Since ancient times ursodeoxycholic acid (UDCA), a constituent of bile, is used against gallstone formation and cholestasis. A neuroprotective action of UDCA was demonstrated recently in models of Alzheimer's disease and retinal degeneration. The mechanisms of UDCA action in the nervous system are poorly understood. We show now that UDCA promotes wakefulness during the active time of the day, lacking this activity in histamine-deficient mice. In cultured hypothalamic neurons UDCA synchronized the firing, an effect not present under the GABAAR antagonist gabazine. In histaminergic neurons recorded in slices UDCA reduced amplitude and duration of spontaneous and evoked IPSCs but left the firing unchanged. In acutely isolated histaminergic neurons UDCA blocked GABA-evoked currents and sIPSCs starting at 10mM (IC₅₀=70mM) and did not affect NMDA- and AMPA-receptor mediated currents at 100mM. Recombinant GABA_A receptors composed of a1, b1-3 and g2L subunits expressed in HEK293 cells displayed similar sensitivity to UDCA as native GABA_A receptors. The mutation a1V256S known to reduce the inhibitory action of pregnenalone sulphate reduced the potency of UDCA. The mutation a1Q241L, which abolishes GABA_AR potentiation by several neurosteroids had no effect on GABA_AR inhibition by UDCA. In conclusion, UDCA enhances alertness through disinhibition of the histaminergic system.