We have studied the effects of serotonin on the histaminergic neurons in the hypothalamic tuberomammillary nucleus. Intracellular recordings of the membrane potential were made with sharp electrodes from superfused rat hypothalamic slices. We found that serotonin increased the firing rate of the neurons to 224% of the control rate and depolarized them dose-dependently. Insensitivity to tetrodotoxin indicated a postsynaptic effect, which was unrelated to any conductance change. The involved receptor appeared to be a 5-HT2C receptor. The depolarization was strongly dependent on temperature and replacement of extracellular Na(+) with Li(+) or with N-methyl-D-glucamine suppressed the depolarization. Pretreatment with Ni(2+), 2',4'-dichlorobenzamil or KB-R7943 strongly attenuated the effect. These features indicate that the depolarization is the result of activation of an electrogenic Na(+)/Ca(2+)-exchanger which leads to an net inward current. These results support the view that the Na(+)/Ca(2+)-exchanger can play a role in determining the excitability of neurons. The results also provide a functional connection between two transmitter systems, the histaminergic and serotonergic, which modulate many physiological functions in the brain.