Serotonin, like dopamine and norepinephrine, is a brain neurotransmitter. When the brain produces serotonin, tension is eased and the subject feels less stressed and more focused and relaxed. In contrast, when it produces dopamine or norepinephrine there is alertness in thinking and acting. Serotonin is called the “calming chemical.” It can be obtained naturally by eating sugar or other carbohydrates, which raise the insulin level in the blood, triggering a greater ratio of a chemical (actually, an enzyme) called tryptophan. This in turn rushes to the brain, where it produces serotonin. Vitamin C is required for the conversion of tryptophan into serotonin. Tryptophan is found in foods such as bananas, plums, turkey, and milk. A diet poor in omega-3 fatty acids may lower brain level serotonin and cause depression.
Serotonin was isolated and named by Maurice M. Rapport, Arda Green, and Irvine Page in 1948. First, Rapport identified it as a vasoconstrictor substance in the blood serum, and because it is a serum agent that affected vascular tone he called it serotonin. Later, in 1950, Rapport identified serotonin chemically and gave it the chemical name 5-hydroxytryptamine. The chemical name of serotonin is 3-(2-aminoethyl)-1 H -indol-5-ol, and in pharmacological terminology 5-HT.
The chemical formula of serotonin is N2OC10H12. Its molecular mass is 176.2182 g/mol, its monoisotopic mass is 176.0950 g/mol, and its composition is as follows: N (15.8970 percent), O (9.0793 percent), C (68.1598 percent), and H (6.8638 percent).
Specifically, serotonin is a monoamine neurotransmitter that is synthesized in the central nervous system by the serotonergic neurons and in the gastrointestinal tract by the enterochromaffin cells. Serotonin is formed by the hydroxylation and decarboxylation of tryptophan. The greatest concentration of serotonin is found in the enterochromaffin cells of the gastrointestinal tract (90 percent), and the rest is found in platelets and in the central nervous system. The effects of serotonin are mostly felt in the cardiovascular system, with additional effects in the respiratory system and the intestines.
The function of serotonin is exerted upon its interaction with specific receptors. Several serotonin receptors have been cloned, such as 5HT1, 5HT2, 5HT3, 5HT4, 5HT5, 5HT6 and 5HT7. Within each group there are subtypes that affect various aspects of bodily functions.
More specifically, serotonin can be found in the human gastrointestinal tract and in the bloodstream. In the human body, serotonin can be synthesized from the amino acid tryptophan by a short metabolic pathway that consists of two enzymes: tryptophan hydroxy lase and amino acid decarboxylase. The first enzyme, tryptophan hydroxylase, has two forms, one that is present in several tissues and the other one in a brain-specific isoform. In contrast, in the central nervous system serotonin can also be synthesized by the neurons of the Raphe nuclei that are distributed along the length of the brainstem in nine pairs. Specifically, there are swellings, called varicosities, along the axon that release serotonin into the extraneuronal space. From there, serotonin can be diffused to activate special receptors that exist on the dendrites, the cell bodies, and the presynaptic terminals of the adjacent neurons.
Serotonin plays an important role in the regulation of mood, sleep, appetite, vomiting, sexuality, memory and learning, temperature regulation, cardiovascular function, and endocrine regulation. Low levels of serotonin have been associated with migraines, bipolar disorders, apathy, fear, feelings of worthlessness, insomnia, fatigue, anxiety, and depression (www.chm.bris.ac.uk/motm/serotonin/depression.htm). Autopsies on suicide cases have revealed very low levels of serotonin in the brain. In turn, low levels of serotonin can be caused by an anxiety disorder because serotonin is required for the metabolism of stress hormones. The most concrete evidence for the connection between serotonin and depression is the decreased concentrations of serotonin in the cerebrospinal fluid and brain tissues of people suffering from depression. Extremely high levels of serotonin in the body cause toxic effects, and are even fatal in some cases; this is termed “serotonin syndrome.”
