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.

Dissociated effects of diazepam and lorazepam on short‐latency afferent inhibition

“…suppression of homonymous SAI, as reported in a recent study (Di Lazzaro et al 2005). Why diazepam increased SAI only at longer ISIs of N20 +4 ms and N20 +6 ms but not the short ISIs of N20 +2 ms (cf.…”

“…The dose of lorazepam was chosen because previous TMS studies proved it effective in altering motor cortical excitability (Ziemann et al 1996a;Di Lazzaro et al 2000b, 2005. Additional measurements of SAI were run 6 h and 24 h after drug administration for both drugs, to obtain information on the time course of drug effects.…”

“…Since this inhibitory phenomenon is reduced or abolished by the muscarinic antagonist scopolamine (Di Lazzaro et al 2000a), we suggested that it might be a non-invasive way of testing cholinergic activity in the SAI pathway. More recently, we showed (Di Lazzaro et al 2005) that also the benzodiazepine lorazepam results in a suppression of SAI, concomitantly with an increase in a different intracortical inhibitory phenomenon, the so-called short-latency intracortical inhibition (SICI) (Kujirai et al 1993). SICI is believed to be mediated by GABA A ergic inhibitory neuronal circuits (Ziemann et al 1996a,b;Di Lazzaro et al 2000b;Ziemann, 2004).…”

Functional involvement of the cerebral cortex following paramedian bithalamic infarction

“…Lasheras, Del Rio, & Ramirez, 2002;Giorgetti et al, 2000) and at the forebrain level (Vasquez & Baghdoyan, 2003); GABA A receptors are localized on forebrain cholinergic neurons projecting to the cortex (Zaborszky, Heimer, Eckenstein, & Leranth, 1986), and their activation results in inhibition (Khateb et al, 1998). It has been recently demonstrated (Di Lazzaro et al, 2005b) that the administration of lorazepam produces a significant increase in SICI and a significant decrease of SAI in normal subjects. It could therefore be hypothesised that in subjects with paramedian thalamic lesions GABAergic activity enhancement determines a suppression of central cholinergic activity, as evaluated by means of SAI.…”

Combination of Transcranial Magnetic Stimulation with Electromyography and Electroencephalography: Application in Diagnosis of Neuropsychiatric Disorders

“…Comparison of TMS and TES and recordings of descending volleys suggest that SAI occurs at the cortical level (Tokimura et al, 2000). The molecular underpinnings of SAI are complex and SAI likely relates to an interaction between several neurotransmitter systems with the possible involvement of the cholinergic neurotransmission (Di Lazzaro et al, 2005;Di Lazzaro et al, 2007;Di Lazzaro et al, 1999c).…”