The effects of histamine on baseline synaptic transmission and long-term potentiation (LTP) were investigated in the CA1 region of rat hippocampal slices. Bath applied histamine reversibly and dose-dependently increased the amplitude of extracellularly recorded population spikes in the concentration range 0.1-100 microM by a maximum of 40%. At higher concentrations (10-100 microM) histamine also caused a small depression of field excitatory postsynaptic potentials (fEPSPs) of approx 10%. The effect of histamine on population spikes was found to be mediated through histamine H2 receptors. Histamine (10-100 microM) was found to produce a statistically significant LTP of fEPSPs when combined with a weak tetanus (0.25 sec, 50 Hz). Histamine H1 (mepyramine, 1 microM) and H2 (cimetidine, 50 microM) receptor antagonists did not block this enhanced potentiation. In addition, histamine (10-100 microM) enhanced the late portion of the response produced by pressure ejection of glutamate receptor agonist N-methyl-D-aspartate into the slice, as recorded extracellularly or intracellularly. This effect of histamine was only apparent when large NMDA responses were obtained, using a high pipette concentration of NMDA (1 mM). In the presence of histamine H1 and H2 antagonists, potassium channel blockers or blockade of inhibition, this enhancement could still be observed. We conclude that histamine facilitated the induction of LTP, most likely by acting directly at the NMDA receptor.