Serotonin 5-HT4 receptors were first described in mouse colliculi neurons. They are positively coupled to adenylyl cyclase, and possess unique pharmacological properties. Indeed, they are not blocked by classical 5-HT1, 5-HT2 or 5-HT3 antagonists. Several classes of specific 5-HT4 receptor agonists (benzamides and benzimidazoles) and antagonists have now been described. The most specific and potent 5-HT4 antagonist is an indole derivative, GR-113808, which has been used to prepare a radioligand for 5-HT4 receptors.
Both functional and radioligand binding studies indicate that 5-HT4 receptors are expressed in the brain of several species, including human brain. The restricted brain distribution of 5-HT4 receptors indicates that specific neurological and psychiatric functions are affected by these receptors. Thus, specific central nervous system disorders may benefit from the development of 5-HT4 ligands.
The similarities between the molecular mechanisms of action of 5-HT4 receptors and those in Aplysia (sea hare) neurons may suggest a role for the receptors in synaptic plasticity events and memory processes. The localisation of 5-HT4 receptors in the limbic structures suggests a role for the receptors in emotional and reward processes, and expression of the receptors in the basal ganglia and substantia nigra indicates a role in the control of visuo-motor activity.