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Brain-Specific Inhibition of mTORC1 by a Dual Drug Strategy: A Novel Approach for the Treatment of Alcohol Use Disorder

Yann Ehinger, Ziyang Zhang, Khanhky Phamluong, Drishti Soneja, View ORCID ProfileKevan M. Shokat, Dorit Ron
doi: https://doi.org/10.1101/2020.10.12.336701
Yann Ehinger
1Department of Neurology, University of California San Francisco
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Ziyang Zhang
2Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute, University of California, San Francisco, California
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Khanhky Phamluong
1Department of Neurology, University of California San Francisco
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Drishti Soneja
1Department of Neurology, University of California San Francisco
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Kevan M. Shokat
2Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute, University of California, San Francisco, California
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  • ORCID record for Kevan M. Shokat
Dorit Ron
1Department of Neurology, University of California San Francisco
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  • For correspondence: dorit.ron@ucsf.edu
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Abstract

Alcohol Use Disorder (AUD) is a devastating psychiatric disorder affecting a large portion of the population. Unfortunately, efficacious medications to treat the disease are limited and thus AUD represents an area of unmet medical need. mTORC1 plays a crucial role in neuroadaptations underlying alcohol use. mTORC1 also contributes to alcohol craving, habit, and relapse. Thus, mTORC1 inhibitors are promising therapeutic agents to treat AUD. However, chronic inhibition of mTORC1 in the periphery produces undesirable side effects in humans, which limit their potential clinical use for the treatment of AUD. To overcome these limitations, we utilized a binary drug strategy in which mice were co-administered the mTORC1 inhibitor RapaLink-1 together with a novel small molecule (RapaBlock) to protect mTORC1 activity in the periphery. We show that the dual administration of RapaLink-1 with RapaBlock, abolishes RapaLink-1-dependent mTORC1 inhibition in the liver and blocks adverse side effects detected in humans including body weight loss, glucose intolerance and liver toxicity. Importantly, we show that co-administration of RapaLink-1 and RapaBlock inhibits alcohol-dependent mTORC1 activation in the Nucleus Accumbens and robustly moderates the level of alcohol use. Our data present a novel approach that could be used to treat individuals suffering from AUD.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted October 12, 2020.
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Brain-Specific Inhibition of mTORC1 by a Dual Drug Strategy: A Novel Approach for the Treatment of Alcohol Use Disorder
Yann Ehinger, Ziyang Zhang, Khanhky Phamluong, Drishti Soneja, Kevan M. Shokat, Dorit Ron
bioRxiv 2020.10.12.336701; doi: https://doi.org/10.1101/2020.10.12.336701
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Brain-Specific Inhibition of mTORC1 by a Dual Drug Strategy: A Novel Approach for the Treatment of Alcohol Use Disorder
Yann Ehinger, Ziyang Zhang, Khanhky Phamluong, Drishti Soneja, Kevan M. Shokat, Dorit Ron
bioRxiv 2020.10.12.336701; doi: https://doi.org/10.1101/2020.10.12.336701

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