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Brain-specific inhibition of mTORC1 eliminates side effects resulting from mTORC1 blockade in the periphery and reduces alcohol intake in mice. | LitMetric

AI Article Synopsis

  • Alcohol Use Disorder (AUD) is widespread, but effective treatment options are scarce, with mTORC1 being a key player in alcohol-related behaviors.
  • Current mTORC1 inhibitors can help treat AUD but lead to negative side effects when used long-term in the body.
  • Researchers developed a dual-drug approach using RapaLink-1 and RapaBlock, which effectively inhibited mTORC1 in targeted areas while minimizing side effects, reducing alcohol-seeking behaviors in mice.

Article Abstract

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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316332PMC
http://dx.doi.org/10.1038/s41467-021-24567-xDOI Listing

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