Role for mammalian target of rapamycin complex 1 signaling in neuroadaptations underlying alcohol-related disorders
Role for mammalian target of rapamycin complex 1 signaling in neuroadaptations underlying alcohol-related disorders
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DOI：
10.1073/pnas.1005554107
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发表时间：
2010-11-16
影响因子：
11.1
通讯作者：
Ron, Dorit
中科院分区：
文献类型：
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作者：
Neasta, Jeremie;Hamida, Sami Ben;Ron, Dorit
酒精成瘾是一种慢性复发性疾病，包括某些适应不良的学习和记忆。丝氨酸和苏氨酸激酶复合物，雷帕霉素复合物1（mTORC 1）的哺乳动物靶，已涉及突触可塑性，学习和记忆，通过控制蛋白质翻译。在这里，我们表明，管理的酒精和过量自愿消费的酒精诱导激活的mTORC1介导的信号通路在啮齿类动物的丘脑核（NAc）。我们进一步表明，蛋白质表达水平的GluR1和荷马，两个突触蛋白的翻译已被证明是由mTORC1调制，上调在NAC的啮齿类动物的历史，过量饮酒。此外，我们的研究结果表明，美国食品和药物管理局批准的mTORC1抑制剂雷帕霉素，降低了酒精诱导的运动敏感和位置偏好的表达，以及过量的酒精摄入和酒精滥用的临床前啮齿动物模型中的寻求。总之，我们的研究结果表明，NAc内的mTORC1是饮酒行为的分子机制的贡献者。此外，尽管酒精滥用对全世界的健康和社会经济产生了巨大影响，但对酒精滥用和成瘾的药物治疗仍然有限。因此，我们的数据提出了一种可能性，即靶向mTORC1信号级联是治疗酒精使用和滥用障碍的一种创新和有价值的策略。
Alcohol addiction is a chronically relapsing disorder that includes certain maladaptive learning and memory. The serine and threonine kinase complex, mammalian target of rapamycin complex 1 (mTORC1), has been implicated in synaptic plasticity, learning, and memory by controlling protein translation. Here we show that administration of alcohol and excessive voluntary consumption of alcohol induce the activation of the mTORC1-mediated signaling pathway in the nucleus accumbens (NAc) of rodents. We further show that the protein expression levels of GluR1 and Homer, two synaptic proteins whose translation has been shown to be modulated by mTORC1, are up-regulated in the NAc of rodents with a history of excessive alcohol consumption. In addition, our results document that the Food and Drug Administration-approved inhibitor of mTORC1, rapamycin, decreases expression of alcohol-induced locomotor sensitization and place preference, as well as excessive alcohol intake and seeking in preclinical rodent models of alcohol abuse. Together, our results suggest that mTORC1 within the NAc is a contributor to molecular mechanisms underlying alcohol-drinking behaviors. Furthermore, despite its massive health and socioeconomic impact worldwide, pharmacotherapies for alcohol abuse and addiction remain limited. Our data therefore put forward the possibility that targeting the mTORC1 signaling cascade is an innovative and valuable strategy for the treatment of alcohol use and abuse disorders.