This study tests the effect of serotonin (5-HT) (1 microM) on the induction of long-term potentiation (LTP) at the commissural/associational (C/A)-CA3 synapse. The C/A input to CA3 was measured by field potentials in rat hippocampal slices. At the concentration used 5-HT had little or no effect on synaptic transmission, but suppressed the induction of LTP. Similar results were observed in normal saline and in saline containing picrotoxin (10 microM) and bicuculline (10 microM) to block GABAA inhibition. Perfusion with methysergide (1 microM), a 5-HT antagonist, had no effect on synaptic transmission, but partially blocked the effect of 5-HT on LTP. The block of LTP by 5-HT could be overcome by using a higher intensity of stimulation suggesting that 5-HT might hyperpolarize the postsynaptic neurons to inhibit LTP induction. We conclude that the activation of serotonergic receptors inhibits the induction of LTP at the C/A-CA3 synapse.