Modulation of Extrasynaptic THIP Conductances by GABAA-Receptor Modulators in Mouse Neocortex

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Abstract
THIP is a hypnotic drug, which displays a unique pharmacological profile, because it activates a subset of extrasynaptic γ-aminobutyric acid type A (GABAA) receptors containing δ-subunits. It is important to study the physiology and pharmacology of these extrasynaptic receptors and to determine how THIP interacts with other hypnotics and anesthetics. Here, we study the modulation of the extrasynaptic response to THIP using three classes of GABAA-receptor ligands. In whole cell recordings from mouse neocortical layer 2/3 pyramidal cells, THIP induced an extrasynaptic tonic current of 44 ± 5 pA. The benzodiazepine site agonist and hypnotic zolpidem (500 nM), which displays selectivity for α1/2/3- and γ2-containing receptors, did not alter the tonic current induced by THIP. The anesthetic etomidate (1 μM), which shows selectivity for β2- and β3-containing GABAA receptors, potentiated the THIP current by 126%. Etomidate also induced a small tonic GABAA current per se. The anesthetic propofol (1 μM), which displays broad-spectrum modulatory effects on several GABAA-receptor subtypes, enhanced the tonic THIP current by 117%. Finally, all three compounds modulated the function of intrasynaptic receptors activated by synaptically released GABA. Our study shows that the extrasynaptic GABAA receptors responsible for the tonic THIP conductance likely do not contain α1-, α2-, α3-, and γ2-subunits. Thus the tonic GABAergic conductance in the neocortex is presumably mediated by α4β2/3δ receptors, which are likely to play a major role for neocortical excitability. Furthermore, our study has deepened the knowledge about the cellular actions of THIP as well as THIP's interactions with other hypnotics and anesthetics.