuated both physical and psychological dependence of the mice to morphine. However, the role of CUL3 and ARIH1 played in morphine dependence hasn’t been defined yet. Therefore, in both cellular and animal models, we will examine our hypothesis that chronic morphine administration induces AC sensitization in mice NAc through enhancing the interaction between ARIH1 and CUL3, which later causes the mice dependence. Executing this project may help us gain more insights in understanding the relationship between heterologous sensitization of AC and drug dependence. Eventually, we may benefit from the potential findings in this project with a novel approach or target in dealing with drug dependence.
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