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. 2006 Sep 15;575(Pt 3):721-6.
doi: 10.1113/jphysiol.2006.114694. Epub 2006 Jun 29.

GABAA receptor subtype specific enhancement of inhibition in human motor cortex

Vincenzo Di Lazzaro  1 , Fabio Pilato, Michele Dileone, Federico Ranieri, Valerio Ricci, Paolo Profice, Pietro Bria, Pietro A Tonali, Ulf Ziemann
Affiliations

GABAA receptor subtype specific enhancement of inhibition in human motor cortex

Vincenzo Di Lazzaro et al. J Physiol. .

Abstract

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.

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Figures

Figure 1
Figure 1. Short latency intracortical inhibition (SICI)
A, mean SICI (n = 7) expressed as the ratio of conditioned over unconditioned MEP (cMEP/uMEP) before (t0) and at three time points (t1–t3) after intake of a single oral dose of 20 mg of diazepam (triangles), 2.5 mg of lorazepam (squares) or 10 mg of zolpidem (circles), tested at interstimulus intervals (ISI) of 2 ms (A1) and 3 ms (A2). Filled symbols indicate significant change from t0 (P < 0.05). B–D, same data as in A but with all seven tested subjects shown individually. Each symbol denotes a single subject tested in randomised order for diazepam (B), lorazepam (C) and zolpidem (D). Note that diazepam and lorazepam but not zolpidem led to a consistent increase in SICI at t1 when compared with t0.
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