Shandong University of Traditional Chinese Medicine, First Clinical Medical College, Jinan, China.
Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China.
Aging (Albany NY). 2023 Mar 21;15(6):2046-2065. doi: 10.18632/aging.204589.
The identity of the mechanism by which the Baixiangdan capsule (BXD) and the Shuyu capsule (SY) control anger-out (AO) and anger-in (AI) in rodents is unclear. The current study clarified the intervention role of BXD and SY on AO and AI male rats. We further explored the differences between BXD and SY in the treatment of AO and AI rats. Social isolation combined with the resident-intruder paradigm was used to establish the anger-out and AI rats models. On this basis, GABA content in the dorsal raphe nucleus (DRN) and serotonin (5-HT) contents in these brain regions were detected using ELISA after various time courses (0, 1, 3, 5, and 7 days) treated with BXD and SY. Co-expression of 5-HT and GB1 in the DRN was detected. GB1-specific agonist baclofen and GB1-specific inhibitor CGP35348 were injected into the DRN. Changes in 5-HT levels in these brain regions were then detected. After treatment, rats in the BXD group exhibited lower aggressive behavior scores, longer latencies of aggression, lower total distances in the open field test, and a higher sucrose preference coefficient. Meanwhile, rats in the SY group exhibited higher aggressive behavior scores, shorter latencies of aggression, higher total distances in the open field test, and higher sucrose preference coefficients. With increasing medication duration, 5-HT levels in these brain regions were increased gradually, whereas GABA levels in the DRN were decreased gradually, and all recovered to normal levels by the 7th day. A large number of 5-HT-positive cells could be found in the immunofluorescence section in the DRN containing GABABR1 (GB1)-positive cells, indicating that 5-HT neurons in the DRN co-expressed with GB1. Furthermore, after the drug intervention, the 5-HT level in the DRN was elevated to a normal level, and the GB1 level in the DRN was decreased to a normal level. After the microinjection of baclofen into the DRN, the 5-HT contents in these brain regions were decreased. By contrast, the 5-HT contents were increased after injection with CGP35348. BXD and SY could effectively improve the abnormal behavior changes of AO and AI rats, and the optimal duration of action was 7 days. The improvement way is as follows: Decreased abnormal increase of GABA and GB1 in the DRN further mediated synaptic inhibition and increased 5-HT level in the DRN, leading to increased 5-HT levels in the PFC, hypothalamus, and hippocampus. Therefore, GB1-mediated GABA in the DRN could regulate 5-HT levels in these brain regions, which may be one of the ways by which BXD and SY treat AO and AI, respectively.
白芍丹胶囊（BXD）和舒郁胶囊（SY）控制啮齿动物愤怒发作（AO）和愤怒内投（AI）的机制尚不清楚。本研究阐明了 BXD 和 SY 对 AO 和 AI 雄性大鼠的干预作用。我们进一步探讨了 BXD 和 SY 在治疗 AO 和 AI 大鼠方面的差异。采用社会隔离结合居民-入侵者范式建立愤怒发作和 AI 大鼠模型。在此基础上，采用 ELISA 法检测 BXD 和 SY 处理后不同时间（0、1、3、5、7 天）大鼠背侧中缝核（DRN）中 GABA 含量和这些脑区 5-羟色胺（5-HT）含量。检测 DRN 中 5-HT 与 GB1 的共表达。将 GB1 特异性激动剂巴氯芬和 GB1 特异性抑制剂 CGP35348 注入 DRN。然后检测这些脑区 5-HT 水平的变化。治疗后，BXD 组大鼠的攻击行为评分较低，攻击潜伏期较长，旷场试验总距离较高，蔗糖偏好系数较高。同时，SY 组大鼠的攻击行为评分较高，攻击潜伏期较短，旷场试验总距离较高，蔗糖偏好系数较高。随着用药时间的延长，这些脑区的 5-HT 水平逐渐升高，而 DRN 中的 GABA 水平逐渐降低，第 7 天恢复正常水平。在 DRN 的免疫荧光切片中可以发现大量 5-HT 阳性细胞含有 GABABR1（GB1）阳性细胞，表明 DRN 中的 5-HT 神经元与 GB1 共表达。此外，药物干预后，DRN 中的 5-HT 水平升高至正常水平，DRN 中的 GB1 水平降低至正常水平。将巴氯芬注入 DRN 后，这些脑区的 5-HT 含量降低。相反，注射 CGP35348 后 5-HT 含量增加。BXD 和 SY 能有效改善 AO 和 AI 大鼠的异常行为变化，最佳作用时间为 7 天。改善方式如下：降低 DRN 中异常增加的 GABA 和 GB1，进一步介导突触抑制，增加 DRN 中的 5-HT 水平，导致 PFC、下丘脑和海马中的 5-HT 水平升高。因此，DRN 中由 GB1 介导的 GABA 可调节这些脑区的 5-HT 水平，这可能是 BXD 和 SY 分别治疗 AO 和 AI 的途径之一。
