Zeng Ze-Hao, Zhang Lin-Xuan, Li Meng-Qing, Wang Xue-Qin, Zou Guang-Jing, Yao Jia-Yu, Li Chang-Qi, Cui Yan-Hui, Li Fang
Department of Anatomy and Neurobiology, Xiangya School of Basic Medical Sciences, Central South University, Changsha, Hunan Province, 410013, China.
Department of Anatomy and Neurobiology, Xiangya School of Basic Medical Sciences, Central South University, Changsha, Hunan Province, 410013, China.
Neurochem Int. 2025 Sep;188:106017. doi: 10.1016/j.neuint.2025.106017. Epub 2025 Jul 3.
Drug addiction is characterized by compulsive drug use despite significant negative consequences. N-acetyltransferase 10 (NAT10), a member of the Gcn5-related N-acetyltransferases (GNAT) family, has been associated with depression, anxiety-like behaviors, and cognitive dysfunction. However, its role in addiction remains largely unknown. In the present study, we observed increased expression of NAT10 in the nucleus accumbens (NAc) of mice treated either singly or repeatedly with 2 mg/kg methamphetamine (METH). To assess the role of NAT10 in addiction-related behaviors, we established mouse models of conditioned place preference (CPP) and hyperlocomotion. Using intraperitoneal administration of 0.1 mg/kg SCH23390, a dopamine D1 receptor (D1R) antagonist, we found that D1R antagonism significantly suppressed the METH-induced upregulation of NAT10 in the NAc and inhibited hyperlocomotion. Furthermore, stereotaxic delivery of a short hairpin RNA (shRNA)-based adeno-associated virus (AAV-shNAT10) into the NAc reduced both METH-induced hyperlocomotion and CPP. AAV-shNAT10 also inhibited METH-induced upregulation of PSD95 and preserved dendritic morphology in the NAc. These findings suggest that NAT10 contributes to the development of METH-induced reward-related behaviors by modulating dendritic plasticity in the NAc.
药物成瘾的特征是尽管有严重的负面后果，仍强迫性使用药物。N-乙酰转移酶10（NAT10）是与Gcn5相关的N-乙酰转移酶（GNAT）家族的成员，与抑郁、焦虑样行为和认知功能障碍有关。然而，其在成瘾中的作用仍 largely未知。在本研究中，我们观察到单次或重复给予2mg/kg甲基苯丙胺（METH）处理的小鼠伏隔核（NAc）中NAT10的表达增加。为了评估NAT10在成瘾相关行为中的作用，我们建立了条件性位置偏爱（CPP）和运动亢进的小鼠模型。通过腹腔注射0.1mg/kg SCH23390（一种多巴胺D1受体（D1R）拮抗剂），我们发现D1R拮抗作用显著抑制了METH诱导的NAc中NAT10的上调，并抑制了运动亢进。此外，将基于短发夹RNA（shRNA）的腺相关病毒（AAV-shNAT10）立体定向注射到NAc中，可减少METH诱导的运动亢进和CPP。AAV-shNAT10还抑制了METH诱导的PSD95上调，并保留了NAc中的树突形态。这些发现表明，NAT10通过调节NAc中的树突可塑性，促进了METH诱导的奖赏相关行为的发展。