In 2005 scientific evidence emerged that genetic polymorphisms in the enzyme tryptophan hydroxylase in both its forms can affect susceptibility to depression and anxiety (Nash et al. 2005; Zhang et al. 2005). Furthermore, a study in 2006 showed that ovarian hormones can affect the expression of tryptophan hydroxylase, triggering postnatal depression and premenstrual stress syndrome (Hiroi et al. 2006). Also, where infants have abnormal serotonergic neurons—those neurons on the brain stem that synthesize serotonin—there is a high possibility of sudden infant death syndrome (SIDS) (Weese-Mayer, et al. 2003). Based on recent research, by Lesurtel et al. (2006), serotonin mediates liver regeneration and induces cell division throughout the body.
The pharmacology of serotonin is very complex because there is a large and diverse range of serotonin receptors in the human body. At least seven types of such receptors have been identified in different places of the body, and they all have different effects. Serotonin receptors can be stimulated by psychoactive drugs such as ecstasy (MDMA), LSD, DMT, and psilocybin (a substance found in psychedelic mushrooms). A small dose of ecstasy, for example, stimulates a big release of serotonin in the body, causing feelings of well-being, comfort, and tactile sensitivity. High doses of such substances can produce feelings of emotional empathy, or entactogenesis.
The 5-HT3 receptor is an antiemetic agent used mainly in cases of postoperative nausea and nausea caused by anticancer chemotherapy using cytotoxic drugs. It is also used to treat depression and other mental and psychological conditions. The 5-HT 1B/D receptor is an agent to treat migraines. The role of 5-HT receptors is a topic of intense research, so more therapeutic applications may be discovered in the future.
If depression is severe as a result of serotonin deficiency, antidepressants—that is, pharmaceutical agents that increase the level of serotonin in the brain—may be used. If depression is mild, it can be cured without medications because levels of serotonin can be increased with rigorous exercise. Studies have shown that the amount of serotonin in the brain is increased with increased activity, and the production of serotonin is raised for some days after exercise.
There are certain psychiatric medications that modulate the levels of serotonin in the human body. These have been classified into four general categories: (1) monoamine oxidase inhibitors, (2) tricyclic antidepressants, (3) atypical antipsychotics, and (4) selective serotonin reuptake inhibitors.
Monoamine oxidase inhibitors (MAIOs) are used to prevent the breakdown of monoamine neurotransmitters (one of which is serotonin). Hence, they increase the concentrations of serotonin in the brain. They are used for patients suffering from depression, but they may have serious side effects, including adverse drug interactions such as hypertensive crisis. Trycyclic antidepressants (TCAs) inhibit the reuptake of both serotonin and norepinephrine. Selective serotonin reuptake inhibitors (SSRIs) are also used in the treatment of depression. They are newer drugs and inhibit only serotonin’s reuptake, hence they are safer, having fewer side effects and fewer adverse drug interactions. One of their side effects is anorgasmia, or a delay of sexual climax.
SSRIs available in the United States (with trade names given in parentheses) include:
Citalopram (Celexa, Cipramil, Emocal, Sepram, Seropram);
Escitalopram oxalate (Lexapro, Cipralex, Esertia);
Fluoxetine (Prozac, Fontex, Seromex, Seronil, Sarafem);
Fluvoxamine maleate (Luvox, Faverin);
Paroxetine (Paxil, Seroxat, Aropax, Deroxat, Paroxat);
Sertraline (Zoloft, Lustral, Serlain);
Dapoxetine (no known trade name).
SSRIs are prescribed for treatment of major depression, anxiety disorders, panic disorders, obsessive-compulsive disorders (OCD), social phobia, eating disorders, irritable bowel syndrome (IBS), and premature ejaculation (which affects up to 60 percent of men).
Briefly, the mechanism of brain cells is as follows: The messages in the brain are passed between two nerve cells through a synapse, which is a small gap between the cells. The sender (presynaptic) cell releases neurotransmitters such as serotonin, dopamine, and norepinephrine into that gap. These neurotransmitters are recognized by special receptors on the surface of the receiver cell (postsynaptic), which, upon this stimulation, relays the signal. During this process, approximately 10 percent of the neurotransmitters are lost; the remaining 90 percent are released from the receptors to be taken back by monoamine transporters into the sender cell (presynaptic). This process is called “reuptake.” When there is a problem in this operation, some type of disorder appears in the person’s behavior.
