{
  "abstract": "Metabotropic γ-aminobutyric acid type B receptors (GABA B Rs) are implicated in alcohol use disorder (AUD) and represent a promising therapeutic target. However, robust biomarkers of GABA B Rs target engagement and sensitivity in humans are lacking. We examined transcranial magnetic stimulation (TMS)–derived cortical inhibition and growth hormone (GH) release as measures of GABA B R function, and whether heavy alcohol use is associated with altered responses to pharmacological GABA B R activation. In a randomized, double-blind, placebo-controlled crossover study, 31 healthy volunteers (16 heavy drinkers, 15 light drinkers) received baclofen 30 mg, baclofen 60 mg, or placebo across three sessions. Long-interval intracortical inhibition (LICI), short-interval intracortical inhibition, and intracortical facilitation were assessed with paired-pulse TMS at baseline and ~60 min post-dose. Baclofen blood concentrations and plasma GH levels were measured. Baclofen produced dose-dependent increases in GH release, confirming neuroendocrine GABA B R engagement. The LICI response to baclofen differed between groups: In light drinkers, baclofen at 30 mg potentiated LICI, and a similar potentiation was seen at 60 mg, indicating that a plateau may have been reached. In contrast, in heavy drinkers, a potentiation of LICI similar to that in light drinkers was seen at 30 mg baclofen, but was absent at the 60 mg dose despite comparable pharmacokinetics, suggesting altered GABA B R function. Effects were selective for GABA B R–mediated inhibition, with no consistent modulation of short-interval intracortical inhibition or corticospinal excitability. Acute baclofen administration reveals altered GABA B R sensitivity in heavy drinkers, with preserved responses at lower doses but reduced response under stronger agonist stimulation. LICI and GH release provide complementary biomarkers of central and peripheral GABA B Rs engagement and may support translational development of mechanism-based treatments for AUD.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": null,
  "arxiv": null,
  "author_total": 10,
  "authors": [
    {
      "name": "Chiara Montemitro",
      "orcid": "0000-0002-3280-1895"
    },
    {
      "name": "Daphne Donahue"
    },
    {
      "name": "Andrea Costumati"
    },
    {
      "name": "Federico Maruottolo"
    },
    {
      "name": "Sara Terezza"
    },
    {
      "name": "Caroline Sjoberg"
    },
    {
      "name": "Irene Perini",
      "orcid": "0000-0002-5972-0913"
    },
    {
      "name": "Markus Roman"
    },
    {
      "name": "Fredrik C. Kugelberg",
      "orcid": "0000-0002-7886-631X"
    },
    {
      "name": "Markus Heilig",
      "orcid": "0000-0003-2706-2482"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/bvjm3b430bh20.bib",
  "cited_by": 0,
  "doi": "10.1038/s41398-026-04530-4",
  "fulltext_url": "https://doi.org/10.1038/s41398-026-04530-4",
  "id": "bvjm3b430bh20",
  "issns": [
    "2158-3188"
  ],
  "landing_url": "https://www.nature.com/articles/s41398-026-04530-4",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0",
  "metadata_licence": null,
  "native_subjects": [
    [
      "lcc",
      "RC321-571"
    ],
    [
      "openalex",
      "2804|Neuroscience and Neuropharmacology Research"
    ]
  ],
  "openalex": "W7223215123",
  "pdf_url": "https://www.nature.com/articles/s41398-026-04530-4.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-23",
  "publisher": "Springer Science and Business Media LLC",
  "ris": "https://research.draconitic.com/paper/bvjm3b430bh20.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:26Z",
      "native_id": "10.1038/s41398-026-04530-4",
      "source": "crossref",
      "url": "https://www.nature.com/articles/s41398-026-04530-4"
    },
    {
      "first_seen": "2026-10-30T13:46:29Z",
      "native_id": "faeeab7ec30346af891b71aaf3d6055c",
      "source": "doaj",
      "url": "https://doi.org/10.1038/s41398-026-04530-4"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2804|Neuroscience and Neuropharmacology Research",
      "subfield": "neuroscience"
    }
  ],
  "title": "Altered GABAB receptor sensitivity in heavy drinkers indexed using a TMS-based biomarker: a randomized controlled experimental medicine trial",
  "title_text": "Altered GABAB receptor sensitivity in heavy drinkers indexed using a TMS-based biomarker: a randomized controlled experimental medicine trial",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T13:46:29Z",
  "url": "https://research.draconitic.com/paper/bvjm3b430bh20",
  "venue": "Translational Psychiatry",
  "versions": []
}