GABAA receptor subtype specific enhancement of inhibition in human motor cortex.

Inhibition is of fundamental importance to regulate activity in cortical circuits. Inhibition is mediated through a diversity of different interneurones and γ-aminobutyric acid A receptor (GABA_AR) subtypes. Here we employed paired-pulse transcranial magnetic stimulation (TMS) to measure short interval intracortical inhibition (SICI), a GABA_AR-mediated inhibition in human motor cortex, to address the question of which GABA_AR subtype is responsible for this form of inhibition. It has been shown that classical benzodiazepines (diazepam and lorazepam) have a non-selective affinity profile at different α-subunit-bearing subtypes of the GABA_AR while zolpidem has a 10-fold greater affinity to the α1-subunit-bearing GABA_AR compared with those bearing the α2- or α3-subunit. We found that, in seven healthy subjects, a single oral dose of 20 mg of diazepam or 2.5 mg of lorazepam significantly increased SICI, whereas 10 mg of zolpidem did not change SICI. This dissociation occurred despite equal sedation by all three drugs, an α1-subunit GABA_AR-mediated effect. The findings strongly suggest that SICI is not mediated by the α1-subunit-bearing subtype of the GABA_AR but by those bearing either the α2- or α3-subunit. This study represents an attempt by means of TMS to identify GABA_AR subtype-specific action at the systems level of human cortex, a highly relevant issue because the different α-subunit-bearing subtypes of the GABA_AR are differently involved in benzodiazepine-mediated effects such as sedation, amnesia or anxiolysis, in developmental cortical plasticity, and in neurological disorders such as epilepsy. [ABSTRACT FROM AUTHOR]