Research press release


Nature Communications

Drug discovery: Two-drug strategy reduces alcohol intake in mice

有害な副作用なしにマウスのアルコール摂取量を減らす2剤併用療法について報告する論文が、Nature Communications に掲載される。この知見は、アルコール使用障害の治療戦略の開発に役立つ可能性がある。


今回の研究で、Dorit Ron、Yann Ehingerたちは、mTORC1阻害剤のRapaLink-1と小分子(RapaBlock)を雄マウスに投与する実験を行った。その結果、RapaLink-1を投与されたマウスの肝臓と脳においてmTORC1の活性が阻害されることが判明した。これに対して、RapaLink-1をRapaBlockと共に投与した場合には、脳内のmTORC1だけが阻害され、肝臓内のmTORC1は阻害されなかった。また、RapaBlockは、mTORC1の阻害に伴う肝毒性や糖代謝障害などの副作用を防ぐことも分かった。アルコールを大量に摂取したマウスに対してこれら2剤の併用療法を行ったところ、脳内のmTORC1活性が低下した。両剤を投与されたマウスでは、アルコール摂取量が減り、アルコール探索行動も減ったことが観察された。


A two-drug strategy that reduces alcohol intake in mice without toxic side effects, is reported in Nature Communications. The findings could potentially aid in the development of a treatment strategy for Alcohol Use Disorder.

Alcohol Use Disorder affects a large number of people, but effective medications to treat the condition are limited. Previous research has shown that alcohol consumption activates the enzyme mTORC1 in certain brain regions in rodents, which suggests it could be a potential target to treat Alcohol Use Disorder. However, mTORC1 has an important role in many organs outside the brain and blocking its activity can cause severe side effects, including low levels of blood platelets, liver toxicity, impairment of glucose metabolism and suppression of the immune system.

Dorit Ron, Yann Ehinger and colleagues administered the mTORC1 inhibitor, RapaLink-1, and a small molecule (RapaBlock) to male mice. They found that treatment of mice with RapaLink-1 inhibited mTORC1 activity in the liver and the brain. However, when it was administered with RapaBlock, mTORC1 was inhibited only in the brain but not in the liver. The authors also found that RapaBlock prevented side effects, including liver toxicity and impairment of glucose metabolism that are associated with inhibition of mTORC1. When mice that heavily consumed alcohol were treated with the two-drug strategy, mTORC1 activity in the brain was reduced. Mice that received both drugs consumed less alcohol and reduced alcohol-seeking behaviour was observed.

The authors suggest more research will be needed, but these findings indicate that a dual-drug strategy to avoid the toxic side effects of mTORC1 inhibition in the body could be used to develop a treatment for Alcohol Use Disorder.

doi: 10.1038/s41467-021-24567-x


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