Long-term plasticity, in the forms of long-term depression (LTD) and long-term potentiation (LTP), of synaptic transmission are thought to underlie memory. Biogenic amino acids modulate the expression of LTD and LTP. The serotonergic 5-hydroxytryptamine4 (5-HT4) receptor has been shown to influence learning and memory. However, little is known about the role of this receptor in synaptic plasticity. Here we show that although induction of LTP is unaffected by either pharmacological activation or inhibition of 5-HT4, application of the 5-HT4 receptor agonist, RS67333, completely blocks learning-induced depotentiation of LTP in the hippocampal CA1 region of freely moving rats, suggesting a role for 5-HT4 receptors in behavioural metaplasticity. In addition, the 5-HT4 antagonist RS39604 enhances the intermediate phase of LTD and converts short-term depression into persistent LTD (>24 h), suggesting a significant role for 5-HT4 receptors in the expression of LTD in CA1. Stimulation at 10 Hz causes transient synaptic depression. However, 5-HT4 antagonist application prior to 10 Hz stimulation leads to LTD, whereas agonist application leads to LTP expression. 5-HT4 receptors thus shift the frequency-response relationship for induction of plasticity. Together, these findings suggest a key role for 5-HT4 receptors in the regulation of synaptic plasticity and the determination of the particular properties of stored synaptic information.