We describe a histamine-activated Cl(-) conductance in the X-organ neurons from crayfish Cherax quadricarinatus, which has comparable properties to the homomultimeric histamine-gated ion channels described in Drosophila. Topical application of histamine inhibited spontaneous neuronal firing in the X-organ sinus gland tract, concomitant with an increase in the membrane conductance. In X-organ neurons in culture and under voltage-clamp conditions, histamine evoked outward currents at -40 mV that reversed at the Cl(-) equilibrium potential. Histamine sensitivity in these neurons had a half-maximal response (EC(50))=3.3+/-1 micromol l(-1), with a Hill number of 2.6+/-0.4. The histamine-evoked current was blocked by tiotidine, cimetidine, ranitidine and 256+/-11 and 483+/-11 micromol l(-1), respectively) and d-tubocurarine (IC(50)=21+/-2 micromol l(-1)), but was insensitive to picrotoxin, bicuculline and strychnine. Neither GABA nor glutamate was capable of desensitizing the histamine response, indicating that histamine activates a particular Cl(-) conductance. The presence of immunoreactive neurons to histamine in the medulla terminalis with axonal projections to the neuropile suggests a possible histaminergic modulation of the X-organ sinus gland system.