Propofol Mediates Ambient GABA-activated Tonic Inhibition of VLPO Noradrenalin-Excited Neurons

Through whole-cell patch recordings, γ-Aminobutyric acid A receptor (GABA
_A
R)-mediated postsynaptic currents (IPSCs) were recorded from NA(+) neurons of the ventrolateral preoptic area (VLPO) in acute brain slices. Our previous study shows that propofol enhances the inhibitory γ-aminobutyric acid receptors (GABAARs) in the NA(+) neurons, thus reduces the activity of these neurons and the release of GABA onto the NA(-) neurons. In the present experiments, we found that propofol elicit a steady and sustained outward current shift on NA(+) neurons, demonstrating that propofol can enhance tonic currents. It is noteworthy that sIPSC frequency and tonic current were increased by gaboxadol, an agonist with preferential effects on extrasynaptic GABA
_A
Rs containing α4βδ subunits. Furosemide, a selective blocker for GABA
_A
Rs containing α6 subunit, which selectively and reversibly eliminated the propofol-evoked increase in sIPSC frequency without altering the propofol-evoked tonic current. Guvacine, a GABA transport blocker, which increases ambient GABA levels, induced tonic outward currents and increase sIPSCs frequency. Thus, the extrasynaptic GABA
_A
Rs may contain α4/6βδ subunits. Since the NA(+) neurons are more sensitive to tonic inhibition induced by propofol, the extrasynaptic GABA
_A
Rs in the NA(+) neurons of VLPO may be a potential therapeutic target for the treatment of insomnia, sleep fragmentation and hypnosia.