Gao Yang, Peng Shuxian, Wen Quan, Zheng Chunming, Lin Jue, Tan Yalun, Ma Yan, Luo Yixiao, Xue Yanxue, Wu Ping, Ding Zengbo, Lu Lin, Li Yanqin
Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University),Ministry of Education and Wuhan University School of Pharmaceutical Sciences,Wuhan, Hubei,China.
National Institute on Drug Dependence,Peking University,Beijing,China.
Int J Neuropsychopharmacol. 2014 Nov;17(11):1881-94. doi: 10.1017/S1461145714000650. Epub 2014 Jun 11.
Repeated exposure to nicotine increases psychomotor activity. Long-lasting neural plasticity changes that contribute to the nicotine-induced development of locomotor sensitization have been identified. The mammalian target of rapamycin complex 1 (mTORC1) signalling pathway is involved in regulating the neuroplasticity of the central nervous system. In this study, we examined the role of mTORC1 in the amygdala in nicotine-induced locomotor sensitization. Rapamycin, an inhibitor of mTORC1, was infused into the basolateral amygdala (BLA) and central amygdala (CeA) or systemically administered to investigate the role of the mTORC1 in the development and expression of nicotine-induced locomotor sensitization. We found that locomotor activity progressively increased during the initiation of nicotine-induced locomotor sensitization and the expression of nicotine sensitization was induced by nicotine challenge injection (0.35 mg/kg s.c.) after five days of withdrawal. The initiation of nicotine-induced locomotor sensitization was accompanied by the increased phosphorylated level of mTORC1 downstream target proteins including p-p70s6k and p-4EBP in the BLA, but not CeA. Intra-BLA infusion or systemic administration of rapamycin blocked locomotor activity. Increased p-p70s6k and p-4EBP were also observed in the expression of nicotine sensitization, which was demonstrated to be inhibited by systemic rapamycin administration. Our findings indicated that mTORC1 activity in the BLA, but not the CeA, mediated the initiation and expression of nicotine-induced locomotor sensitization, and may become a potential target for the treatment of nicotine addiction.
反复接触尼古丁会增加精神运动活性。已经确定了有助于尼古丁诱导的运动敏化发展的持久神经可塑性变化。雷帕霉素靶蛋白复合物1（mTORC1）信号通路参与调节中枢神经系统的神经可塑性。在本研究中，我们研究了杏仁核中mTORC1在尼古丁诱导的运动敏化中的作用。将mTORC1抑制剂雷帕霉素注入基底外侧杏仁核（BLA）和中央杏仁核（CeA），或进行全身给药，以研究mTORC1在尼古丁诱导的运动敏化的发展和表达中的作用。我们发现，在尼古丁诱导的运动敏化开始期间，运动活性逐渐增加，并且在戒断五天后，尼古丁激发注射（0.35mg/kg皮下注射）诱导了尼古丁敏化的表达。尼古丁诱导的运动敏化开始伴随着BLA中mTORC1下游靶蛋白（包括p-p70s6k和p-4EBP）磷酸化水平的增加，但CeA中没有。向BLA内注入或全身给予雷帕霉素可阻断运动活性。在尼古丁敏化的表达中也观察到p-p70s6k和p-4EBP增加，这被证明可被全身给予雷帕霉素所抑制。我们的研究结果表明，BLA而非CeA中的mTORC1活性介导了尼古丁诱导的运动敏化的起始和表达，并且可能成为治疗尼古丁成瘾的潜在靶点。
