Chen He, Chen Limei, Yuan Zhirong, Yuan Jiajie, Li Yitong, Xu Yuesi, Wu Jieyi, Zhang Lu, Wang Guohua, Li Juan
Department of Histology and Embryology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Key Laboratory of Functional Proteomics of Guangdong Province, Key Laboratory of Mental Health of the Ministry of Education, School of Basic Medical Sciences, Pediatric Center of Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Front Cell Neurosci. 2022 Nov 3;16:979078. doi: 10.3389/fncel.2022.979078. eCollection 2022.
The nucleus accumbens (NAc) is involved in the expression of cocaine addictive phenotypes, including acquisition, extinction, and reinstatement. In the NAc, D1-medium spiny neurons (MSNs) encode cocaine reward, whereas D2-MSNs encode aversive responses in drug addiction. Glutamate receptor-interacting protein 1 (GRIP1) is known to be associated with cocaine addiction, but the role of GRIP1 in D1-MSNs and D2-MSNs of the NAc in cocaine acquisition and reinstatement remains unknown.
A conditioned place preference apparatus was used to establish cocaine acquisition, extinction, and reinstatement in mouse models. GRIP1 expression was evaluated using Western blotting. Furthermore, GRIP1-siRNA and GRIP1 overexpression lentivirus were used to interfere with GRIP1 in the NAc. After the behavioral test, green fluorescent protein immunostaining of brain slices was used to detect spine density.
GRIP1 expression decreased during cocaine acquisition and reinstatement. GRIP1-siRNA enhanced cocaine-induced CPP behavior in acquisition and reinstatement and regulated associated spine plasticity. Importantly, the decreased GRIP1 expression that mediated cocaine acquisition and reinstatement was mainly driven by the interference of the GRIP1-GluA2 interaction in D1-MSNs and could be blocked by the interference of the GRIP1-GluA2 interaction in D2-MSNs. Interference with the GRIP1-GluA2 interaction in D1- and D2-MSNs decreased spine density in D1- and D2-MSNs, respectively.
GRIP1 in D1- and D2-MSNs of the NAc differentially modulates cocaine acquisition and reinstatement. GRIP1 downregulation in D1-MSNs has a positive effect on cocaine acquisition and reinstatement, while GRIP1 downregulation in D2-MSNs has a negative effect. Additionally, GRIP1 downregulation in D1-MSNs plays a leading role in cocaine acquisition and reinstatement.
伏隔核（NAc）参与可卡因成瘾表型的表达，包括获取、消退和复吸。在伏隔核中，D1型中型多棘神经元（MSNs）编码可卡因奖赏，而D2型MSNs编码药物成瘾中的厌恶反应。已知谷氨酸受体相互作用蛋白1（GRIP1）与可卡因成瘾有关，但GRIP1在伏隔核的D1型MSNs和D2型MSNs中对可卡因获取和复吸的作用尚不清楚。
使用条件性位置偏爱装置在小鼠模型中建立可卡因获取、消退和复吸。采用蛋白质免疫印迹法评估GRIP1表达。此外，使用GRIP1-siRNA和GRIP1过表达慢病毒干扰伏隔核中的GRIP1。行为测试后，采用脑片绿色荧光蛋白免疫染色检测树突棘密度。
可卡因获取和复吸期间GRIP1表达降低。GRIP1-siRNA增强了可卡因诱导的获取和复吸中的条件性位置偏爱行为，并调节相关的树突棘可塑性。重要的是，介导可卡因获取和复吸的GRIP1表达降低主要由D1型MSNs中GRIP1-GluA2相互作用的干扰驱动，并且可以被D2型MSNs中GRIP1-GluA2相互作用的干扰阻断。干扰D1型和D2型MSNs中的GRIP1-GluA2相互作用分别降低了D1型和D2型MSNs中的树突棘密度。
伏隔核的D1型和D2型MSNs中的GRIP1对可卡因获取和复吸有不同的调节作用。D1型MSNs中GRIP1的下调对可卡因获取和复吸有积极作用，而D2型MSNs中GRIP1的下调有消极作用。此外，D1型MSNs中GRIP1的下调在可卡因获取和复吸中起主导作用。
