自噬诱导的背外侧纹状体区CP-AMPA受体功能异常在可卡因成瘾中的作用及机制研究

CP-AMPA receptors play an important roal in cocaine intake behavior in drug-exposed individuals. The dorsolateral striatum is a key brain region regulating the development of compulsive cocaine use. However, the exact relationship between the CP-AMPA receptors in the dorsolateral striatum and compulsive cocaine intake behavior has not yet been investigated. In our preliminary experiment, we found that the expression of GluA1, which was an important subunit of CP-AMPA receptors, was decreased in the dorsolateral striatum of rats with a history of extended access to cocaine. Overexpression of GluA1 in dorsolateral striatum increases cocaine intake in rats. Meanwhile, neither ubiquitination nor mRNA level of GluA1 in dorsal striatum was changed. Intrestingly, we found that autophagy was activated. To this end, we propose the hypothesis: chronic cocaine self-administration activates autophagy, which regulates the motivational properties of cocaine by degrading GluA1 selectively. To test this hypothesis, first of all, we will apply cocaine self-administration rat models and employ Western Blotting, Real Time PCR, Electrophysiological technique ，immunofluorescence, electron microscope, overexpression and shRNA technology to clear the role of autophagy in cocaine intake behavior. Secondly, by co-immunoprecipitation, shRNA and peptide interrupts technology to clarify the potential molecular mechanisms accounting for selective autophagy in degrading GluA1 invoved in autophagy receptor p62.Thus, this study will provide us new ideas that striatal autophagy pathway may be a new regulator that control the complex actions of cocaine in brain reward circuitries.

钙透性AMPA受体（CP-AMPA）与可卡因成瘾关系密切。背外侧纹状体是介导强迫性摄药行为的关键脑区，但该脑区中CP-AMPA受体在摄药行为中的作用机制未被阐明。我们的预实验结果发现可卡因成瘾大鼠背外侧纹状体中CP-AMPA受体的关键亚基GluA1表达减少。同时，GluA1的基因转录与泛素化降解水平没有变化，但该脑区的自噬通路被激活。为进一步探讨CP-AMPA受体在强迫性摄药行为中的作用机制，我们提出假说：可卡因激活自噬通路，后者选择性地吞噬并降解GluA1，从而调控摄药行为。为验证该假说：我们应用大鼠可卡因成瘾模型，免疫荧光，电镜，基因调控和电生理等技术，明确自噬激活介导摄药行为；另一方面，应用多肽干预，免疫共沉淀等技术，在细胞、离体脑片与整体动物水平探讨自噬激活后选择性降解GluA1的分子机制。本研究将从自噬性调节这一新视点来揭示强迫性摄药行为的发生机制，为药物成瘾的防治提供理论依据。

钙透性AMPA受体（CP-AMPA）与可卡因成瘾关系密切。背外侧纹状体是介导强迫性摄药行 为的关键脑区，但该脑区中CP-AMPA受体在摄药行为中的作用机制未被阐明。我们的研究发现可卡因成瘾大鼠背外侧纹状体中CP-AMPA受体的关键亚基GluA1表达减少。同时，GluA1 的基因转录与泛素化降解水平没有变化，但该脑区的自噬通路被激活。我们进一步探明CP-AMPA 受体在强迫性摄药行为中的作用机制，发现可卡因激活自噬通路，后者选择性地吞 噬并降解GluA1，从而调控摄药行为。本研究从自噬性调节这一新视点揭示了强迫性摄药行为的发生机制，为药物成瘾 的防治提供理论依据。