Altered GABAB receptor sensitivity in heavy drinkers indexed using a TMS-based biomarker: a randomized controlled experimental medicine trial
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.
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BibTeX
@article{montemitro2026altered,
title = {{Altered GABAB receptor sensitivity in heavy drinkers indexed using a TMS-based biomarker: a randomized controlled experimental medicine trial}},
author = {Chiara Montemitro and Daphne Donahue and Andrea Costumati and Federico Maruottolo and Sara Terezza and Caroline Sjoberg and Irene Perini and Markus Roman and Fredrik C. Kugelberg and Markus Heilig},
journal = {Translational Psychiatry},
year = {2026},
month = oct,
doi = {10.1038/s41398-026-04530-4},
url = {https://www.nature.com/articles/s41398-026-04530-4},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Altered GABAB receptor sensitivity in heavy drinkers indexed using a TMS-based biomarker: a randomized controlled experimental medicine trial
AU - Chiara Montemitro
AU - Daphne Donahue
AU - Andrea Costumati
AU - Federico Maruottolo
AU - Sara Terezza
AU - Caroline Sjoberg
AU - Irene Perini
AU - Markus Roman
AU - Fredrik C. Kugelberg
AU - Markus Heilig
PY - 2026
DA - 2026/10/23
JO - Translational Psychiatry
DO - 10.1038/s41398-026-04530-4
UR - https://www.nature.com/articles/s41398-026-04530-4
AB - 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.
SN - 2158-3188
ER -