Propofol stimulates noradrenalin-inhibited neurons in the ventrolateral preoptic nucleus by reducing GABAergic inhibition.

Abstract

The cellular mechanisms underlying the sedative effect of general anesthetics are not completely understood. Accumulating evidence indicates that the ventrolateral preoptic area (VLPO) of the hypothalamus plays a critical role. The VLPO contains 2 major types of neurons, the noradrenalin-inhibited GABAergic projecting neurons (NA(-) neurons) and the noradrenalin-excited interneurons (NA(+) neurons) which are probably also γ-aminobutyric acid (GABA)-containing neurons. Our previous work suggests that NA(-) neurons are normally under the inhibitory control of NA(+) neurons. Previous studies also show that GABAergic agents including propofol activate GABAergic projecting neurons in the VLPO, which is believed to lead to the inhibition of the arousal-producing nuclei in the tuberomammillary nucleus and sedation. However, how propofol activates VLPO neurons remains unclear. We explored the possibility that propofol activates NA(-) neurons indirectly, by inhibiting GABAergic transmission including those from VLPO NA(+) neurons. Electrophysiological activities were recorded from VLPO cells in acute brain slices of rats. Propofol facilitates the discharges of NA(-) neurons and reduces the frequency, but not the amplitude of spontaneous GABAergic inhibitory postsynaptic currents in NA(-) neurons. Conversely, propofol suppressed the discharges of NA(+) neurons. Propofol excites VLPO NA(-) neurons by reducing GABAergic transmission, at least in part by inhibiting VLPO NA(+) neurons. This may be a critical mechanism contributing to propofol-induced sedation.