482. Altered GABAb receptor–mediated cortical inhibition in heavy alcohol use: evidence from a pharmaco-TMS study using baclofen

Abstract

Abstract Background Gamma-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter of the central nervous system, and dysregulation of GABAergic signaling has been consistently implicated in Alcohol Use Disorder (AUD). In particular, metabotropic GABAb receptors (GABAbRs) play a key role in regulating cortical excitability, synaptic inhibition, and neuroendocrine function. However, objective and translatable biomarkers of GABAbR function in humans are limited, hindering the development and evaluation of neuroscience-based treatments for AUD. Long-interval intracortical inhibition (LICI), measured using paired-pulse transcranial magnetic stimulation combined with electromyography (TMS–EMG), reflects GABAbR-mediated cortical inhibition and is potentiated by the GABAbR agonist baclofen. Previous evidence indicates that LICI is attenuated in individuals with AUD, supporting its potential as a biomarker of GABAbR dysfunction. Aims & Objectives Our study aimed to establish effective and easy-to-collect biomarkers of GABAB function in healthy subjects with different levels of alcohol consumption, using baclofen as a tool to manipulate GABAB receptors and TMS-EMG to measure receptors activation. Method In a randomized, double-blind, placebo-controlled, crossover experimental medicine study, 32 non-treatment-seeking healthy volunteers (16 heavy drinkers and 16 light drinkers; balanced for sex) completed three experimental sessions separated by at least seven days. Across sessions, participants received oral baclofen 30 mg, baclofen 60 mg, or placebo in counterbalanced order. LICI was assessed using paired-pulse TMS–EMG at baseline and approximately 60 minutes after drug administration, corresponding to peak baclofen concentrations. Repeated-measures ANOVAs examined the effects of treatment (placebo, baclofen 30 mg, baclofen 60 mg), time (pre- vs post-drug), and drinking group (heavy vs light). Gender and visit order were initially included in the model, and then discarded because of lack of meaningful effects. Results Across conditions, a significant main effect of time was observed (F(1,29) = 11.65, p = 0.002), indicating overall modulation of cortical inhibition after drug administration. Importantly, a significant treatment × group × time interaction emerged (F(1.95,56.42) = 3.36, p = 0.043), demonstrating differential baclofen effects between drinking groups. Post-hoc analyses revealed that baclofen 30 mg significantly increased LICI in both light drinkers (p = 0.005) and heavy drinkers (p = 0.043). In contrast, baclofen 60 mg increased LICI in light drinkers (p = 0.014) but not in heavy drinkers (p = 0.73), resulting in a significant group difference at the high dose (p = 0.003). These effects remained robust after controlling for plasma baclofen concentrations, treatment order, and visit effects, with the group × treatment interaction remaining significant (p = 0.015). Baseline inhibitory tone strongly predicted post-drug LICI (p < 0.001) but did not account for the selective attenuation of the high-dose baclofen effect in heavy drinkers. Discussion & Conclusions These findings demonstrate dose- and group-dependent modulation of GABAbR-mediated cortical inhibition by baclofen. While lower-dose baclofen enhances LICI across drinking groups, heavy drinkers exhibit a blunted inhibitory response at higher doses, consistent with alcohol-related neuroadaptations in GABAbR signaling. LICI emerges as a sensitive, non-invasive biomarker of GABAbR function and pharmacodynamic target engagement, with potential utility for stratifying neurobiological heterogeneity and informing the development of GABAbR-targeting treatments for AUD.