Modulation of membrane properties and excitability of retinal ganglion cells (RGCs) by dopamine was investigated in rat retinal slices, using whole cell patch clamp techniques. Application of dopamine (10 microM) caused a small depolarization of the membrane potential, a reduction of the input resistance and a decrease in the number of current-evoked action potentials of RGCs, and these effects were blocked by a D1 antagonist (SCH23390, 10 microM), but not by a D2 antagonist (sulpiride, 10 microM). SKF38393 (10 microM), a D1 agonist, but not quinpirole (10 microM), a D2 agonist, mimicked the effects of dopamine on RGCs. Like dopamine, 8-Br-cAMP, a membrane-permeable analog of cAMP, produced similar changes in the membrane properties and the excitability of RGCs. All these results suggest that these effects of dopamine are likely mediated by D1 receptors. Pre-application of KT5720, an inhibitor of protein kinase A (PKA), blocked the dopamine effects, indicating that the effects were PKA-dependent. Possible involvement of hyperpolarization-activated cation currents (I(h)) in the dopamine effects was tested. Inward currents were induced by voltage steps, with an activation threshold of around -70 mV, in the presence of TTX, Cd(2+), TEA-Cl and 4-AP. These currents, with a reversal potential of -33.2 mV, displayed inward rectification and were blocked by ZD7288, a specific I(h) channel blocker. These results are indicative of the presence of I(h) in rat RGCs. Dopamine increased the amplitude of I(h) and shifted the activation curve of I(h) to a range of more positive potentials. SKF38393 and 8-Br-cAMP increased the amplitude of I(h), which was blocked by KT5720. The dopamine effects were abolished when the preparations were pre-incubated by ZD7288. These data strongly suggest that the dopamine effects on rat RGCs may be, at least in part, mediated by modulation of I(h) through the cAMP- and PKA-dependent pathway.