Serotonin is found body wide, distributed through many tissues. 5-HIAA, the metabolite of serotonin (5-HT), is used as a diagnostic indicator for carcinoid tumor, a cancer of the GIT that results in overproduction of 5-HT.

Pineal gland -- 5-HT serves as a precursor to melatonin

Enterochromaffin Cells -- GIT -- contain over 90% of the body load of 5-HT.  This is a major site of synthesis of circulating 5-HT.

Platelets -- do not synthesis serotonin, but do have an uptake mechanism, and serotonin is stored and released from platelets.

Raphe nuclei of the brain -- serotonin's role in the CNS is complex and may be involved in mood and depression, sleep, appetite, pain perception, and control of body temperature and blood pressure.

Cardiovascular System

Vasculature -- Vasoconstriction (EXCEPT vessels in the heart and skeletal muscle -- Vasodilatation) -- Both 5-HT_{1B and 1D}  and 5-HT₂ have been shown to cause vasoconstriction.  5-HT_2B and possibly 5-HT₇ have been implicated in vasodilation.  However, other serotonergic receptors may also modulate vascular tone.

Heart -- direct mild positive chronotropic and inotropic effects.  The primary effects on the heart are secondary to actions on the 5-HT₃ receptors which stimulate chemoreceptors that cause reflex bradycardia and reduced cardiac output.

Platelets -- 5-HT₂ receptors mediate platelet aggregation.  This effect is more prominent in the presence of collagen and/or vascular injury.

Direct actions -- Serotonin causes contraction via 5-HT₂ receptors.  It appears that serotonin is a major neurotransmitter in controlling GI motility.

Indirect actions -- Serotonin also causes contraction by acting at 5-HT₄ receptors which in turn increases the release of acetylcholine.  There is also evidence that the 5-HT₄ receptor may be present directly on the smooth muscle.

Activation of 5-HT₃ receptors both in the area postrema and peripheral nerves innervating the GIT will induce emesis.

Nervous System --

Serotonergic nerves at least in part mediate the sensation of pain and itch.

Activation of 5-HT₃ receptors both in the area postrema and peripheral nerves will induce emesis.

Behaviour --

Aggression -- serotonin has been correlated to increased aggression and impulsivity.  Specifically the 5-HT_1A receptor, among others, has been implicated.

Serotonin also plays a role in anxiety and depression.  These effects may be mediated through 5-HT_1A, 5-HT_2A, 5-HT_2C, and 5-HT₃ receptors.

Dexfenfluramine and other anorexigenic drugs -- These agents may exert their effect by either acting as agonists at serotonergic receptors, increasing the release of serotonin, or blocking its re-uptake (or a combination of all three actions).  Side effects include headache, insomnia, CNS excitation, cardiovascular acceleration, and pulmonary hypertension.

Buspirone -- this drug is a 5-HT_1A agonist.  It is effective in certain types of anxiety, has minimal abuse potential, no marked sedation, and produces little CNS depression.  Side effects include tachycardia, palpitations, paraesthesias, and GI distress.

Selective Serotonin Re-Uptake Inhibitors (Fluoxetine, Sertraline, Paroxetine, Fluvoxamine) are active on the serotonergic system and have been previously covered in Pharmacology I.

Cisapride -- is a 5-HT₄ agonist.  It causes the release of acetylcholine which, in turn, increases GI motility.  It was used in the treatment of GERD.  Cisapride effectively lowers oesophageal sphincter pressure, increases gastric emptying, and increases colonic motility.  Food increases its' absorption and it should therefore be taken with meals.  The primary side effect observed with cisapride is diarrhoea.  This drug has been removed from the market due to the development of life-threatening arrhythmias, including torsade de pointes with accompanying prolonged QT intervals.   This effect was most often observed when the drug was administered with an inhibitor of the CYP 3A4 metabolising system such as the macrolide antibiotics (erythromycin) or the imidazole/triazole antifungals (ketoconazole or itraconazole).  There were approximately 340 reported cases of arrhythmia with at least 80 deaths due to cisapride-induced QT lengthening, thus prompting its voluntary removal by the manufacturer.

Sumatriptan and similar drugs are 5-HT_1D agonists currently used in the treatment of migraine headaches.  These agents will be discussed more in-depth below.

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