Altered GABA_B receptor sensitivity in heavy drinkers indexed using a TMS-based biomarker: a randomized controlled...

Metabotropic γ-aminobutyric acid type B receptors (GABA_BRs) are implicated in alcohol use disorder (AUD) and represent a promising therapeutic target. However, robust biomarkers of GABA_BRs 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_BR function, and whether heavy alcohol use is associated with altered responses to pharmacological GABA_BR 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_BR 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_BR function. Effects were selective for GABA_BR-mediated inhibition, with no consistent modulation of short-interval intracortical inhibition or corticospinal excitability. Acute baclofen administration reveals altered GABA_BR 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_BRs engagement and may support translational development of mechanism-based treatments for AUD.