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Chronic MAP4343 reverses escalated alcohol drinking in a mouse model of alcohol use disorder

Alcohol use disorders can be driven by negative reinforcement. Alterations of the microtubule cytoskeleton have been associated with mood regulation in the context of depression. Notably, MAP4343, a pregnenolone derivative known to promote tubulin assembly, has antidepressant properties. In the pres...

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Autores principales: Macedo, Giovana C., Kreifeldt, Max, Goulding, Scott P., Okhuarobo, Agbonlahor, Sidhu, Harpreet, Contet, Candice
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10066354/
https://www.ncbi.nlm.nih.gov/pubmed/36670228
http://dx.doi.org/10.1038/s41386-023-01529-z
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author Macedo, Giovana C.
Kreifeldt, Max
Goulding, Scott P.
Okhuarobo, Agbonlahor
Sidhu, Harpreet
Contet, Candice
author_facet Macedo, Giovana C.
Kreifeldt, Max
Goulding, Scott P.
Okhuarobo, Agbonlahor
Sidhu, Harpreet
Contet, Candice
author_sort Macedo, Giovana C.
collection PubMed
description Alcohol use disorders can be driven by negative reinforcement. Alterations of the microtubule cytoskeleton have been associated with mood regulation in the context of depression. Notably, MAP4343, a pregnenolone derivative known to promote tubulin assembly, has antidepressant properties. In the present study, we tested the hypothesis that MAP4343 may reduce excessive alcohol drinking in a mouse model of alcohol dependence by normalizing affect during withdrawal. Adult male C57BL/6J mice were given limited access to voluntary alcohol drinking and ethanol intake escalation was induced by chronic intermittent ethanol (CIE) vapor inhalation. Chronic, but not acute, administration of MAP4343 reduced ethanol intake and this effect was more pronounced in CIE-exposed mice. There was a complex interaction between the effects of MAP4343 and alcohol on affective behaviors. In the elevated plus maze, chronic MAP4343 tended to increase open-arm exploration in alcohol-naive mice but reduced it in alcohol-withdrawn mice. In the tail suspension test, chronic MAP4343 reduced immobility selectively in Air-exposed alcohol-drinking mice. Finally, chronic MAP4343 countered the plasma corticosterone reduction induced by CIE. Parallel analysis of tubulin post-translational modifications revealed lower α-tubulin acetylation in the medial prefrontal cortex of CIE-withdrawn mice. Altogether, these data support the relevance of microtubules as a therapeutic target for the treatment of AUD.
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spelling pubmed-100663542023-04-02 Chronic MAP4343 reverses escalated alcohol drinking in a mouse model of alcohol use disorder Macedo, Giovana C. Kreifeldt, Max Goulding, Scott P. Okhuarobo, Agbonlahor Sidhu, Harpreet Contet, Candice Neuropsychopharmacology Article Alcohol use disorders can be driven by negative reinforcement. Alterations of the microtubule cytoskeleton have been associated with mood regulation in the context of depression. Notably, MAP4343, a pregnenolone derivative known to promote tubulin assembly, has antidepressant properties. In the present study, we tested the hypothesis that MAP4343 may reduce excessive alcohol drinking in a mouse model of alcohol dependence by normalizing affect during withdrawal. Adult male C57BL/6J mice were given limited access to voluntary alcohol drinking and ethanol intake escalation was induced by chronic intermittent ethanol (CIE) vapor inhalation. Chronic, but not acute, administration of MAP4343 reduced ethanol intake and this effect was more pronounced in CIE-exposed mice. There was a complex interaction between the effects of MAP4343 and alcohol on affective behaviors. In the elevated plus maze, chronic MAP4343 tended to increase open-arm exploration in alcohol-naive mice but reduced it in alcohol-withdrawn mice. In the tail suspension test, chronic MAP4343 reduced immobility selectively in Air-exposed alcohol-drinking mice. Finally, chronic MAP4343 countered the plasma corticosterone reduction induced by CIE. Parallel analysis of tubulin post-translational modifications revealed lower α-tubulin acetylation in the medial prefrontal cortex of CIE-withdrawn mice. Altogether, these data support the relevance of microtubules as a therapeutic target for the treatment of AUD. Springer International Publishing 2023-01-20 2023-04 /pmc/articles/PMC10066354/ /pubmed/36670228 http://dx.doi.org/10.1038/s41386-023-01529-z Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Macedo, Giovana C.
Kreifeldt, Max
Goulding, Scott P.
Okhuarobo, Agbonlahor
Sidhu, Harpreet
Contet, Candice
Chronic MAP4343 reverses escalated alcohol drinking in a mouse model of alcohol use disorder
title Chronic MAP4343 reverses escalated alcohol drinking in a mouse model of alcohol use disorder
title_full Chronic MAP4343 reverses escalated alcohol drinking in a mouse model of alcohol use disorder
title_fullStr Chronic MAP4343 reverses escalated alcohol drinking in a mouse model of alcohol use disorder
title_full_unstemmed Chronic MAP4343 reverses escalated alcohol drinking in a mouse model of alcohol use disorder
title_short Chronic MAP4343 reverses escalated alcohol drinking in a mouse model of alcohol use disorder
title_sort chronic map4343 reverses escalated alcohol drinking in a mouse model of alcohol use disorder
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10066354/
https://www.ncbi.nlm.nih.gov/pubmed/36670228
http://dx.doi.org/10.1038/s41386-023-01529-z
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