serotonin

serotonin After blood is allowed to clot a substance can be extracted from the fluid serum which, when injected, causes an increase in blood vessel ‘tone’ (the vessels' state of contraction). This serum-derived substance was therefore called serotonin or vasotonin. Similarly, extraction of animal intestines yielded a material with similar actions termed enteramine — the name being derived from the term enteron (gut). Serotonin, vasotonin, and enteramine were found to be identical. Chemically the vasoactive agent was 5-hydroxytryptamine (5HT). This is an endogenous autacoid (a substance made by body cells, which has some action on other cells) and is derived from the amino acid tryptophan, obtained from protein in the diet.

It is now known that 5HT is widely distributed throughout the body, with a multitude of actions. Ninety per cent of the total body content of 5HT is found in the enterochromaffin cells in the wall of the intestine. Most of the rest is found in blood platelets, and released from these when blood clots. A small amount is also found in the brain, especially the mid-brain, where it acts as a neurotransmitter.

5HT can act on a cell only if the cell membrane has specific 5HT receptors, and there are sub-types of these receptors on different cells, associated with different actions of 5HT upon them. 5HT causes many smooth muscles (involuntary muscles) to contract, such that gut motility and peristalsis are increased and contraction of the smooth muscle of blood vessels causes the blood pressure to rise. The smallest arterioles, however, are dilated, resulting in increased capillary pressure and capillary permeability, causing an increase in the rate of formation of tissue fluid. But 5HT also reduces the release of noradrenaline from sympathetic nerves, by acting on 5HT₁ receptors on the nerve terminals, which tends to reduce blood pressure. The vasoconstrictor response on the larger blood vessels is mediated by 5HT₂ receptors. Consequently, in the presence of a 5HT₂ antagonist, when 5HT can act only on the 5HT₁ receptors, it causes a fall rather than a rise in blood pressure.

5HT exerts many of its actions indirectly by either stimulating or inhibiting the release of other neurotransmitters. An example of inhibition of neurotransmitter release is given above, whereas in the gut it is stimulation of acetylcholine release from neurons of the myenteric plexus in the gut wall that increases contractions and secretions. 5HT can also stimulate sensory nerve endings directly, causing a pain sensation — well known to those who have suffered nettle stings, which contain 5HT.

Although only 1% of the body's total 5HT occurs in the brain it is here that the actions of this substance are the most profound. The neurons containing 5HT are concentrated in the raphe nuclei in the mid-brain and their fibres project in a diffuse way to the cerebral cortex, hippocampus, limbic system, and hypothalamus as well as down the spinal cord — a distribution not dissimilar to that of noradrenergic fibres.

Modern molecular biological studies have shown that there are many different types of receptors for 5HT — perhaps as many as ten — whose precise functional responsibilities are not yet clear. There is clear evidence that 5HT is involved in sleep, wakefulness, and mood. Descending 5HT pathways (from the brain down the spinal cord) affect the excitability of spinal motorneurons, activating those involved in simple reflexes and inhibiting more complex reflexes. Animals deprived of 5HT (by giving agents that prevent its synthesis) show exaggerated responses to many types of sensory stimulus, indicating that 5HT normally exerts a modifying effect, allowing irrelevant stimuli to be ignored and the response to pain palliated. 5HT is also involved at the level of the hypothalamus in temperature regulation and in the control of factors which release hormones from the anterior pituitary gland; also in the central control of vomiting.

There is much evidence to suggest that major changes in the blood vessels on the surface of the brain, which underlie migraine, are caused by release of 5HT. After an initial vasoconstrictor phase has passed the brain vessels dilate, and it is thought this is responsible for the pain. Drugs used to treat this condition, such as Sumatriptan, are antagonists at the receptor sub-type 5HT_1d.

Lysergic acid diethylamide (LSD) is one of the most notorious mood-altering (psychomimetic/hallucinogenic) drugs, producing bizarre visual experiences together with marked motor unrest and vocalization of extraordinary utterances. Mental function is altered so that perception of all sensory input — visual, auditory, tactile or olfactory — is distorted. In the brain LSD is able to activate 5HT receptors although elsewhere LSD is an antagonist. The psychomimetic effects of LSD certainly involve interference with the multiple actions of 5HT in the brain. Users of LSD describe both good and bad ‘trips’, which may mean that the response to LSD is dependent on the state of the 5HT system when the drug is taken. With 5HT, as with many neurotransmitters, the body economizes by using reuptake mechanisms: after a neurotransmitter has been released and has acted on post synaptic receptors the transmitter in the vicinity of the nerve terminal is taken up, stored, and recycled when the next nerve impulse arrives. In recent years drugs have been developed which specifically block the reuptake of 5HT. Clearly this is useful if reduction in the effectiveness of 5HT transmission in the brain has led to depression. Selective serotonin reuptake inhibitors (SSRIs) have proved useful mood-improving drugs; the best known is fluoxetine (Prozac), although there have been adverse criticisms of its use as many patients are reluctant to give it up, even when the condition precipitating the depression has passed.

Alan W. Cuthbert

See also neurotransmitters; membrane receptors.