Cannabinoid-induced motor dysfunction via autophagy inhibition.
Cristina Blázquez, Andrea Ruiz-Calvo, Raquel Bajo-Grañeras, Jerome M Baufreton, Eva Resel, Marjorie Varilh, Antonio C Pagano Zottola, Yamuna Mariani, Astrid Cannich, José A Rodríguez-Navarro, Giovanni Marsicano, Ismael Galve-Roperh, Luigi Bellocchio, Manuel Guzmán
Autophagy December 2020 DOI: 10.1080/15548627.2020.1827560 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal study (in vivo mouse experiments) Peer reviewed |
|---|---|
| Population | Mice (striatum) |
| Interventions | Δ9-tetrahydrocannabinol (THC) temsirolimus trehalose |
| Keywords | Autophagy Mtor Cannabinoid Drug abuse Motor behavior Striatum |
| Key findings | THC impairs autophagy in the mouse striatum, and autophagy activators (temsirolimus, trehalose) rescue both this inhibition and motor dyscoordination. CNR1 on direct-pathway striatonigral neurons is required for THC's autophagy- and motor-impairing effects, suggesting autophagy links THC to motor performance. |
Abstract
The recreational and medical use of cannabis is largely increasing worldwide. Cannabis use, however, can cause adverse side effects, so conducting innovative studies aimed to understand and potentially reduce cannabis-evoked harms is important. Previous research conducted on cultured neural cells had supported that CNR1/CB1R (cannabinoid receptor 1), the main molecular target of cannabis, affects macroautophagy/autophagy. However, it was not known whether CNR1 controls autophagy in the brain in vivo, and, eventually, what the functional consequences of a potential CNR1-autophagy connection could be. We have now found that Δ9-tetrahydrocannabinol (THC), the major intoxicating constituent of cannabis, impairs autophagy in the mouse striatum. Administration of autophagy activators (specifically, the rapalog temsirolimus and the disaccharide trehalose) rescues THC-induced autophagy inhibition and motor dyscoordination. The combination of various genetic strategies in vivo supports the idea that CNR1 molecules located on neurons belonging to the direct (striatonigral) pathway are required for the autophagy- and motor-impairing activity of THC. By identifying autophagy as a mechanistic link between THC and motor performance, our findings may open a new conceptual view on how cannabis acts in the brain.