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

Abstract

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.

PDGF Modulates Synaptic Excitability and Short-Latency Afferent Inhibition in Multiple Sclerosis

“…Indeed, alterations of SAI have been observed in association with cognitive deficits [46][47][48], movement preparation [49], modifications of cholinergic [48], GABAergic [50] and dopaminergic activity [51]. This may also account for the weak, although significant, correlation that we here report between SAI and PDGF-CSF.…”

Transcranial Magnetic Stimulation in Different Current Directions Activates Separate Cortical Circuits

“…This is consistent with the different effects of benzodiazepines on SICI and SAI. SICI is increased by both lorazepam and diazepam but SAI is only slightly increased by diazepam and is reduced by lorazepam (Di Lazzaro et al 2005). Therefore the cortical circuits activated by SAI and SICI are likely to be different.…”

“…Previous studies investigating SAI in PA current direction also reported that SAI inhibits late I-waves (Di Lazzaro et al 2005;Sailer et al 2003;Tokimura et al 2000), suggesting that the cortical circuits mediating late Iwaves are more susceptible to cortical inhibition than those mediating early I-waves. Consistent with these previous studies, we found that sensory afferent input inhibited the output from M1 at the ISIs around 20 ms not only for PA but also for AP current direction.…”

Transcranial Magnetic Stimulation to Investigate Motor Cortical Circuitry and Plasticity in Spinal Cord Injury

“…Cholinergic and GABAergic systems appear to mediate and/or modulate SAI. Scopolamine, an anti cholinergic drug, reduces SAI [58,59] while diazepam, a GABA A modulator, increases SAI [60]. LAI however, is thought to proceed through only a GABAergic system.…”