The neurons responsible for the onset of sleep are thought to be located in the ventrolateral preoptic nucleus (VLPO), which receives a dense histaminergic innervation from the tuberomammillary nucleus (TMN). Yet, the role of histamine in the VLPO remains unclear. Here we report that microinjection of histamine into the VLPO increases the motor activity of rats. Moreover, a bath application of histamine to acute brain slices inhibits the majority of VLPO neurons, which are also inhibited by noradrenaline. Histamine hyperpolarizes the membrane potential and lowers the firing rate. These effects are associated with an increase in the frequency but not in the amplitude of spontaneous GABA(A) receptor-mediated inhibitory postsynaptic currents, and are blocked by gabazine or tetrodotoxin, indicating an indirect action. Conversely, on the noradrenaline-excited VLPO neurons, histamine depolarizes the membrane potential and increases the firing rate via activation of H(1) and H(2) subtype histamine receptors. Moreover, histamine-induced depolarization persists in the presence of gabazine or tetrodotoxin, indicating a direct action. Based on these findings, we propose that in the VLPO, noradrenaline-inhibited neurons may normally be under the inhibitory control of noradrenaline-excited neurons. By facilitating the inhibitory control of the noradrenaline-excited neurons, histamine may inhibit the noradrenaline-inhibited neurons, resulting in excitation of histamine-releasing neurons in the TMN through disinhibition. This effect of histamine in the VLPO may contribute to the maintenance of wakefulness.