Effects of the Selective α5-GABAAR Antagonist S44819 on Excitability in the Human Brain: A TMS–EMG and TMS–EEG Phase I Study

Abstract

The extrasynaptic α-5 gamma-aminobutyric acid type A receptor (α5-GABAAR) regulates neuronal excitability through tonic inhibition in the mammalian brain. Tonic inhibition is important for many fundamental processes such as plasticity and learning. Pharmacological modulation of α5-GABAAR-mediated tonic inhibition has never been investigated in the human brain. This study demonstrates that S44819, a selective α5-GABAAR antagonist, increases cortical excitability in healthy human subjects, as indicated by specific markers of transcranial magnetic stimulation-induced muscle and brain responses measured by electromyography and electroencephalography. Our findings imply that tonic inhibition in human cortex can be modified effectively and that this modification can be quantified with noninvasive brain stimulation methods. The actions of S44819 may be suitable to improve plasticity and learning.