The influence of melatonin on hippocampal evoked potentials initiated by low- and high-frequency electrical stimulations and by two pulses applied in rapid succession was investigated. In confirmation of our previous studies, melatonin attenuated the population spike triggered by low-frequency stimulation (0.03 Hz). High-frequency stimulation (HFS; 100 Hz for 1 sec, three times every 10 sec), which in control slices permanently facilitated neuronal excitability (347% ± 32%), was also able to amplify the melatonin-depressed potential (467.8% ± 59.6%). Because melatonin is a hydrophobic molecule, it was dissolved and applied in ethanol. Ethanol (0.4%) by itself reduced the magnitude of HFS-induced potentiation (233.5% ± 16.8%). The slices stimulated with two pulses separated with a delay longer than 15 msec demonstrated a facilitation of the response to the second stimuli (paired-pulse facilitation; PPF). The influence of melatonin (100 μM) on PPF was biphasic: Shortly after addition of melatonin, PPF was briefly (5–10 min) reversed to paired-pulse inhibition (PPI), which gradually returned to a stable PPF. Ethanol (0.4%) applied without melatonin exerted only a marginal, facilitatory effect on PPF. The delay between two successively applied pulses, shorter than 13 msec, resulted in attenuation of the response to the second stimuli (PPI). Melatonin (100 μM) reversed the attenuation of the second potential within 15–20 min following its application. Ethanol applied by itself at the concentration of 0.4% temporarily (5–10 min), but significantly, depressed the second potential. These results demonstrate the ability of melatonin to modulate specific forms of plasticity in hippocampal pyramidal neurons. © 2003 Wiley-Liss, Inc.