title: GABAA receptor subtype specific enhancement of inhibition in human motor cortex.
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.
authors.affiliation: Istituto di Neurologia, Università Cattolica, L.go A. Gemelli 8, 00168 Rome, Italy. vdilazzaro@rm.unicatt.it
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Lazzaro
authors.forename: Fabio
authors.initials: F
authors.lastname: Pilato
authors.forename: Michele
authors.initials: M
authors.lastname: Dileone
authors.forename: Federico
authors.initials: F
authors.lastname: Ranieri
authors.forename: Valerio
authors.initials: V
authors.lastname: Ricci
authors.forename: Paolo
authors.initials: P
authors.lastname: Profice
authors.forename: Pietro
authors.initials: P
authors.lastname: Bria
authors.forename: Pietro A
authors.initials: PA
authors.lastname: Tonali
authors.forename: Ulf
authors.initials: U
authors.lastname: Ziemann
mesh_terms: D000328:Adult; D003975:Diazepam / Q000494:pharmacology; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D008140:Lorazepam / Q000494:pharmacology; D008297:Male; D009044:Motor Cortex / Q000187:drug effects / Q000378:metabolism*; D009433:Neural Inhibition; D011725:Pyridines / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000032:analysis / Q000187:drug effects / Q000378:metabolism*; D050781:Transcranial Magnetic Stimulation; D000077334:Zolpidem
chemical_list: C546240:GABRA1 protein, human; C484841:GABRA2 protein, human; C546257:GABRA3 protein, human; D006993:Hypnotics and Sedatives; D011725:Pyridines; D011963:Receptors, GABA-A; D000077334:Zolpidem; D008140:Lorazepam; D003975:Diazepam