Waking Action of Ursodeoxycholic Acid (UDCA) Involves Histamine and GABAA Receptor Block

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 period of the day, lacking this activity in histamine-deficient mice. In cultured hypothalamic neurons UDCA did not affect firing rate but synchronized the firing, an effect abolished by the GABA(A)R antagonist gabazine. In histaminergic neurons recorded in slices UDCA reduced amplitude and duration of spontaneous and evoked IPSCs. In acutely isolated histaminergic neurons UDCA inhibited GABA-evoked currents and sIPSCs starting at 10 mu M (IC50 = 70 mu M) and did not affect NMDA- and AMPA-receptor mediated currents at 100 mu M. Recombinant GABA(A) receptors composed of alpha 1, beta 1-3 and gamma 2L subunits expressed in HEK293 cells displayed a sensitivity to UDCA similar to that of native GABA(A) receptors. The mutation alpha 1V256S, known to reduce the inhibitory action of pregnenolone sulphate, reduced the potency of UDCA. The mutation alpha 1Q241L, which abolishes GABA(A)R potentiation by several neurosteroids, had no effect on GABA(A)R inhibition by UDCA. In conclusion, UDCA enhances alertness through disinhibition, at least partially of the histaminergic system via GABA(A) receptors.