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

Abstract

THIP is a hypnotic drug, which displays a unique pharmacological profile, because it activates a subset of extrasynaptic gamma-aminobutyric acid type A (GABA(A)) receptors containing delta-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 GABA(A)-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 alpha(1/2/3)- and gamma(2)-containing receptors, did not alter the tonic current induced by THIP. The anesthetic etomidate (1 microM), which shows selectivity for beta(2)- and beta(3)-containing GABA(A) receptors, potentiated the THIP current by 126%. Etomidate also induced a small tonic GABA(A) current per se. The anesthetic propofol (1 microM), which displays broad-spectrum modulatory effects on several GABA(A)-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 GABA(A) receptors responsible for the tonic THIP conductance likely do not contain alpha(1)-, alpha(2)-, alpha(3)-, and gamma(2)-subunits. Thus the tonic GABAergic conductance in the neocortex is presumably mediated by alpha(4)beta(2/3)delta 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.