Brain-specific inhibition of mTORC1 eliminates side effects resulting from mTORC1 blockade in the periphery and reduces alcohol intake in mice.
Brain-specific inhibition of mTORC1 eliminates side effects resulting from mTORC1 blockade in the periphery and reduces alcohol intake in mice.
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DOI：
10.1038/s41467-021-24567-x
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发表时间：
2021-07-27
影响因子：
16.6
通讯作者：
Ron D
中科院分区：
文献类型：
--
作者：
Ehinger Y;Zhang Z;Phamluong K;Soneja D;Shokat KM;Ron D
酒精使用障碍（AUD）影响了很大一部分人口。不幸的是，治疗这种疾病的有效药物有限。啮齿类动物的研究表明，mTORC1在诸如重度酒精摄入、习惯和复发等表型的机制中起着至关重要的作用。因此，临床上使用的mTORC1抑制剂是治疗AUD的有希望的治疗药物。然而，慢性抑制外周mTORC1会产生不良的副作用，这限制了它们治疗AUD的潜在用途。为了克服这些限制，我们设计了一种二元药物策略，将mTORC1抑制剂RapaLink-1与小分子（RapaBlock）一起治疗雄性小鼠，以保护外周的mTORC1活性。我们发现，RapaLink-1阻断了肝脏中mTORC1的激活，而RapaBlock则消除了RapaLink-1的抑制作用。RapaBlock还能预防慢性抑制mTORC1产生的不良副作用。重要的是，RapaLink-1和RapaBlock联合使用可抑制伏隔核中酒精依赖性mTORC1的激活，并减少酒精寻找和饮酒。长期使用mTORC1抑制剂在人类中产生不良的副作用，这限制了它们对中枢神经系统疾病治疗的价值。作者提出了一种保护外周mTORC1活性的二元药物策略，并展示了其在酒精使用障碍临床前模型中的潜在效用。
Alcohol Use Disorder (AUD) affects a large portion of the population. Unfortunately, efficacious medications to treat the disease are limited. Studies in rodents suggest that mTORC1 plays a crucial role in mechanisms underlying phenotypes such as heavy alcohol intake, habit, and relapse. Thus, mTORC1 inhibitors, which are used in the clinic, are promising therapeutic agents to treat AUD. However, chronic inhibition of mTORC1 in the periphery produces undesirable side effects, which limit their potential use for the treatment of AUD. To overcome these limitations, we designed a binary drug strategy in which male mice were treated with the mTORC1 inhibitor RapaLink-1 together with a small molecule (RapaBlock) to protect mTORC1 activity in the periphery. We show that whereas RapaLink-1 administration blocked mTORC1 activation in the liver, RapaBlock abolished the inhibitory action of Rapalink-1. RapaBlock also prevented the adverse side effects produced by chronic inhibition of mTORC1. Importantly, co-administration of RapaLink-1 and RapaBlock inhibited alcohol-dependent mTORC1 activation in the nucleus accumbens and attenuated alcohol seeking and drinking. Chronic use of mTORC1 inhibitors produces undesirable side effects in humans which limit their value for CNS disorders treatment. The authors present a binary drug strategy to protects mTORC1 activity in the periphery and show its potential utility in preclinical models of alcohol use disorder.
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影响因子：
7.7
作者：
Houde VP;Brûlé S;Festuccia WT;Blanchard PG;Bellmann K;Deshaies Y;Marette A
通讯作者：
Marette A
影响因子：
14.8
作者：
Leger, Marianne;Quiedeville, Anne;Freret, Thomas
通讯作者：
Freret, Thomas
影响因子：
5.4
作者：
Lamming DW
通讯作者：
Lamming DW
影响因子：
16.2
作者：
Laguesse S;Morisot N;Shin JH;Liu F;Adrover MF;Sakhai SA;Lopez MF;Phamluong K;Griffin WC 3rd;Becker HC;Bender KJ;Alvarez VA;Ron D
通讯作者：
Ron D
DOI：
10.1073/pnas.92.11.4947
发表时间：
1995-05-23
影响因子：
11.1
作者：
CHEN, J;ZHENG, XF;SCHREIBER, SL
通讯作者：
SCHREIBER, SL