Nat Commun: Brain-specific inhibition of mTORC1 helps treat alcohol addiction

Alcohol use disorder (AUD) is characterized by compulsive intake of alcohol regardless of adverse consequences
.

The existence of AUD is very common, affecting 10-15% of the population, and can cause significant medical, social and economic burdens

diagnosis

Unfortunately, there are limited drug treatment options for AUD
.

At present, only three drugs, naltrexone, acamprosate, and disulfiram, by the US Food and Drug Administration Bureau ( the FDA ) approved the drug for the treatment of AUD

At present, only three drugs, naltrexone, acamprosate, and disulfiram, by the US Food and Drug Administration Bureau ( the FDA ) approved the drug for the treatment of AUD present, only three drugs, naltrexone, acamprosate, and disulfiram Lun, the US food and Drug Administration Agency ( FDA ) approved drug for the treatment of AUD management FDA

Studies in rodents have shown that mTORC1 plays a key role in the mechanisms behind phenotypes such as heavy alcohol intake, addiction, and relapse
.

It is known that mTORC1 is a multi-protein complex, including serine/threonine protein kinase mTOR and adaptation proteins (including Raptor, Deptor and mLST8)

mTORC1 plays a key role in the mechanism behind phenotypes such as heavy alcohol intake, addiction and relapse mTORC1 plays a key role in the mechanism behind phenotypes such as heavy alcohol intake, addiction and relapse

Existing studies have shown that the excessive activation of mTORC1 is related to a variety of pathological conditions, such as insulin resistance and cancer
.

In the central nervous system (CNS), mTORC1 can be activated by neurotransmitters and neuromodulators, such as glutamate and BDNF

The mTORC1 inhibitors used clinically are promising therapeutic drugs for the treatment of AUD
.

However, long-term inhibition of mTORC1 in peripheral tissues can produce undesirable side effects, which limits their potential use in the treatment of AUD

In order to overcome these limitations, researchers recently designed a dual drug strategy, that is , to treat male mice with the mTORC1 inhibitor RapaLink-1 and a small molecule (RapaBlock) to protect the mTORC1 activity in peripheral tissues
.

Treat male mice with mTORC1 inhibitor RapaLink-1 and a small molecule (RapaBlock) to protect the activity of mTORC1 in peripheral tissues.
Treat male mice with mTORC1 inhibitor RapaLink-1 and a small molecule (RapaBlock) together.
To protect mTORC1 activity in peripheral tissues

Schematic diagram of the strategy

Schematic diagram of the strategy Schematic diagram of the strategy

The results of the study showed that although the administration of RapaLink-1 blocked the activation of mTORC1 in the liver, RapaBlock eliminated the inhibitory effect of Rapalink-1
.

RapaBlock can also prevent the adverse side effects of long-term inhibition of mTORC1

RapaBlock can also prevent the adverse side effects of long-term inhibition of mTORC1 RapaBlock can also prevent the adverse side effects of long-term inhibition of mTORC1

RapaBlock effectively prevents RapaLink-1-dependent weight loss, glucose intolerance and liver toxicity

RapaBlock effectively prevents RapaLink-1-dependent weight loss, glucose intolerance and hepatotoxicity RapaBlock effectively prevents RapaLink-1-dependent weight loss, glucose intolerance and hepatotoxicity prevention

Importantly, the co-administration of RapaLink-1 and RapaBlock inhibited the activation of alcohol-dependent mTORC1 in the transverse nucleus and weakened the need for and drinking of alcohol

Inhibits the activation of alcohol-dependent mTORC1 in the transverse nucleus, and weakens the demand and drinking of alcohol.

Original source:

Original source:

Yann Ehinger et al.

Yann Ehinger et al.

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