Effects of Compound 511 on BDNF-TrkB Signaling in the Mice Ventral Tegmental Area in Morphine-Induced Conditioned Place Preference
Effects of Compound 511 on BDNF-TrkB Signaling in the Mice Ventral Tegmental Area in Morphine-Induced Conditioned Place Preference
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化合物 511 对吗啡诱导的条件性位置偏好小鼠腹侧被盖区 BDNF-TrkB 信号传导的影响
DOI：
10.1007/s10571-020-00848-9
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发表时间：
2020-04
影响因子：
4
通讯作者：
Zhigang Lu
中科院分区：
文献类型：
--
作者：
Han Zhang;Qisheng Wang;Qinmei Sun;Fenfen Qin;Dengyun Nie;Qian Li;Yun Gu;Yongwei Jiang;Shengfeng Lu;Zhigang Lu
化合物511（511）是根据中国古代戒毒文献专门为阿片类药物成瘾治疗而开发的，其组合物在各种临床试验和动物实验中对药物成瘾的治疗效果深刻。511对吗啡奖赏特性和渴望反应的影响及其潜在机制尚不清楚。在这里，我们在小鼠中应用条件位置偏好（CPP）范式来测量吗啡在511处理下诱导的奖励效应。然后我们使用RNA测序策略来筛选其潜在机制。在本研究中，我们首先发现511可以降低CPP评分、运动活动、自我管理、跳跃行为、体重减轻、湿狗颤抖和刻板印象行为。然后对脑VTA区组织进行mRNA测序，以检测可能的机制。我们发现脑源性神经营养因子（BDNF）和原肌球蛋白相关激酶B （TrkB）在吗啡诱导的CPP中下调，而BDNF和TrkB的下降在511治疗后逆转。我们使用qRT-PCR和Western blot重新检测BDNF和TrkB水平，发现与mRNA测序结果相似。据报道，VTA内BDNF-TrkB信号通路参与成瘾的多个方面，包括奖励和动机，因此我们将重点关注BDNF-TrkB信号通路，研究吗啡成瘾小鼠511的抗成瘾机制。我们研究了BDNF-TrkB的下游通路和多巴胺能神经元的胞体大小。结果表明，511能提高吗啡诱导的CPP中PI3K和AKT的磷酸化水平，而这些磷酸化水平在吗啡诱导的CPP中是降低的。同时，511能降低吗啡诱导的CPP中增高的plc - γ - 1水平和ERK、S6K磷酸化水平。此外，511还使VTA多巴胺能神经元的胞体增大，而吗啡诱导的CPP则使其胞体减小。因此，我们的研究表明511可能介导VTA中的BDNF-TrkB信号通路以改善吗啡成瘾行为。
Compound 511 (511) is specially developed for opioid addiction treatment based on the Ancient Chinese drug rehabilitation literature, and its composition has profound effects in the treatment of drug addiction in various clinical trials and animal experiments. The effect of 511 on the rewarding properties of morphine and craving responses and its potential mechanisms remain unclear. Here, we have applied a conditioned place preference (CPP) paradigm in mice to measure morphine-induced rewarding effects under the treatment of 511. Then we used the RNA sequencing strategy to screen its potential mechanisms. In our research, firstly, we found 511 could decrease CPP score, locomotor activity, self-administration, jumping behavior, weight loss, wet-dog shakes, and stereotyped behavior. Then the brain VTA region tissues were performed mRNA sequencing to detect potential mechanisms. We found the brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) were downregulated in morphine-induced CPP, whereas the decreased BDNF and TrkB were reversed after 511 treatment. We retested the levels of BDNF and TrkB using qRT-PCR and Western blot and found the similar results to mRNA sequencing. It has been widely reported that BDNF-TrkB signaling in the VTA is involved in multiple facets of addiction, including reward and motivation, so we focused on the BDNF-TrkB signaling to investigate the anti-addiction mechanisms of 511 in morphine addiction mice. We studied the downstream pathway of BDNF-TrkB and the soma size of dopaminergic neurons. The results showed 511 could increase the phosphorylation levels of PI3K and AKT, which were decreased in morphine-induced CPP. Simultaneously, 511 could decrease the level of PLCγ1 and the phosphorylation levels of ERK and S6K, which were increased in morphine-induced CPP. In addition, 511 also enlarged the soma size of VTA dopaminergic neurons, which was reduced in morphine-induced CPP. Hence, our research indicated 511 maybe mediate the BDNF-TrkB signaling in VTA to improve morphine addiction behavior.
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一种用于寻找阿片类药物依赖性的新靶标和治疗化合物的计算策略。
影响因子：
3.7
作者：
Wu X;Xie S;Wang L;Fan P;Ge S;Xie XQ;Wu W
通讯作者：
Wu W
伏隔核中肿瘤坏死因子-α 的上调减弱了神经病理性疼痛模型中吗啡诱导的奖赏
影响因子：
3.1
作者：
Wu Ying;Na Xiaodong;Zang Ying;Cui Yu;Xin Wenjun;Pang Ruiping;Zhou Lijun;Wei Xuhong;Li Yongyong;Liu Xianguo
通讯作者：
Liu Xianguo
影响因子：
4.6
作者：
Yin ZY;Li L;Chu SS;Sun Q;Ma ZL;Gu XP
通讯作者：
Gu XP
DOI：
10.1523/jneurosci.12-02-00483.1992
发表时间：
1992-02
期刊：
--
影响因子：
--
作者：
S. Johnson;R. North
通讯作者：
S. Johnson;R. North
DOI：
--
发表时间：
--
期刊：
--
影响因子：
--
作者：
A. Tessitore;A. Giordano;R. De Micco;A. Russo;G. Tedeschi
通讯作者：
A. Tessitore;A. Giordano;R. De Micco;A. Russo;G. Tedeschi