The function of serotonin in enterochromaffin cells is not fully understood. These cells synthesize serotonin, store the amine in a complex with adenosine triphosphate (ATP) and other substances in granules, and release serotonin in response to mechanical and neuronal stimuli. This serotonin interacts in a paracrine fashion with several different 5-HT receptors in the gut (see Chapter 62). Some of the released serotonin diffuses into blood vessels and is taken up and stored in platelets.
Serotonin is metabolized by MAO, and the intermediate product, 5-hydroxyindoleacetaldehyde, is further oxidized by aldehyde dehydrogenase to 5-hydroxyindoleacetic acid (5-HIAA). In humans consuming a normal diet, the excretion of 5-HIAA is a measure of serotonin synthesis. Therefore, the 24-hour excretion of 5-HIAA can be used as a diagnostic test for tumors that synthesize excessive quantities of serotonin, especially carcinoid tumor. A few foods (eg, bananas) contain large amounts of serotonin or its precursors and must be prohibited during such diagnostic tests.
A. Mechanisms of Action
Serotonin exerts many actions and, like histamine, displays many species differences, making generalizations difficult. The actions of serotonin are mediated through a remarkably large number of cell membrane receptors. The serotonin receptors that have been characterized thus far are listed in Table 16–3. Seven families of 5-HT-receptor subtypes (those given numeric subscripts 1 through 7) have been identified, six involving G protein-coupled receptors of the usual seven-transmembrane serpentine type and one a ligand-gated ion channel. The latter (5-HT3) receptor is a member of the nicotinic family of Na+/K+ channel proteins.
B. Tissue and Organ System Effects 1. Nervous system—Serotonin is present in a variety of sites in the brain. Its role as a neurotransmitter and its relation to the actions of drugs acting in the central nervous system are discussed in Chapters 21 and 30. Serotonin is also a precursor of melatonin in the pineal gland (Figure 16–2; see Box: Melatonin Pharmacology). Repinotan, a 5-HT1A agonist currently in clinical trials, appears to have some antinociceptive action at higher doses while reversing opioid-induced respiratory depression.
5-HT3 receptors in the gastrointestinal tract and in the vomiting center of the medulla participate in the vomiting reflex (see Chapter 62). They are particularly important in vomiting caused
TABLE 16–3 Serotonin receptor subtypes currently recognized. (See also Chapter 21.) 1Research agents; for chemical names see Alexander SPH, Mathie A, Peters JA: Guide to receptors and channels (GRAC). Br J Pharmacol 2011;164 (Suppl 1):S16–17, 116–117. cAMP, cyclic adenosine monophosphate; EPSP, excitatory postsynaptic potential; IP3, inositol trisphosphate.
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