{
  "abstract": "Cannabinoids, the active components of cannabis, lose efficacy after repeated use due to tolerance, limiting their therapeutic value and safety. Although short-term desensitization of cannabinoid receptors is well understood, the molecular basis of long-term cannabinoid tolerance has remained unclear. This study identifies a molecular mechanism by which cannabinoids trigger selective ubiquitination and proteasomal degradation of the CB 1 receptor in the brain. This process is driven by protein kinase C-dependent activation of the E3 ubiquitin ligase neural precursor cell-expressed developmentally downregulated 4-like and is required for behavioral cannabinoid tolerance in mice. These findings provide a molecular framework for cannabinoid tolerance, a process that can contribute to cannabis use disorder and cannabis hyperemesis syndrome, and suggest strategies to improve cannabinoid-based therapies. Cannabinoids, the active components of cannabis, exert numerous acute effects in the brain by engaging cannabinoid CB 1 receptors (CB 1 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 1 R short-t erm desensitization (i.e., receptor uncoupling and internalization) are well characterized, the mechanisms underlying CB 1 R long-term tolerance (i.e., downregulation of receptor protein levels) remain elusive. Here, we identify a ubiquitin-dependent pathway that couples CB 1 R activation to its proteasomal degradation. We show that cannabinoids engage a G q/11 -PLC-P KC signaling cascade that phosphorylates and activates the E3 ubiquitin ligase neural precursor cell-expressed developmentally downregulated 4-like (NEDD4L), promoting its recruitment to CB 1 R and the ubiquitination of four specific lysine residues. This modification targets the receptor for proteasomal clearance, reducing neuronal CB 1 R abundance in vitr o and in the mouse brain. Using molecular, pharmacological, and circuit-s pecific rescue approaches, we demonstrate that preventing CB 1 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 1 R stability and identify NEDD4L-mediated ubiquitination as a central driver of cannabinoid tolerance.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": null,
  "arxiv": null,
  "author_total": 11,
  "authors": [
    {
      "name": "Alicia Álvaro-Blázquez"
    },
    {
      "name": "Rui S Rodrigues"
    },
    {
      "name": "Carlos Montero-Fernández"
    },
    {
      "name": "Marta Isasa"
    },
    {
      "name": "Astrid Cannich"
    },
    {
      "name": "Doriane Gisquet"
    },
    {
      "name": "Ignacio Rodríguez-Crespo"
    },
    {
      "name": "Luigi Bellocchio"
    },
    {
      "name": "Giovanni Marsicano"
    },
    {
      "name": "Carlos Costas-Insua"
    },
    {
      "name": "Manuel Guzmán"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/0zqbb9jw7njjz.bib",
  "cited_by": 0,
  "doi": "10.1073/pnas.2606671123",
  "fulltext_url": null,
  "id": "0zqbb9jw7njjz",
  "issns": [
    "0027-8424",
    "1091-6490"
  ],
  "landing_url": "https://hal.science/hal-05848884v1",
  "language": "en",
  "licence": "CC-BY-NC-ND-4.0",
  "licence_label": "CC BY-NC-ND 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "hal",
      "0.sdv"
    ],
    [
      "hal",
      "1.sdv.neu"
    ],
    [
      "openalex",
      "2736|Cannabis and Cannabinoid Research"
    ]
  ],
  "openalex": "W7204172343",
  "pdf_url": "https://hal.science/hal-05848884/document",
  "pmcid": null,
  "pmid": "42640804",
  "published": "2026-11-02",
  "publisher": "National Academy of Sciences",
  "ris": "https://research.draconitic.com/paper/0zqbb9jw7njjz.ris",
  "sources": [
    {
      "first_seen": "2026-11-03T12:20:18Z",
      "native_id": "hal-05848884",
      "source": "hal",
      "url": "https://hal.science/hal-05848884v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "hal:1.sdv.neu",
      "subfield": "neuroscience"
    }
  ],
  "title": "Cannabinoid tolerance relies on CB1 receptor ubiquitination by NEDD4L",
  "title_text": "Cannabinoid tolerance relies on CB1 receptor ubiquitination by NEDD4L",
  "type": "peer-reviewed",
  "updated_at": "2026-11-04T12:20:48Z",
  "url": "https://research.draconitic.com/paper/0zqbb9jw7njjz",
  "venue": "Proceedings of the National Academy of Sciences of the United States of America",
  "versions": []
}