Inhibitory circuits are crucial in modulating corticospinal output in the primary motor cortex (M1). Relatively little is known about how these inhibitory circuits interact. Here we measured three forms of inhibition in M1 by paired-pulse transcranial magnetic stimulation: short-interval intracortical inhibition (SICI), long-interval intracortical inhibition (LICI) and short-interval interhemispheric inhibition (SIHI). We specifically tested their interactions under pharmacological challenge with a single oral dose of diazepam, a positive allosteric modulator of the γ-aminobutyric acid type A receptor (GABAAR), or baclofen, a specific agonist at the GABA type B receptor (GABABR). Motor evoked potentials were recorded bilaterally from the first dorsal interosseous muscle in eight right-handed healthy volunteers. Diazepam enhanced SICI, and baclofen produced a trend towards enhanced LICI, corroborating the view that SICI reflects inhibition mediated by the GABAAR, and LICI very likely reflects inhibition mediated by the GABABR. The pharmacology of SIHI was inconclusive and warrants further investigation. Findings strongly suggest that SICI, LICI and SIHI recruit three distinct inhibitory circuits in the human M1. The interactions between SIHI and SICI, LICI and SIHI, and LICI and SICI were all negative, that is SIHI suppressed SICI, and LICI suppressed both SIHI and SICI. Diazepam partially restored SICI in the presence of LICI, while all other interactions remained unaffected by diazepam or baclofen. It will be argued that the negative interactions between SIHI and SICI, LICI and SIHI, and LICI and SICI are most likely due to presynaptic GABABR-mediated autoinhibition
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