Cannabinoid-induced motor dysfunction via autophagy inhibition

Autophagy. 2020 Dec;16(12):2289-2291. doi: 10.1080/15548627.2020.1827560. Epub 2020 Oct 20.

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.

Keywords: Autophagy; MTOR; cannabinoid; drug abuse; motor behavior; striatum.

Publication types

  • Research Support, Non-U.S. Gov't
  • Comment

MeSH terms

  • Animals
  • Autophagy
  • Brain
  • Cannabinoids*
  • Dronabinol / pharmacology
  • Mice

Substances

  • Cannabinoids
  • Dronabinol

Grant support

This work was supported by the INSERM; Human Frontiers Science Program [RGP0036/2014]; Region Nouvelle Aquitaine; Agence Nationale de la Recherche [ANR 18-CE16-0001-02/ANR-19-CE14/ANR-18-CE14-0029-01/ANR-16-CE37-0010-01/ANR-10-LABX-0043]; H2020 European Research Council [ERC-2018-AdG-786467/ERC-2014-PoC-640923/ERC–2010–StG–260515]; Fondation pour la Recherche Medicale [DRM20101220445/ARF20140129235/DPP20151033974]; Ministerio de Ciencia, Innovación y Universidades [RTI2018-095311-B-I00/SAF2015-64945-R/SAF2016-78666-R/PI98-0941].