AKT signaling pathway in the nucleus accumbens mediates excessive alcohol drinking behaviors.
AKT signaling pathway in the nucleus accumbens mediates excessive alcohol drinking behaviors.
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DOI：
10.1016/j.biopsych.2011.03.019
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发表时间：
2011-09-15
影响因子：
10.6
通讯作者：
Ron, Dorit
中科院分区：
文献类型：
--
作者：
Neasta, Jeremie;Ben Hamida, Sami;Yowell, Quinn V.;Carnicella, Sebastien;Ron, Dorit
神经核内的神经适应（NAc）已被牵连的分子机制的发展和/或维持酒精滥用障碍。我们最近报道了啮齿类动物NAc中雷帕霉素复合物1（mTORC 1）信号通路的激活，在暴露于酒精后，有助于饮酒行为。激酶AKT是mTORC 1通路的主要上游激活剂。因此，我们假设，激活AKT在NAc响应酒精暴露中起着重要作用的机制，过度饮酒的基础。使用蛋白质印迹分析来评估酶的磷酸化水平。通过腹膜内（i. p.）给予2 g/kg酒精，实现小鼠急性暴露于酒精。两瓶选择和操作性自我管理程序被用来评估大鼠的饮酒行为。我们发现，急性全身给药的酒精和反复循环的过度自愿消费的酒精和戒断导致激活的AKT信号在NAC的啮齿动物。重要的是，我们表明，抑制AKT，或其上游激活剂，磷脂酰肌醇-3-激酶（PI 3 K），在大鼠的NAc减弱酗酒以及酒精，但不蔗糖操作性自我管理。我们的研究结果表明，激活AKT通路在NAc响应酒精暴露是一个重要的贡献者的分子机制饮酒行为。因此，AKT信号通路抑制剂是用于治疗酒精使用和滥用障碍的药物开发的潜在候选物。
Neuroadaptations within the nucleus accumbens (NAc) have been implicated in molecular mechanisms underlying the development and/or maintenance of alcohol abuse disorders. We recently reported that the activation of mammalian target of rapamycin complex 1 (mTORC1) signaling pathway in the NAc of rodents, following exposure to alcohol, contributes to alcohol drinking behaviors. The kinase AKT, is the main upstream activator of the mTORC1 pathway. We therefore hypothesized that the activation of AKT in the NAc in response to alcohol exposure plays an important role in mechanisms that underlie excessive alcohol consumption. Western blot analysis was used to assess the phosphorylation levels of enzymes. Acute exposure of mice to alcohol was achieved by the administration of 2 g/kg alcohol intraperitoneally, (i.p.). Two-bottle choice and operant self-administration procedures were used to assess drinking behaviors in rats. We found that acute systemic administration of alcohol and recurring cycles of excessive voluntary consumption of alcohol and withdrawal result in the activation of AKT signaling in the NAc of rodents. Importantly, we show that inhibition of AKT, or its upstream activator, phosphatidylinositol-3-kinase (PI3K), within the NAc of rats attenuates binge drinking as well as alcohol but not sucrose operant self-administration. Our results suggest that the activation of the AKT pathway in the NAc in response to alcohol exposure is an important contributor to the molecular mechanisms underlying alcohol-drinking behaviors. AKT signaling pathway inhibitors are therefore potential candidates for drug development for the treatment of alcohol use and abuse disorders.
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影响因子：
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作者：
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DOI：
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