Blázquez Ortiz, CristinaRuiz-Calvo, AndreaBajo-Grañeras, RaquelBaufreton, Jérôme M.Resel, EvaVarilh, MarjoriePagano Zottola, Antonio C.Mariani, YamunaCannich, AstridRodríguez-Navarro, José A.Marsicano, GiovanniGalve Roperh, IsmaelBellocchio, LuigiGuzmán Pastor, Manuel2023-06-172023-06-172020-08-10Electronic: 2050-084X10.7554/eLife.56811https://hdl.handle.net/20.500.14352/7941The 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 D 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 D 9 -tetrahydrocannabinol-induced impairment of motor coordination in mice. The combination of conditional knockout mouse models and viral vector-mediated autophagymodulating 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 D 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.engAtribución 3.0 Españajournal articlehttps://elifesciences.org/articles/56811open access615.9577.1615.9AutophagyCannabinoidDrug abusemTORMotor behaviourMouseNeuroscienceStriatumBioquímica (Biología)Neurociencias (Biológicas)2302 Bioquímica2490 Neurociencias