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

Abstract

Through whole-cell patch recordings, ?-Aminobutyric acid A receptor (GABAAR)-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 ?-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 extra synaptic GABAARs containing a4sd subunits. Furosemide, a selective blocker for GABAARs containing a6 subunit, which selectively and reversibly eliminated the propofolevoked increase in sIPSC frequency without altering the propofolevoked tonic current. Guvacine, a GABA transport blocker, which increases ambient GABA levels, induced tonic outward currents and increase sIPSCs frequency. Thus, the extra synaptic GABAARs may contain a4/6sd subunits. Since the NA(+) neurons are more sensitive to tonic inhibition induced by propofol, the extra synaptic GABAARs in the NA(+) neurons of VLPO may be a potential therapeutic target for the treatment of insomnia, sleep fragmentation and hypnosia.