Serotonin is produced from tryptophan and stored in vesicles in the enterochromaffin

cells of the gut and neurons of the CNS and enteric nervous system. After release, it is
metabolized by monoamine oxidase. Excess production in the body (eg, in carcinoid
syndrome) can be detected by measuring its major metabolite, 5-hydroxyindole acetic
acid(5-HIAA), in the urine. Serotonin plays a physiologic role as a neurotransmitter in
both the CNS and the enteric nervous system and may have a role as a local hormone
that modulates gastrointestinal activity. After release from neurons, it is partially taken
back up into the nerve ending by a serotonin reuptake transporter (SERT). Serotonin
is also stored (but synthesized to only a minimal extent) in platelets. In spite of the very
large number of serotonin receptors (14 identified to date), most of the
serotonin agonists in clinical use act at 5-HT1D/1B and 5-HT2C receptors. Serotonin
antagonists in use or under investigation act at 5-HT2 and 5-HT3 receptors (see drug
overview figure at the beginning of the chapter).

A. Receptors and Effects

1. 5-HT1 RECEPTORS

5-HT1 receptors are most important in the brain and mediate synaptic inhibition via
increased potassium conductance (Table 16–1). Peripheral 5-HT1 receptors mediate
both excitatory and inhibitory effects in various smooth muscle tissues. 5-HT1 receptors
are Gi-protein-coupled.

2. 5-HT2 RECEPTORS

5-HT2 receptors are important in both brain and peripheral tissues. These receptors
mediate synaptic excitation in the CNS and smooth muscle contraction (gut, bronchi,
uterus, some vessels) or relaxation (other vessels). Several mechanisms are involved,
including (in different tissues) increased IP3, decreased potassium conductance, and
decreased cAMP. This receptor probably mediates some of the vasodilation, diarrhea,
and bronchoconstriction that occur as symptoms of carcinoid tumor, a neoplasm that
releases serotonin and other substances. In the CNS, 5-HT2Creceptors mediate a
reduction in appetite that has been used in the treatment of obesity.

3. 5-HT3 RECEPTORS

5-HT3 receptors are found in the CNS, especially in the chemoreceptive area and
vomiting center, and in peripheral sensory and enteric nerves. These receptors mediate
excitation via a 5-HT-gated cation channel. Antagonists acting at this receptor are
extremely useful antiemetic drugs.
4. 5-HT4 RECEPTORS

5-HT4 receptors are found in the gastrointestinal tract and play an important role in
intestinal motility.

B. Clinical Uses

Serotonin has no clinical applications, but other more selective agonists are useful.

1. 5-HT1D/1B AGONISTS

Sumatriptan is the prototype. Naratriptan and other “-triptans” are similar

to sumatriptan (see Drug Summary Table). They are the first-line treatment for
acute migraine and cluster headache attacks, an observation that strengthens the
association of serotonin abnormalities with these headache syndromes. These drugs
are active orally; sumatriptan is also available for nasal and parenteral administration.
Ergot alkaloids, discussed later, are partial agonists at some 5-HT receptors.

2. 5-HT2C AGONISTS

Lorcaserin has recently been approved for the treatment of obesity. It activates
receptors in the CNS and appears to moderately reduce appetite. Older
drugs, fenfluramine and dexfenfluramine, appear to act directly and by releasing
neuronal 5-HT or inhibiting SERT, and thereby activating central 5-HT2C receptors. They
were withdrawn in the USA because their use was associated with damage to cardiac
valves. Dexfenfluramine was combined with phentermine, an amphetamine-like
anorexiant, in a weight-loss product known as “dex-phen.” Because of toxicity, this
combination product is also banned in the USA.

3. 5-HT4 PARTIAL AGONIST

Tegaserod is a newer drug that acts as an agonist in the colon. It was approved and
briefly marketed for use in chronic constipation, but because of cardiovascular toxicity,
its use is now restricted.

4. SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRI)

A number of important antidepressant drugs act to increase activity at central

serotonergic synapses by inhibiting the serotonin reuptake transporter, SERT. These
drugs are discussed in Chapter 30.

C. Hyperthermic Syndromes
Serotonin and drugs with 5-HT agonist effects are sometimes associated with drug
reactions with high fever, skeletal muscle effects, and cardiovascular abnormalities that
can be life-threatening. These important syndromes are summarized in Table 16–2.

TABLE 16–2Characteristics of serotonin syndrome and other hyperthermic syndromes.

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