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Inhibition of striatonigral autophagy as a link between cannabinoid intoxication and impairment of motor coordination

The use of cannabis is rapidly expanding worldwide. Thus, innovative studies aimed to identify, understand and potentially reduce cannabis-evoked harms are warranted. Here, we found that Δ(9)-tetrahydrocannabinol, the psychoactive ingredient of cannabis, disrupts autophagy selectively in the striatu...

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Autores principales: Blázquez, Cristina, Ruiz-Calvo, Andrea, Bajo-Grañeras, Raquel, Baufreton, Jérôme M, Resel, Eva, Varilh, Marjorie, Pagano Zottola, Antonio C, Mariani, Yamuna, Cannich, Astrid, Rodríguez-Navarro, José A, Marsicano, Giovanni, Galve-Roperh, Ismael, Bellocchio, Luigi, Guzmán, Manuel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417168/
https://www.ncbi.nlm.nih.gov/pubmed/32773031
http://dx.doi.org/10.7554/eLife.56811
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author Blázquez, Cristina
Ruiz-Calvo, Andrea
Bajo-Grañeras, Raquel
Baufreton, Jérôme M
Resel, Eva
Varilh, Marjorie
Pagano Zottola, Antonio C
Mariani, Yamuna
Cannich, Astrid
Rodríguez-Navarro, José A
Marsicano, Giovanni
Galve-Roperh, Ismael
Bellocchio, Luigi
Guzmán, Manuel
author_facet Blázquez, Cristina
Ruiz-Calvo, Andrea
Bajo-Grañeras, Raquel
Baufreton, Jérôme M
Resel, Eva
Varilh, Marjorie
Pagano Zottola, Antonio C
Mariani, Yamuna
Cannich, Astrid
Rodríguez-Navarro, José A
Marsicano, Giovanni
Galve-Roperh, Ismael
Bellocchio, Luigi
Guzmán, Manuel
author_sort Blázquez, Cristina
collection PubMed
description The use of cannabis is rapidly expanding worldwide. Thus, innovative studies aimed to identify, understand and potentially reduce cannabis-evoked harms are warranted. Here, we found that Δ(9)-tetrahydrocannabinol, the psychoactive ingredient of cannabis, disrupts autophagy selectively in the striatum, a brain area that controls motor behavior, both in vitro and in vivo. Boosting autophagy, either pharmacologically (with temsirolimus) or by dietary intervention (with trehalose), rescued the Δ(9)-tetrahydrocannabinol-induced impairment of motor coordination in mice. The combination of conditional knockout mouse models and viral vector-mediated autophagy-modulating strategies in vivo showed that cannabinoid CB(1) receptors located on neurons belonging to the direct (striatonigral) pathway are required for the motor-impairing activity of Δ(9)-tetrahydrocannabinol by inhibiting local autophagy. Taken together, these findings identify inhibition of autophagy as an unprecedented mechanistic link between cannabinoids and motor performance, and suggest that activators of autophagy might be considered as potential therapeutic tools to treat specific cannabinoid-evoked behavioral alterations.
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spelling pubmed-74171682020-08-12 Inhibition of striatonigral autophagy as a link between cannabinoid intoxication and impairment of motor coordination Blázquez, Cristina Ruiz-Calvo, Andrea Bajo-Grañeras, Raquel Baufreton, Jérôme M Resel, Eva Varilh, Marjorie Pagano Zottola, Antonio C Mariani, Yamuna Cannich, Astrid Rodríguez-Navarro, José A Marsicano, Giovanni Galve-Roperh, Ismael Bellocchio, Luigi Guzmán, Manuel eLife Neuroscience The use of cannabis is rapidly expanding worldwide. Thus, innovative studies aimed to identify, understand and potentially reduce cannabis-evoked harms are warranted. Here, we found that Δ(9)-tetrahydrocannabinol, the psychoactive ingredient of cannabis, disrupts autophagy selectively in the striatum, a brain area that controls motor behavior, both in vitro and in vivo. Boosting autophagy, either pharmacologically (with temsirolimus) or by dietary intervention (with trehalose), rescued the Δ(9)-tetrahydrocannabinol-induced impairment of motor coordination in mice. The combination of conditional knockout mouse models and viral vector-mediated autophagy-modulating strategies in vivo showed that cannabinoid CB(1) receptors located on neurons belonging to the direct (striatonigral) pathway are required for the motor-impairing activity of Δ(9)-tetrahydrocannabinol by inhibiting local autophagy. Taken together, these findings identify inhibition of autophagy as an unprecedented mechanistic link between cannabinoids and motor performance, and suggest that activators of autophagy might be considered as potential therapeutic tools to treat specific cannabinoid-evoked behavioral alterations. eLife Sciences Publications, Ltd 2020-08-10 /pmc/articles/PMC7417168/ /pubmed/32773031 http://dx.doi.org/10.7554/eLife.56811 Text en © 2020, Blázquez et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Neuroscience
Blázquez, Cristina
Ruiz-Calvo, Andrea
Bajo-Grañeras, Raquel
Baufreton, Jérôme M
Resel, Eva
Varilh, Marjorie
Pagano Zottola, Antonio C
Mariani, Yamuna
Cannich, Astrid
Rodríguez-Navarro, José A
Marsicano, Giovanni
Galve-Roperh, Ismael
Bellocchio, Luigi
Guzmán, Manuel
Inhibition of striatonigral autophagy as a link between cannabinoid intoxication and impairment of motor coordination
title Inhibition of striatonigral autophagy as a link between cannabinoid intoxication and impairment of motor coordination
title_full Inhibition of striatonigral autophagy as a link between cannabinoid intoxication and impairment of motor coordination
title_fullStr Inhibition of striatonigral autophagy as a link between cannabinoid intoxication and impairment of motor coordination
title_full_unstemmed Inhibition of striatonigral autophagy as a link between cannabinoid intoxication and impairment of motor coordination
title_short Inhibition of striatonigral autophagy as a link between cannabinoid intoxication and impairment of motor coordination
title_sort inhibition of striatonigral autophagy as a link between cannabinoid intoxication and impairment of motor coordination
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417168/
https://www.ncbi.nlm.nih.gov/pubmed/32773031
http://dx.doi.org/10.7554/eLife.56811
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