Dense core vesicles

Serotonin is stored in eccentric, electron-opaque granules that are referred to as "dense core granules" or "dense core vesicles." The diameter of a dense core vesicle is 750-1000 Angstroms, with a variably dense center that does not completely fill the vesicle. Dense core organelles are known to contain various neurotransmitters, including 5-HT, adrenaline, noradrenaline, dopamine, histamine, ATP, or peptides.

Dense core vesicles can be highly purified and obtained in large quantity from rabbit platelets, which are a rich source of dense core vesicles and contain 10X more 5-HT than human platelets. Figure 2 (below) is an electron micrograph of 5-HT dense core vesicles that have been purified from rabbit platelets.

From Dense core vesicles

Dense osmiophilic organelles were first identified in the adrenal medulla of the gut. The cytoplasm of enterochromaffin cells stains readily with potassium bichromate, showing fine brown granules as chromium salts. The investigation of these "chromaffin vesicles" in the gut led to the discovery of amine-containing vesicles in the brain (Wolfe,D.E. 1962).

The electron micrograph below shows monoaminergic dense core vesicles forming a synapse in the cortex of 6-day-old rat. Vesicles nearest to the cell membrane can fuse with it, emptying neurotransmitters that may cross to the adjacent cell.

From Dense core vesicles

Dense core vesicles are found in the axon terminals of noradrenaline-, dopamine-, and 5-HT-containing neurons, but the majority of dense core vesicles are located in dendrites.

The dendrites of raphe neurons are characterized by many 5-HT-containing dense core vesicles. Dopamine in the dendrites of rat substantia nigra and norepinephrine in dendrites of rhesus monkey locus coeruleus suggest that the storage, release, and uptake of catecholamines may not be exclusive properties of the terminal axons.

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. The 5-HT content in varies conspicuously from one animal species to another. Remarkable also are individual variations in the same species.

From 5-HT pain

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 the enterochromaffin cells are the major source of 5-HT in the body, since certain groups of fishes do not contain 5-HT, such as the fish Teleostei and Cyclostomata, and these fish lack enterochromaffin cells altogether.

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 is much more 5-HT in stomach, small intestine, and tongue than brain. 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, thus platelets are a rich source of 5-HT in nature.

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

From 5-HT pain

Spleen is a rich source of 5-HT (Table 9). In mammals and birds, 1 gram of spleen tissue usually contains from 2 to 7 times more than 1 mL of the blood serum. 5-HT is produced in the enterochromaffin cells and thence released into the plasma, where it is taken up by platelets and thrombocytes. The origin of the 5-HT in the spleen is due to disintegrating thrombocytes, since the spleen is the organ which destroys thrombocytes.

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." (R. Schneckloth, 1957)

In patients with carcinoid tumor in whom the peripheral production of 5-HT is excessive, no particular behavioral effects can be described. The fact that patients with carcinoid tumors have large amounts of circulating 5-HT without showing marked symptoms of mental derangement could represent an adaptation to very high levels of 5-HT that has developed and accumulated gradually. The sources of serotonin in nature indicate that it has an important role in the digestive and circulation system.


References

ERSPAMER V. (1954). Pharmacology of indole-alkylamines. Pharmacol. Rev. 6, 425-487.

Lewis, G. P., Ed. 5-Hydroxytryptamine. Pergamon Press: New York, 1958.

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. Am. J. Med. 23, 5-15.
10.1016/0002-9343(57)90353-4

From Terrence Mckenna,

"There are thousands of altered states. We know them - orgasm, indigestion, two cappuccinos, where tequila takes you, so endless altered states. And I'm not really interested in them more or less than any of you are, I mean they're part of life. But what I'm interested in, as an experimentalist, as a connoisoir of nature, as someone who loves fossils, butterflies, rainforests, that kind of thing, is this family of compounds called the indole hallucinogens. Indoles. And they cause hallucination.

"Some people say that I am a fetishist, or that "who cares," or that there are other things besides hallucinations. Yes, I know, maybe, and of course, there are other things besides hallucination. But the reason I'm so fascinated by hallucinations is, to my mind, when you're hallucinating, you have an absolutely clear proof that _you_ are not generating this material. Its not funny ideas, its not racing thoughts, its not insight into what your boyfriend really meant yesterday. That kind of thing we can all generate by just inspecting our own minds. But a hallucination is to be in the presence of that which could previously not be imagined. And if it could previously not be imagined, then there is no grounds for believing that you generated it out of yourself.

"I mean, we should each know our own inventory. You know what's in your cupboard, you know what's in your chest of drawers, for God's sake, you ought to know what's in your mind. Then if something comes forward, and you say, "That's not mine, That's not in my inventory," then you have a kind of perfect proof that this is coming from somewhere else. Then the question becomes, where? And we can set off into that, opinions differ."