Noribogaine, but not 18-MC, exhibits similar actions as ibogaine on GDNF expression and ethanol self-administration
Noribogaine, but not 18-MC, exhibits similar actions as ibogaine on GDNF expression and ethanol self-administration
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DOI：
10.1111/j.1369-1600.2010.00251.x
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发表时间：
2010-10-01
影响因子：
3.4
通讯作者：
Ron, Dorit
中科院分区：
文献类型：
--
作者：
Carnicella, Sebastien;He, Dao-Yao;Ron, Dorit
伊博格碱是一种天然存在的生物碱，据报道，在人类和啮齿动物模型中，伊博格碱可以减少与滥用药物和酒精暴露相关的各种不良表型。不幸的是，由于严重的副作用，伊博加因不能用作治疗成瘾的药物。之前，我们报道了伊波加因减少自我给药和复发的理想作用，通过上调中脑腹侧被盖区（VTA）的胶质细胞系来源的神经营养因子（GDNF）的表达，以及随之而来的GDNF通路的激活来介导。伊博格碱代谢物去甲博格碱和伊博格碱的合成衍生物18-甲氧基冠状苯胺（18-MC）在啮齿类动物模型中具有与伊博格碱相似的抗成瘾特性，但没有伊博格碱的一些不良副作用。在这里，我们确定去甲博格碱和/或18-MC是否像伊博格碱一样增加GDNF的表达，以及它们减少酒精消耗的作用部位是否在上动脉区。我们使用SH-SY5Y细胞作为细胞培养模型，发现去甲博格碱与伊博格碱一样，诱导GDNF mRNA水平的显著增加，而不是18-MC。接下来，我们测试了VTA内输注去甲bogaine和18-MC对大鼠操作性酒精自我给药的影响，发现VTA内输注去甲bogaine而不是18-MC降低了对酒精的反应。总之，我们的研究结果表明，去甲烟碱和18-MC具有不同的作用机制和作用部位。
Ibogaine is a naturally occurring alkaloid that has been reported to decrease various adverse phenotypes associated with exposure to drugs of abuse and alcohol in human and rodent models. Unfortunately, ibogaine cannot be used as a medication to treat addiction because of severe side effects. Previously, we reported that the desirable actions of ibogaine to reduce self-administration of, and relapse to, alcohol consumption are mediated via the upregulation of the expression of the glial cell line-derived neurotrophic factor (GDNF) in the midbrain ventral tegmental area (VTA), and the consequent activation of the GDNF pathway. The ibogaine metabolite, noribogaine, and a synthetic derivative of ibogaine, 18-Methoxycoronaridine (18-MC), possess a similar anti-addictive profile as ibogaine in rodent models, but without some of its adverse side effects. Here, we determined whether noribogaine and/or 18-MC, like ibogaine, increase GDNF expression, and whether their site of action to reduce alcohol consumption is the VTA. We used SH-SY5Y cells as a cell culture model and found that noribogaine, like ibogaine, but not 18-MC, induces a robust increase in GDNF mRNA levels. Next, we tested the effect of intra-VTA infusion of noribogaine and 18-MC on rat operant alcohol self-administration and found that noribogaine, but not 18-MC, in the VTA decreases responding for alcohol. Together, our results suggest that noribogaine and 18-MC have different mechanisms and sites of action.