Cannabinoid tolerance relies on CB₁ receptor ubiquitination by NEDD4L.

Authors

Alicia Álvaro-Blázquez, Rui S Rodrigues, Carlos Montero-Fernández, Marta Isasa, Astrid Cannich, Doriane Gisquet, Ignacio Rodríguez-Crespo, Luigi Bellocchio, Giovanni Marsicano, Carlos Costas-Insua, Manuel Guzmán

Published in

Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 35. Pages e2606671123. Epub Aug 25, 2026.

Abstract

Cannabinoids, the active components of cannabis, exert numerous acute effects in the brain by engaging cannabinoid CB₁ receptors (CB₁Rs). However, tolerance emerges rapidly after repeated drug exposure, undermining the efficacy of cannabinoid-based therapies and contributing to cannabis-associated adverse effects. Although the processes of CB₁R short-term desensitization (i.e., receptor uncoupling and internalization) are well characterized, the mechanisms underlying CB₁R long-term tolerance (i.e., downregulation of receptor protein levels) remain elusive. Here, we identify a ubiquitin-dependent pathway that couples CB₁R activation to its proteasomal degradation. We show that cannabinoids engage a G_q/11-PLC-PKC signaling cascade that phosphorylates and activates the E3 ubiquitin ligase neural precursor cell-expressed developmentally downregulated 4-like (NEDD4L), promoting its recruitment to CB₁R and the ubiquitination of four specific lysine residues. This modification targets the receptor for proteasomal clearance, reducing neuronal CB₁R abundance in vitro and in the mouse brain. Using molecular, pharmacological, and circuit-specific rescue approaches, we demonstrate that preventing CB₁R ubiquitination stabilizes receptor levels and abolishes behavioral cannabinoid tolerance in mice without impairing acute drug responses. These findings reveal a molecular mechanism that controls CB₁R stability and identify NEDD4L-mediated ubiquitination as a central driver of cannabinoid tolerance.

PMID:
42640804
Bibliographic data and abstract were imported from PubMed on 26 Aug 2026.

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