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Inhibition is of fundamental importance to regulate activity in cortical circuits. Inhibition is mediated through a diversity of different interneurones and gamma-aminobutyric acid A receptor (GABA(A)R) subtypes. Here we employed paired-pulse transcranial magnetic stimulation (TMS) to measure short interval intracortical inhibition (SICI), a GABA(A)R-mediated inhibition in human motor cortex, to address the question of which GABA(A)R 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 alpha-subunit-bearing subtypes of the GABA(A)R while zolpidem has a 10-fold greater affinity to the alpha1-subunit-bearing GABA(A)R compared with those bearing the alpha2- or alpha3-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 alpha1-subunit GABA(A)R-mediated effect. The findings strongly suggest that SICI is not mediated by the alpha1-subunit-bearing subtype of the GABA(A)R but by those bearing either the alpha2- or alpha3-subunit. This study represents an attempt by means of TMS to identify GABA(A)R subtype-specific action at the systems level of human cortex, a highly relevant issue because the different alpha-subunit-bearing subtypes of the GABA(A)R are differently involved in benzodiazepine-mediated effects such as sedation, amnesia or anxiolysis, in developmental cortical plasticity, and in neurological disorders such as epilepsy.

Peripheral nerve inputs have an inhibitory effect on motor cortex excitability at short intervals (short-latency afferent inhibition, SAI). This can be tested by coupling electrical stimulation of peripheral nerve with transcranial magnetic stimulation (TMS) of the motor cortex. SAI is reduced by the anticholinergic drug scopolamine, and in patients with Alzheimer's disease. Therefore, it is possible that SAI is a marker of central cholinergic activity important for memory function. The benzodiazepine lorazepam also reduces SAI. Since benzodiazepines impair memory formation, but do not do so uniformly, with a maximum amnesic effect after lorazepam but less or no effect after diazepam, we were interested in testing in this non-behavioural study to what extent the effects of lorazepam and diazepam on circuits involved in SAI could be dissociated. In addition, and for control, we tested the effects of lorazepam and diazepam on short-interval intracortical inhibition (SICI), a motor cortical inhibition mediated through the GABA(A) receptor. Lorazepam markedly reduced SAI, whereas diazepam slightly increased it. In contrast, both benzodiazepines uniformly increased SICI. Our findings demonstrate opposite effects of lorazepam and diazepam on SAI, an inhibition modulated by central cholinergic activity, but the same effects on SICI, a marker of neurotransmission through the GABA(A) receptor. This dissociation suggests, for the first time, that TMS measures of cortical inhibition provide the opportunity to segregate differences of benzodiazepine action in human central nervous system circuits.