Serotonin: From Cell Biology to Pharmacology and Therapeutics

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Pharmacology - Wikipedia

Discover the best of shopping and entertainment with Amazon Prime. Prime members enjoy FREE Delivery on millions of eligible domestic and international items, in addition to exclusive access to movies, TV shows, and more. Back to top. After the original discovery of serotonin, many laboratories were conducting parallel studies identifying the localization of serotonin along with investigating its function.

Serotonin was quickly identified as being present in many tissues including brain, lung, kidney, platelets, and the gastrointestinal tract.


Serotonin was only the third neurotransmitter to have been discovered at the time and but then has been linked to a variety of central nervous system functions such as mood, behavior, sleep cycles, and appetite. It was evident early on that serotonin was an important chemical in the vertebrate system and since its discovery research in the field has ballooned. In this review, we will present what is currently known about the role of serotonin in normal physiology and serotonin involvement in the pathogenesis of certain diseases such as migraine, irritable bowel syndrome IBS , systemic, and pulmonary hypertension.

We hope to demonstrate that much of what is known about serotonin physiology in health and disease has been based on animal models. Furthermore, we will review the emerging problem of serotonin toxicity known as serotonin syndrome in humans and animals. Serotonin is produced in two steps. The specific activity of tryptophan hydroxylase is in contrast to the nonspecific enzymatic activity of tryptophan decarboxylase. As it is not the limiting factor in serotonin synthesis, it is difficult to reduce serotonin levels by inhibiting this enzyme.

Within the central nervous system CNS , serotonin is synthesized and stored in the presynaptic neurons serotonergic neurons, pineal gland, and catecholaminergic neurons. Serotonin synthesis outside the CNS is limited to enterochromaffin cells and to a lesser extent platelets. Platelets may have very little ability to produce serotonin, however, platelets represent a major storage site for serotonin outside the CNS. The concentration of serotonin in tissues is dependent upon the rate of synthesis and the rate of metabolism Tyce, Major sites of MAO activity include the brain, gastrointestinal tract, lungs, liver, and platelets Tyce, Although metabolism occurs very rapidly, storage protects serotonin against metabolism.

Glucuronidation and sulfation represent minor metabolic pathways for serotonin and occurs in the liver, lung, kidney, and brain Tyce, In the CNS serotonin is processed in several ways. Upon neuronal depolarization, serotonin is released into the synaptic cleft. The highly selective serotonin transporter SERT located on the presynaptic membrane is responsible for removing serotonin from the synaptic cleft Fig.

Once transported into the presynpatic neuron, serotonin is recycled back into presynaptic vesicles where it is protected from metabolism. Metabolism by MAO occurs within the cytosol of the neuron. An alternative pathway for serotonin in the pineal gland is the conversion to melatonin. Serotonin that originates from enterochromaffin cells is released into portal circulation and is quickly eliminated from the plasma via uptake into platelets and metabolism by the liver.

Serotonin transporters located on the platelet membrane and enterochromaffin cells are responsible for uptake into those cells.

Serotonin: a review

Serotonin that escapes uptake and liver metabolism reaches the lung where is it then metabolized Tyce, There are a few important factors that determine the strength and duration of signaling on the postsynaptic serotonin receptor. Abundance of serotonin in the synaptic cleft is the major determinant of its effects. The two mechanisms directly involved in controlling the availability of serotonin in the synaptic cleft are binding of serotonin to its autoreceptor and the activity of the SERT both of which are located on the presynaptic membrane.

The SERT is a member of a more general class of monoamine transporters. This is the mechanism by which serotonin is taken up by platelets and enterochromaffin cells. The functions of serotonin in the CNS are very broad and are related to the action of the serotonergic system on the forebrain, brainstem, and cerebellum.

Projections from the rostral nuclei of this system help regulate temperature, appetite, sleep cycles, emesis, and sexual behavior.


