Hippocampal slices from rat brain were exposed to histamine and related substances in a perfusion chamber. Granule cells of the dentate gyrus were studied with conventional extra- and intracellular recording and a single electrode voltage clamp. Histamine caused, through activation of H(2)-receptors, a small depolarization, an increase in the number of synaptic and action potentials, a block of the long lasting (but not the early) component of spike afterhyperpolarizations and a reduction of the accommodation of action potential firing. These effects were mimicked by forskolin (suggests activation of adenylate cyclase). In voltage clamp, histamine blocked a long lasting calcium-dependent outward tail current without any reduction of inward current. Thus histamine selectively blocks the late calcium-dependent potassium current in dentate granule cells which receive histaminergic input from the posterior hypothalamus. Histamine also reduces the field excitatory postsynaptic potential evoked by perforant path stimulation. These actions allow for a powerful modulation of excitatory signals and an effective regulation of hippocampal excitability.