According to some theories, a lack of stimulation of the receiver cell (a postsynaptic neuron) at a synapse can cause depression. In order to stimulate this receiver cell, SSRIs, as their name implies, inhibit the reuptake of serotonin only from the three neurotransmitters. In contrast, TCAs inhibit the reuptake of both serotonin and norepinephrine. When medication is used, serotonin stays in the synaptic gap longer than it normally would so that it can be recognized again by the receptors of the postsynaptic cell and the process can be repeated, thus the postsynaptic cell can finally be stimulated fully, as it should have been originally.
Adverse effects of SSRIs include general side effects, suicidality, sexual side effects, and “discontinuation syndrome.” Specifically, during the first four weeks of treatment with SSRIs symptoms may include nausea, drowsiness, headache, changes in weight and appetite, changes in sexual behavior, increased feelings of depression and anxiety, tremors, and increased sweating. These symptoms usually disappear after the adaptation period, but they are highly individual and drug-specific.
Regarding suicidality, there have been many accusations by patients and their families that SSRIs cause suicidal ideation and behavior. However, there is little scientific support for these claims, and manufacturers of SSRIs usually have vehemently denied them. But in early 2006 GlaxoSmithKline announced to the media that new meta-analysis of their clinical trial data revealed a statistically significant higher frequency of suicidality in patients treated with their SSRI, paroxetine (Paxil) (GlaxoSmithKline, May 2006, “Clinical Worsening and Suicide Risk,” Press release; (www.healthfoundation.healthspace.eu/health/antidepressants-paxil.php.)
Regarding the sexual side effects, SSRIs can cause various types of sexual dysfunctions such as anorgasmia, erectile dysfunction, and diminished libido (Landen et al. 2005; Hu Xh et al. 2004). It is believed that sexual dysfunction is caused by an SSRI-induced reduction in dopamine. If the postsynaptic receptors 5-HT2 and 5-HT3 are stimulated, they decrease dopamine release from the Substantia Nigra. Because of these problems, the SSRI fluoxetine (Prozac) was recently classified as a reproductive and developmental toxin by the Center for the Evolution of Risks to Human Reproduction (CERHR), which is an expert panel at the National Institute of Environmental Health Sciences and people were advised to avoid it.
Finally, regarding the discontinuation syndrome, SSRIs have not been found to be addictive. However, a sudden discontinuation of their use may cause both somatic and psychological withdrawal symptoms that collectively are called the “SSRI discontinuation syndrome.” These reactions are different from and usually less significant than the withdrawal symptoms of drugs such as opium, alcohol, or cocaine, but occasionally they have been extreme, and some patients can never withdraw completely from the SSRI drugs. In some cases, stopping the use of SSRIs can cause unpredictable and irregular acts and behaviors (e.g., violent rages, suicidal ideation), as well as an intensification of previous symptoms. In Europe, SSRI products cannot be advertised as “non-habit-forming,” as they are in the United States. According to the World Health Organization, SSRIs meet the definition of “addictive” (Tamam and Ozpoyraz 2002).
Serotonin toxicity, commonly referred to as “serotonin sydrome,” is a toxidrome (a form of poisoning) caused by medical treatment. Increased serotonin levels in the central nervous system can result from the use of archetypal serotonergic drugs, examples being the specific or selective serotonin reuptake inhibitors (SSRIs). The toxicity of SSRIs increases with greater dosages, but overdose of an SSRI alone is not fatal in healthy adults. The toxicity can be fatal, however, when drugs with different mechanisms are mixed together. The most common combination of therapeutic drugs likely to raise serotonin to a fatal level is the combination of MAOIs with SRIs or TCAs (Gillman 2004; Isbister et al. 2004). The duration of an episode of serotonin toxicity depends on the type of drugs that precipitated it. Many of them have durations of less than twenty-four hours, and side effects or toxicity will subside over this time, without specific treatment, if one or all of the offending drugs are reduced or ceased completely. As of the mid-2000s there was no evidence of permanent or long-term neurological effects or damage from serotonin toxicity (Whyte 2004).
