Qi Yize, Fan Shuyuan, Sun Yu, Shi Hanqing, Li Hailing, Xiao Gang, Shen Qingfeng
Institute for Stem Cell and Neural Regeneration and Key Laboratory of Cardiovascular &Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu, China.
Department of Substance Dependence, The Affiliated Xuzhou Eastern Hospital of Xuzhou Medical University, Xuzhou Eastern People's Hospital, Xuzhou, China.
CNS Neurosci Ther. 2025 Aug;31(8):e70588. doi: 10.1111/cns.70588.
Compulsive relapse (reinstatement) behavior of methamphetamine underlies the difficulty of withdrawal and is associated with abnormal BDNF-mediated synaptic plasticity. However, how to intervene in this aberrant synaptic plasticity to prevent its reinstatement behavior in mice has not fully been studied.
The CPP was used to establish a model of methamphetamine-induced reinstatement behavior in C57BL/6 mice. Intraperitoneal injections of TEN were administered during the remission phase after the successful establishment of the CPP model to investigate the therapeutic effects on reinstatement. Immunofluorescence experiments were used to detect c-fos expression in hippocampal CA1 neurons. Electrophysiological methods were used to determine glutamatergic transmission in hippocampal CA1 neural circuits. Western blotting was used to detect BDNF/TrKB and PSD-95 protein expressions. Molecular docking was used to predict TEN molecule-protein binding.
Compared with control mice, METH-treated mice presented increased CPP scores during the reinstatement phase, whereas, compared to METH-treated mice, TEN-treated mice presented significantly lower CPP scores. Immunofluorescence experiments indicated that TEN was able to inhibit the METH-induced increase in c-fos content. In addition, we found that TEN alleviates the METH-triggered increase in glutamatergic transmission in mouse hippocampal CA1 neurons. Importantly, molecular docking studies demonstrated that TEN binds with BDNF, which may be important targets for its biological function. We also demonstrated that interfering with BDNF inhibits the therapeutic effect of TEN on the reinstatement of METH addiction.
Our findings suggest that TEN treats METH-induced reinstatement behavior by binding to BDNF, which may provide a novel target for treating relapse in patients addicted to METH.
甲基苯丙胺的强迫性复发（复吸）行为是戒毒困难的根源，且与脑源性神经营养因子（BDNF）介导的异常突触可塑性有关。然而，如何干预这种异常的突触可塑性以预防小鼠的复吸行为尚未得到充分研究。
采用条件性位置偏爱（CPP）法在C57BL/6小鼠中建立甲基苯丙胺诱导的复吸行为模型。在CPP模型成功建立后的缓解期腹腔注射TEN，以研究其对复吸的治疗效果。采用免疫荧光实验检测海马CA1神经元中c-fos的表达。用电生理方法测定海马CA1神经回路中的谷氨酸能传递。采用蛋白质免疫印迹法检测BDNF/TrKB和PSD-95蛋白表达。用分子对接预测TEN分子与蛋白的结合。
与对照小鼠相比，甲基苯丙胺处理的小鼠在复吸期CPP得分增加，而与甲基苯丙胺处理的小鼠相比，TEN处理的小鼠CPP得分显著降低。免疫荧光实验表明，TEN能够抑制甲基苯丙胺诱导的c-fos含量增加。此外，我们发现TEN减轻了甲基苯丙胺引发的小鼠海马CA1神经元谷氨酸能传递增加。重要的是，分子对接研究表明，TEN与BDNF结合，这可能是其生物学功能的重要靶点。我们还证明，干扰BDNF会抑制TEN对甲基苯丙胺成瘾复吸的治疗效果。
我们的研究结果表明，TEN通过与BDNF结合来治疗甲基苯丙胺诱导的复吸行为，这可能为治疗甲基苯丙胺成瘾患者的复发提供一个新的靶点。