Projections from caudal nuclei participate in nociception and motor tone. The most clinically relevant aspect has been the role of serotonin in psychological disorders in humans. An evolution of theories regarding the role of biogenic amines in the pathophysiology of psychological disorders led to the consensus that depression, mania, and anxiety disorders are associated with decreased availability of serotonin in the CNS Kandel, Although the earliest antidepressants, the MAO inhibitors, and tricyclic antidepressants TCA , enhanced availability of serotonin as well as other biogenic amines such as DAT and NET, the drugs aimed specifically at altering serotonin levels were considered the most effective.

The most potent and specific antidepressant is the class of drugs known as the selective serotonin reuptake inhibitors SSRI. These drugs bind specifically to the SERT, increasing availability of serotonin at the synaptic junction for receptor binding. SSRIs also have the added effect of inhibiting the presynaptic autoreceptor further enhancing availability of serotonin in the synaptic cleft Owens, The veterinary community can greatly benefit from what has been learned in the human field.

Although psychological disorders are less recognized in companion animals, several disorders have been characterized in both dogs and cat. Obsessive compulsive disorder and anxiety disorders have been documented in companion animals.

Some examples include storm phobias and separation anxiety in dogs, and inappropriate elimination in cats. Recently, several serotonergic agents have been approved by the FDA for treatment of separation anxiety in dogs.

They concluded that serotonin plays an important role in the amplification of platelet aggregation, by recruiting additional platelets once platelet aggregation has been initiated. The original intent of investigating serotonin was for its vasoconstrictor effects. Early studies in dogs established a triphasic response to serotonin when injected i. This can, in part, be explained by the receptors involved as well as the activity of the vascular endothelium at the time of serotonin exposure.

With few exceptions, isolated vascular smooth muscle strips contract when exposed to serotonin. In vivo , serotonin released from activated platelets can induce vasoconstriction in most large arteries, large veins, and venules. Serotonin also indirectly contributes to vasoconstriction by amplifying the contractile response of other vasoactive substances such as NET, angiotensin II, and histamine Vanhoutte, Vasodilatory effects on the arterial tree are most prominent at the arteriolar level and in a few isolated larger vessels.

As previously mentioned the health and activity of the endothelium is a determining factor in how serotonin affects vascular smooth muscle. Vascular disease results in phenotypic changes to the endothelium such as increased cell adhesion, fat deposition, decreased NO release, and decreased MAO activity. In basic terms the lack of NO may dampen vasodilatory response to serotonin predisposing to vasocontriction.

From a clinical perspective, vascular disease not only sensitizes patients to serotonin but may enhance its ill effects, namely, systemic hypertension.

Serotonin: From Cell Biology to Pharmacology and Therapeutics by Springer (Paperback, 2011)

Like control of vasomotor tone, the role of serotonin as a regulator of peripheral blood pressure is not straightforward. The simplest explanation is that the pressor effects of serotonin are both central and peripheral in origin. Experimentally, serotonin injected directly into the CNS has been reported to cause both hypertension and hypotension. There are few clinically relevant agonists and antagonists for manipulating vascular tone.

Most drugs are for research purposes only. However, one notable exception is ketanserin. The possible involvement of adrenergic receptors in hypertension further clouds the exact role of serotonin in the development of essential hypertension. However, the effect of serotonin on a hypertensive vascular bed has been well documented.

A hypertensive vascular bed is markedly more sensitive to the vasoconstrictive effects of serotonin when compared to a normal vascular bed. The threshold for the constrictor effect of serotonin is lower, the dose—response curve is steeper and the maximal response is much greater in hypertensive animals than normotensive ones. The discovery of the serotonin receptors led scientists to believe that serotonin can only exert its actions through these receptors.

However, a unique mechanism of action was discovered in the cardiopulmonary system. There was speculation that SERT was important in this mechanism. The drug was subsequently taken off of the market. This research refuted the decades old dogma that serotonin only exerted its action via receptors and that the singular role of the transporter was to recycle serotonin.

There has already been much progress in the treatment of pulmonary arterial hypertension through the manipulation of nitric oxide pathways with phosphodiesterase inhibitors.