Effects of lorazepam on short latency afferent inhibition and short latency intracortical inhibition in humans

Abstract

Experimental studies have demonstrated that the GABAergic system modulates acetylcholine release and, through GABA(A) receptors, tonically inhibits cholinergic activity. Little is known about the effects of GABA on the cholinergic activity in the human central nervous system. In vivo evaluation of some cholinergic circuits of the human brain has recently been introduced using a transcranial magnetic stimulation (TMS) protocol based on coupling peripheral nerve stimulation with TMS of the motor cortex. Peripheral nerve inputs have an inhibitory effect on motor cortex excitability at short intervals (short latency afferent inhibition, SAI). We investigated whether GABA(A) activity enhancement by lorazepam modifies SAI. We also evaluated the effects produced by lorazepam on a different TMS protocol of cortical inhibition, the short interval intracortical inhibition (SICI), which is believed to be directly related to GABA(A) activity. In 10 healthy volunteers, the effects of lorazepam were compared with those produced by quetiapine, a psychotropic drug with sedative effects with no appreciable affinity at cholinergic muscarinic and benzodiazepine receptors, and with those of a placebo using a randomized double-blind study design. Administration of lorazepam produced a significant increase in SICI (F(3,9) = 3.19, P = 0.039). In contrast to SICI, SAI was significantly reduced by lorazepam (F(3,9) = 9.39, P = 0.0002). Our findings demonstrate that GABA(A) activity enhancement determines a suppression of SAI and an increase of SICI.

Figures

Figure 1. Effects of lorazepam on short latency intracortical inhibition (SICI)

Bar graph showing mean values in baseline conditions and 2, 6 and 24 h after lorazepam administration; error bars are standard deviations. Amplitude of the conditioned EMG response is reported as a percentage of control EMG response. The amount of inhibition is increased after lorazepam (F3,9 = 3.19, P = 0.039). The decrease in SICI is significant 2 h after drug intake (P = 0.005).

Figure 2. Effects of lorazepam on short latency afferent inhibition (SAI)

Bar graph showing mean values in baseline conditions and 2, 6 and 24 h after lorazepam administration; error bars are standard deviations. Amplitude of the conditioned EMG response is reported as a percentage of control EMG response. The amount of inhibition is reduced after lorazepam (F3,9 = 9.39, P = 0.0002). The decrease in SAI is significant 2 and 6 h after drug intake (P = 0.0003 and P = 0.0001, respectively).

Figure 3. Short latency intracortical inhibition (SICI) at 2 and 3 ms interstimulus intervals and short latency afferent inhibition (SAI)

The top traces on the left show the average (of 5 trials each) of EMG responses evoked in the FDI by cortical stimulation alone and cortical stimulation conditioned by a cortical stimulus subthreshold for motor responses (5% of maximum magnetic stimulator output below active motor threshold) given 2–3 ms earlier. The lower traces on the left show the average (of 5 trials each) of EMG responses evoked in the FDI by cortical stimulation alone and cortical stimulation conditioned by a median nerve stimulus with an interstimulus interval corresponding to the N20 latency plus 2 and 3 ms. Traces on the right show SICI and SAI after lorazepam. After lorazepam SICI is increased while, in contrast, SAI is suppressed.