Background There is much evidence that the sedative component of anesthesia is mediated by γ-aminobutyric acid A receptors on hypothalamic neurons responsible for arousal, notably in the tuberomammillary nucleus. These γ-aminobutyric acid A receptors are targeted by GABAergic neurons in the ventrolateral preoptic area (VLPO): when these neurons become active, they inhibit the arousal-producing nuclei and induce sleep. According to recent studies, propofol induces sedation by enhancing VLPO-induced synaptic inhibition, making the target cells more responsive to γ-aminobutyric acid A. We explored the possibility that propofol also promotes sedation less directly by facilitating excitatory inputs to the VLPO GABAergic neurons. Methods Spontaneous excitatory postsynaptic currents were recorded from VLPO cells – principally mechanically isolated, but also in slices from rats. Results In isolated VLPO GABAergic neurons, propofol increased the frequency of glutamatergic spontaneous excitatory postsynaptic currents without affecting their mean amplitude. Propofol’s action was mimicked by muscimol and prevented by gabazine, respectively a specific agonist and antagonist at γ-aminobutyric acid type-A receptors. It was also suppressed by bumetanide, a blocker of Na+-K+-Cl− cotransporter-mediated inward Cl− transport. In slices, propofol also increased the frequency of spontaneous excitatory postsynaptic currents and, at low doses, accelerated firing of VLPO cells. Conclusion Propofol induces sedation, at least in part, by increasing firing of GABAergic neurons in ventrolateral preoptic area, indirectly by activation of γ-aminobutyric acid type-A receptors on glutamatergic afferents: because these axons/terminals have a relatively high internal Cl− concentration, they are depolarized by GABAergic agents such as propofol which thus enhance glutamate release.

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