Department of Forensic Medicine, Shanxi Medical University, Taiyuan, 030001, PR China.
Department of Forensic Medicine, Shanxi Medical University, Taiyuan, 030001, PR China; Department of Hematology, The Second Hospital of Shanxi Medical University, Taiyuan, 030001, PR China.
Neurosci Lett. 2021 Jun 21;756:135984. doi: 10.1016/j.neulet.2021.135984. Epub 2021 May 21.
Levo-tetrahydropalmatine (L-THP) is the main active ingredient of Corydalis and Stephania and is widely used for its sedative, analgesic, and neuroleptic effects. Though L-THP is an antagonist of dopamine receptors and has been proven to be effective in treating drug addiction, its effect on fentanyl-induced reward learning still remains unclear. This experiment was designed to investigate the effects of L-THP on fentanyl-induced rewarding behavior through conditioned place preference (CPP) in mice. Western blot assays were used to dissect the accompanying changes in the phosphorylation of extracellular signal-regulated kinase (ERK) and cAMP response element binding protein (CREB) in related brain regions, including the hippocampus (Hip), caudate putamen (CPu), prefrontal cortex (PFC), and nucleus accumbens (NAc), which may mediate the effects of L-THP on fentanyl-induced CPP. The results revealed that fentanyl could induce CPP in mice at doses of 0.025 mg/kg, 0.05 mg/kg, 0.1 mg/kg, and 0.2 mg/kg, and L-THP could attenuate the acquisition of fentany-induced CPP at a dose of 10.0 mg/kg. The levels of p-ERK and p-CREB of the saline+fentanyl group (0.05 mg/kg) increased significantly in the Hip, NAc, and PFC compared to the saline+saline group. Furthermore, L-THP (10.0 mg/kg) co-administered with fentanyl during conditioning prevented the enhanced phosphorylation of ERK and CREB in the Hip, NAc, and PFC. Our research revealed that L-THP could suppress the rewarding properties of fentanyl-induced CPP, the inhibitory effect may be related to the suppression of ERK and CREB phosphorylation in the Hip, NAc, and PFC of mice. Thus, L-THP may have therapeutic potential for fentanyl addiction.
左四氢巴马汀（L-THP）是紫堇属和千金藤属的主要活性成分，具有镇静、镇痛和神经安定作用而被广泛应用。尽管 L-THP 是多巴胺受体的拮抗剂，并已被证明在治疗药物成瘾方面有效，但它对芬太尼诱导的奖赏学习的影响仍不清楚。本实验旨在通过小鼠条件性位置偏爱（CPP）来研究 L-THP 对芬太尼诱导的奖赏行为的影响。Western blot 分析用于剖析相关脑区（包括海马体（Hip）、尾壳核（CPu）、前额叶皮层（PFC）和伏隔核（NAc））中细胞外信号调节激酶（ERK）和 cAMP 反应元件结合蛋白（CREB）磷酸化的伴随变化，这些变化可能介导 L-THP 对芬太尼诱导的 CPP 的影响。结果表明，芬太尼在 0.025 mg/kg、0.05 mg/kg、0.1 mg/kg 和 0.2 mg/kg 剂量下可诱导小鼠 CPP，而 10.0 mg/kg 的 L-THP 可减弱芬太尼诱导的 CPP 的获得。与盐水+盐水组相比，盐水+芬太尼组（0.05 mg/kg）的 Hip、NAc 和 PFC 中 p-ERK 和 p-CREB 水平显著升高。此外，在条件作用期间，L-THP（10.0 mg/kg）与芬太尼共同给药可防止 Hip、NAc 和 PFC 中 ERK 和 CREB 的磷酸化增强。我们的研究表明，L-THP 可抑制芬太尼诱导的 CPP 的奖赏特性，这种抑制作用可能与抑制小鼠 Hip、NAc 和 PFC 中的 ERK 和 CREB 磷酸化有关。因此，L-THP 可能对芬太尼成瘾具有治疗潜力。
