Tuesday, April 11, 2017

Sources of 5-HT in nature

5-Hydroxytryptamine (5-HT) has a widespread occurrence in nature. It occurs in plants, insect stingers, sea creatures, and mammals.
“The occurrence of 5-HT in groups so far removed from a common ancestor as vertebrates and flowering plants indicates either that the ability to produce 5-HT is primitive in evolution, or that this capacity is readily evolved as occasion demands.” (Lewis,G.P. 1958)
Table 4 (below) lists sources of 5-HT in different species. Among Vertebrates, dogs, rabbits, hens, ducks, tortoises, grass snakes, and fish have 5-HT in the gut, while in some frogs, 5-HT can be found in the skin. There is 5-HT found within the stinging fluid of some Angiosperms and Arthropoda. The 5-HT content in varies from one species to another. Remarkable also are individual variations in the same species.


Serotonin was first studied as the specific secretion product (enteramine) of the enterochromaffin cells. Located in the gastrointestinal tract, the enterochromaffin cells synthesize about 90% of the total 5-HT in the body, thus enterochromaffin cells are the primary source of 5-HT in the body. Enterochromaffin cells fluoresce after fixation with formaldehyde, showing the characteristic fluorescence reaction of 5-HT with formaldehyde. It is further indicated that enterochromaffin cells are the major source of 5-HT in the body, since some groups of fish including those from Teleostei and Cyclostomata do not contain 5-HT while other groups of fish do, and Teleostei and Cyclostomata lack enterochromaffin cells altogether (Erspamer,V. 1954).

Tunicates and echinoderms are unable to uptake radioactive 5-HT (3H-5-HT), and lack 5-HT in the gut or elsewhere. In comparison, abundant amounts of 5-HT can be found in the digestive tracts of hagfish, goldfish and bullfrog. In goldfish and bullfrog, 3H-5-HT labeling was most intense over the intestinal cells, Auerbach's plexus and the circular muscle layer.

There are high amounts of 5-HT in stomach, small intestine, and tongue. Accordingly the early 5-HT researchers believed that 5-HT was concerned with intestinal mobility. According to these researchers, enterochromaffin cells are a “diffuse endocrine organ” designed for the production and storage of 5-HT. They believed that 5-HT was released in the digestive tract and carried away by the blood stream. They also thought that high concentrations of amine oxidase in the liver were to help prevent a flooding of the general circulation with free 5-HT. Once 5-HT enters the blood stream, it is absorbed by platelets.

Another rich source of 5-HT in nature is the spleen (Table 9 below). In mammals and birds, 1 gram of spleen tissue usually contains from 2 to 7 times more than 1 mL of blood serum. The origin of 5-HT in spleen is attributed to disintegrating platelets, since the spleen is the organ that destroys platelets.


Rabbit platelets are known to contain 10X more 5-HT than human platelets. As shown in Table 9 (above), rabbit platelets have approx. 500 ug 5-HT/mL blood as compared to approx. 50 ug 5-HT/mL in human platelets. Poison salivary glands of octopus, the skin of frogs, and human carcinoid tumors are also very rich in 5-HT (Table 9 above).

Brain has relatively little 5-HT compared to other areas of the body. Brain areas richest in 5-HT are the hypothalamus, the midbrain, colliculi, grey matter of spinal cord, the medial part of thalamus and layer 4 of the cortex. It has been noted that the medial thalamus, which is connected with autonomic activity and the hypothalamus, contains a much higher concentration of 5-HT and of noradrenaline than the lateral thalamus, which relays sensory impulses to the cortex. 5-HT is also found in high quantities in area postrema, pineal organ, and cranial nerves 10 (vagus) and 12 (hypoglossal).

Finally we see in Table 9 that the highest amounts of 5-HT in nature are found in human carcinoid tumors, which are derived from enterochromaffin cells. Malignant gastrointestinal carcinoid tumors can produce excessive amounts of 5-HT in the carcinoid patient. The side effects of carcinoid tumors in humans are flushing, diarrhea, abdominal cramps, and attacks of breathing difficulties. In carcinoid patients, the 5-HT content of blood platelets and urinary excretion of 5-HIAA is consistently elevated, leading to flushed skin. Episodes of flushing are thought to be accompanied by an increased release of 5-HT from the tumor, as explained below.
"Intravenous injections of serotonin in both control and carcinoid subjects were followed by flushes of the skin similar to spontaneous attacks occurring in the carcinoid patient and by pressor responses of 29 to 58 mm Hg systolic and 9 to 57 mm Hg diastolic. The flush, involving the face, neck, and extremities, was intense in 4 patients and mild in 1. Subjective discomfort was profound in all subjects and characterized by nausea, paresthesias, breathlessness, and an urge to empty the bowel and bladder. These effects were transient and lasted for about the same length of time, 2 to 3 minutes, as the rise in arterial pressure." (Schneckloth,R. 1957)
In patients with carcinoid tumors in whom the peripheral production of 5-HT is excessive, no particular mental effects can be described. It is interesting to consider their symptoms, since there is some question about the significance of high 5-HT levels in organisms. As described above in the quote by Schneckloth, delivery of intravenous 5-HT to the already hyperserotonemic patients caused a flushing reaction. This fits with what is known about serotonin as a vasoconstrictor.

The sources of serotonin in nature indicate that it has an important role in the digestive and circulation system.


Reference

ERSPAMER V. (1954). Pharmacology of indole-alkylamines. Pharmacological Reviews 6, 425-487.

SCHNECKLOTH R., I. H. PAGE, F. DEL GRECO and A. C. CORCORAN (1957). Effects of serotonin antagonists in normal subjects and patients with carcinoid tumors. Circulation 16, 523-532. 

SJOERDSMA A., H. WEISSBACH, L. L. TERRY and S. UDENFRIEND (1957). Further observations on patients with malignant carcinoid. The American Journal of Medicine 23, 5-15.10.1016/0002-9343(57)90353-4

Lewis G. P. (Ed.) Symposium on 5-hydroxytryptamine (1957: London). New York: Pergamon Press, 1958.

Collier H. O. J. 1958. The occurrence of 5-hydroxytryptamine (HT) in nature; In 5-Hydroxytryptamine, Lewis G. P. (Ed.), New York: Pergamon Press, pp. 5-19.