Controversy exists regarding the site where anesthetics act in the brain to produce sedation and unconsciousness. Actions in the cerebral cortex and thalamus are likely, although the relative importance of each site is unclear. We used in computo modeling to investigate the sensitivity of cortical and thalamic neurons to midazolam (MDZ) at concentrations that produce unconsciousness. The GABA(A) receptor conductance of the model was manipulated to simulate the effects of MDZ at free-drug plasma concentrations ranging from 8 nM to 100 nM; sleepiness to complete unconsciousness occurs in humans in the 10-40 nM range. Prolongation of phasic inhibition was simulated by increasing the decay time constant and tonic inhibition was simulated by introducing a tonic current; the extent of phasic and tonic inhibition was appropriate for each simulated MDZ concentration. Phasic and tonic inhibition was simulated in cortex, and phasic inhibition was simulated in thalamus. Simulation of MDZ effect decreased cortical neuronal firing rate. For example, the mean cortical neuronal firing rate decreased by 15% (P<0.01) and 26% (P<0.01) at MDZ concentrations of 10 nM and 40 nM, respectively. However, thalamic firing rate did not change. In computo modeling of the thalamocortical system indicates that MDZ-induced GABAergic inhibition of cortical neurons plays a significant role in the transition from waking to unconsciousness. Although MDZ produces phasic inhibition in the thalamus, computer simulation suggests it is riot significant enough to decrease thalamic neuronal firing. Thus, based on in computo modeling, MDZ at sedative/hypnotic concentrations produces its effects by decreasing cortical neuronal firing. (C) 2009 Elsevier Ireland Ltd. All rights reserved.