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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,9,1]]},"abstract":"<jats:p>\n                    Cannabinoids, the active components of cannabis, exert numerous acute effects in the brain by engaging cannabinoid CB\n                    <jats:sub>1<\/jats:sub>\n                    receptors (CB\n                    <jats:sub>1<\/jats:sub>\n                    Rs). 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 CB\n                    <jats:sub>1<\/jats:sub>\n                    R short-term desensitization (i.e., receptor uncoupling and internalization) are well characterized, the mechanisms underlying CB\n                    <jats:sub>1<\/jats:sub>\n                    R long-term tolerance (i.e., downregulation of receptor protein levels) remain elusive. Here, we identify a ubiquitin-dependent pathway that couples CB\n                    <jats:sub>1<\/jats:sub>\n                    R activation to its proteasomal degradation. We show that cannabinoids engage a G\n                    <jats:sub>q\/11<\/jats:sub>\n                    -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 CB\n                    <jats:sub>1<\/jats:sub>\n                    R and the ubiquitination of four specific lysine residues. This modification targets the receptor for proteasomal clearance, reducing neuronal CB\n                    <jats:sub>1<\/jats:sub>\n                    R abundance in vitro and in the mouse brain. Using molecular, pharmacological, and circuit-specific rescue approaches, we demonstrate that preventing CB\n                    <jats:sub>1<\/jats:sub>\n                    R ubiquitination stabilizes receptor levels and abolishes behavioral cannabinoid tolerance in mice without impairing acute drug responses. These findings reveal a molecular mechanism that controls CB\n                    <jats:sub>1<\/jats:sub>\n                    R stability and identify NEDD4L-mediated ubiquitination as a central driver of cannabinoid tolerance.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2606671123","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T16:36:09Z","timestamp":1787675769000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Cannabinoid tolerance relies on CB\n                    <sub>1<\/sub>\n                    receptor ubiquitination by NEDD4L"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-0632-9912","authenticated-orcid":false,"given":"Alicia","family":"\u00c1lvaro-Bl\u00e1zquez","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Instituto Universitario de Investigaci\u00f3n Neuroqu\u00edmica, 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