Alpha-5 gamma-aminobutyric acid type A receptors (␣5-GABAARs) are located extrasynaptically, regulate neuronal excitability through tonic inhibition, and are fundamentally important for processes such as plasticity and learning. For example, pharmacological blockade of ␣5-GABAAR in mice with ischemic stroke improved recovery of function by normalizing exaggerated perilesional ␣5-GABAARdependent tonic inhibition. S44819 is a novel competitive selective antagonist of the ␣5-GABAAR at the GABA-binding site. Pharmacological modulation of ␣5-GABAAR-mediated tonic inhibition has never been investigated in the human brain. Here, we used transcranial magnetic stimulation (TMS) to test the effects of a single oral dose of 50 and 100 mg of S44819 on electromyographic (EMG) and electroencephalographic (EEG) measures of cortical excitability in 18 healthy young adults in a randomized, double-blinded, placebocontrolled, crossover phase I study. A dose of 100 mg, but not 50 mg, of S44819 decreased active motor threshold, the intensity needed to produce a motor evoked potential of 0.5 mV, and the amplitude of the N45, a GABAAergic component of the TMS-evoked EEG response. The peak serum concentration of 100 mg S44819 correlated directly with the decrease in N45 amplitude. Short-interval intracortical inhibition, a TMS-EMG measure of synaptic GABAAergic inhibition, and other components of the TMS-evoked EEG response remained unaffected. These findings provide first time evidence that the specific ␣5-GABAAR antagonist S44819 reached human cortex to impose an increase in cortical excitability. These data warrant further development of S44819 in a human clinical trial to test its efficacy in enhancing recovery of function after ischemic stroke.

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Brain responses to transcranial magnetic stimulation (TMS) recorded by electroencephalography (EEG) are emergent noninvasive markers of neuronal excitability and effective connectivity in humans. However, the underlying physiology of these TMS‐evoked EEG potentials (TEPs) is still heavily underexplored, impeding a broad application of TEPs to study pathology in neuropsychiatric disorders. Here we tested the effects of a single oral dose of three antiepileptic drugs with specific modes of action (carbamazepine, a voltage‐gated sodium channel (VGSC) blocker; brivaracetam, a ligand to the presynaptic vesicle protein VSA2; tiagabine, a gamma‐aminobutyric acid (GABA) reuptake inhibitor) on TEP amplitudes in 15 healthy adults in a double‐blinded randomized placebo‐controlled crossover design. We found that carbamazepine decreased the P25 and P180 TEP components, and brivaracetam the N100 amplitude in the nonstimulated hemisphere, while tiagabine had no effect. Findings corroborate the view that the P25 represents axonal excitability of the corticospinal system, the N100 in the nonstimulated hemisphere propagated activity suppressed by inhibition of presynaptic neurotransmitter release, and the P180 late activity particularly sensitive to VGSC blockade. Pharmaco‐physiological characterization of TEPs will facilitate utilization of TMS‐EEG in neuropsychiatric disorders with altered excitability and/or network connectivity.