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

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

eLife (2020-08-11)
Cristina Blázquez, Andrea Ruiz-Calvo, Raquel Bajo-Grañeras, Jérôme 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
ABSTRACT

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 Δ9-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 Δ9-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 CB1 receptors located on neurons belonging to the direct (striatonigral) pathway are required for the motor-impairing activity of Δ9-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.

MATERIALS
Product Number
Brand
Product Description

Millipore
D-(+)-Trehalose dihydrate, ≥99.0%, suitable for microbiology, composed of two α-glucose units that is used as a protectant, stabilizer and to support proper folding
Sigma-Aldrich
Monoclonal Anti-β-Actin antibody produced in mouse, clone AC-15, ascites fluid
Sigma-Aldrich
Anti-LC3B antibody produced in rabbit, ~1 mg/mL, affinity isolated antibody, buffered aqueous solution
Sigma-Aldrich
Temsirolimus, ≥98% (HPLC)
Sigma-Aldrich
Triton X-100, laboratory grade
Sigma-Aldrich
HU-210, solid (air sensitive)