In approximate order of seriousness (from least to most serious), the symptoms of serotonin toxicity, according to Dunkley (2003), include:
- neuromuscular hyperactivity: tremor, clonus, myoclonus, hyperreflexia, and (only in late or severe stage) rigidity, which may effect truncal muscles;
- altered mental status: excitement, agitation, and (only in late or severe stage) confusion;
- autonomic hyperactivity: diaphoresis (excessive sweating), fever, mydriasis (eye dilation), tachycardia (elevated heart rate), moderately elevated blood pressure, and tachypnoea (rapid breathing).
The usual clinical picture is of a hypervigilant or agitated patient with tremor and hyperreflexia. Clonus and myoclonus (involuntary muscle contractions) usually begin in lower limbs and may spread and become generalized. Pyramidal rigidity (a rigidity of certain muscles) is a late development (usually it happens when MAOIs have beed mixed with SRIs) and may impair respiration if it affects truncal muscles. Serious toxicity is indicated by high rigidity, a fever higher than 38.5 degrees Celsius, and an increasing PaCO2 (arterial carbon dioxide pressures).
SEE ALSO Anxiety; Depression, Psychological; Dopamine; Drugs of Abuse; Emotion; Neuroscience; Psychoneuroendocrinology; Psychopathology; Suicide
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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 5HT1d.
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.
serotonin (sĕr´ətō´nĬn), organic compound that was first recognized as a powerful vasoconstrictor occurring in blood serum. It was partially purified, crystallized, and named in 1948, and its structure was deduced a year later. Independent work indicated that serotonin was widely distributed in nature and occurred in tissues other than blood. It has been shown to be in many representatives of the animal kingdom, in wasp stings and scorpion venom, in various fruits, such as pineapples, bananas, and plums, and in various nuts. It has been estimated that an adult human contains about 5 to 10 mg of serotonin, 90% of which is in the intestine and the rest in blood platelets and the brain. One role of the compound is as a neurotransmitter whose participation is being sought in diverse functions including learning, sleep, and control of mood. The structural similarity of serotonin to several drugs known to cause mental aberrations, such as LSD, has prompted much speculation as to the role of serotonin in naturally occurring mental disorders such as schizophrenia or depression. Serotonin also acts as a hormone. Serotonin produced by the intestines inhibits the production of the bone tissue by osteoblasts, while in the brain it acts indirectly to promote the formation of bone. The placenta has been discovered to produce serotonin that stimulates the development of neural connections in the forebrain of the embryo. The function of serotonin in blood platelets is not entirely clear, but by acting as a vasoconstrictor and possibly in other ways it helps to regulate the clotting process. Its function in stings and venoms might be that of an irritant, since intravenous injections of serotonin in humans produce pain at the site of injection, gasping, coughing, a general tingling and prickling sensation, nausea, cramps, and other unpleasant symptoms.
Chemically named 5-hydroxy-tryptamine, this Monoamine transmitter is a widely distributed substance particularly prevalent in the gut, blood, platelets, and pineal gland, as well as in nine major sets of brain neurons (nerve cells). In the 1950s, chemical similarity between serotonin and the chemical Hallucinogen Lysergic Acid Diethylamide (LSD) focused attention on this Neurotransmitter in mental illness, a link strengthened by experimental studies in animals and humans. Neurons containing serotonin, a typical monoamine, project widely throughout the brain and spinal cord, and a large number of well-characterized serotonin-receptor subtypes mediate both direct and indirect regulation of ion channels that exist in the membranes of neurons. By regulating these channels, these serotonin Receptors influence the concentration within the neuron of such ions as K+ (potassium) and Ca++ (calcium) and thereby the activity of the cell.
(See also: Brain Structures and Drugs ; Dopamine ; Neurotransmission ; Reward Pathways and Drugs ; Serotonin-Uptake Inhibitors in Treatment of Substance Abuse )