Serotonin

Serotonin, or 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a variety of physiological functions. Although most of the body's serotonin supply is found in the gastrointestinal tract, it remains a vital neurotransmitter in the central nervous system. Many drugs affect the release, arrest and efficacy of serotonin, including antidepressants, psychedelic hallucinogens, synthetic opiates, dissociatives, drugs for treating migraines, antihistamines, and stimulants such as MDMA.

Introduction to Serotonin

[​IMG]Neurotransmitters are chemical messengers that mediate the function of the brain by binding to receptors to cause a new nerve impulse. As a monoamine neurotransmitter, serotonin is derived from the amino acid tryptophan. It has a wide distribution in the brain, but is particularly localised in the Raphe nuclei of the pons and upper brain stem, with projections to the hippocampus and cerebral cortices. It is a ligand for the 5-HT family of receptors, and its action can be excitatory or inhibitory.
Chemicals that increase serotonin levels in the brain's synapses are called serotonergic drugs.

Only a small percentage of the body's serotonin is found in the brain, as serotonin plays an important role in the blood platelets, where it acts as a vasocontristor (it narrows blood vessels) and in the gastrointestinal tract (the digestive system) where it causes secretion and contracts intestines, causing nausea.

The Basics: What Do I Need To Know About Serotonin?


When using drugs that affect serotonin, it is important to know the effects serotonin can have on the body and the mind. Serotonin can be dangerous when either too much or too little serotonin is being released in the brain. Understanding the effects of serotonin deficiency and excess is extremely important in harm reduction and using drugs safely.

Serotonin deficiency

It has been well established that a deficiency of serotonin is linked with clinical depression, anxiety, suicide ideation and similar mood disorders. This deficiency may be caused by genetic factors, where serotonin is poorly expressed in the brain. People with this deficiency are likely to suffer from major depressive disorder and have a higher risk of committing suicide and self-harm. It is often treated with antidepressant drugs that increase the amount of serotonin released. These drugs include SSRIs such as fluoxetine (Prozac), sertraline (Zoloft, Lustral), escitalopram (Lexapro) and many others. Other antidepressants that increase serotonin release include SNRIs such as duloxetine (Cymbalta), tricyclic antidepressants such as the trazodone, and tetracyclic mirtazepine (Remeron) .

Because of the action of these drugs on serotonin, it is worthwhile to understand and expect their side-effects, particularly nausea. A controversial aspect of antidepressants is their ability to occasionally cause paradoxical effects. This means that, when someone begins taking antidepressants, feelings of depression and suicidality may get worse. If this occurs, it is extremely important to consult the physician who prescribed you the antidepressant and discuss possible options.

Serotonin deficiency can also be caused by a poor diet. Serotonin is made in the brain by an amino acid called tryptophan (explained in the Chemistry section below). Dietary sources of tryptophan include red meat, poultry, eggs, chocolate, bananas and dairy products.

Drugs that release large amounts of serotonin, such as MDMA and similar empathogenic drugs, cause a sudden deficiency in serotonin which often leads to symptoms of depression, emptiness, unhappiness and anxiety. It is important to realise, when using drugs like MDMA, that although the body's serotonin will eventually restore itself, it helps to focus your diet on tryptophan-rich foods or trytophan supplements to reduce unwanted side effects of serotonergic drugs.


Serotonin excess and Serotonin Syndrome


When too much serotonin is released in the brain, the levels of the neurotransmitter become toxic, and can lead to serious physiological dysfunction, which may be fatal. An excess of serotonin in the brain is called Serotonin Syndrome or Serotonin Toxicity. This syndrome is usually caused by combining serotonergic drugs. Drug combinations that lead to this syndrome often involve antidepressants combined with recreational drugs. An antidepressant combined with MDMA, synthetic opioids like tramadol and pethidine, 2C-X drugs, dextromethorphan and many others can very easily lead to this syndrome. If you are taking a serotonergic drug, you should never take any other serotonergic drug of any kind.

The syndrome has many symptoms which may be difficult for a doctor to diagnose. If you suspect you have serotonin syndrome, immediate medical help should be sought, and you should inform your physician of all drugs you have taken/been taking.

Serotonin syndrome symptoms include: headaches, mania, confusion, agitation, hallucinations, shivering, excessive sweating, tachycardia (very fast, irregular heartbeat), nausea, diarrhea, panic-like symptoms and jerks of the limbs and head. Medical attention is strongly recommended following any combination of these symptoms. They can lead to a coma, and death.

Chemistry of Serotonin

Column 1 Column 2
Systematic (IUPAC) name: 3-(2-aminoethyl)-1H-indol-5-ol
Synonyms: 5-hydroxytryptamine, 3-(ß-aminoethyl)-5-hydroxyindole, 5-hydroxy-3-(ß-aminoethyl)-indole, enteramine, thrombocytin, thrombotonin, 5-HT; Antemovis (complex with creatinine sulfate, monohydrate)
Molecular Formula: C10H12N2O, C10H12N2O.HCl (hydrochloride), C14H21N5O6S.H2O
Molar mass: 176.22 g/mol, 212.68 g/mol (hydrochloride), 405.43 g/mol (complex with creatinine sulfate, monohydrate) [2]
CAS Registry Number: 50-67-9
Melting Point: 167-168°C (hydrochloride)
Boiling Point: 416±30°C
Flash Point: no data
Solubility: Hydrochloride soluble in water. Complex with creatinine sulfate, monohydrate soluble in glacial acetic acid; very sparingly soluble in methanol, 95% ethanol; insoluble in asolute ethanol, acetone, pyridine, chloroform, benzene, ether, ethyl acetate
Additionnal data: Complex with creatinine sulfate, monohydrate decomposes at 215°C; pK1 4.9, pK2 9.8; pH (0.01M aqueous solution) 3.6
Notes: Hydrochloride aspect : hygroscopic crystals; sensitive to light; aqueous solutions are stable at pH 2-6.4. Complex with creatinine sulfate, monohydrate aspect : plates.
[1]

Serotonin is an indolealkyl amine. It cannot cross the blood-brain barrier (BBB), and therefore neurons in the brain must synthesise their own serotonin for use in the central nervous system (CNS). Serotonin's precursor is the aromatic amino acid tryptophan, derived from dietary sources (see above) and transported across the BBB by neutral amino acid carriers.

The enzyme tryptophan hydroxylase (of which there are two variants) converts tryptophan (at the 5 position) to form 5-hydroxytryptophan (5-HTP), which is then decarboxylated to serotonin. Further enzymatic metabolism of 5-HTP yields the important neurohormone melatonin.

As a tryptamine, serotonin is closely related in structure to several potent hallucinogenic drugs such as DMT (Dimethyltryptamine), DET (Diethyltryptamine) and psilocin (4-hydroxy, DMT, an active compound of "magic mushrooms").

The chemistry of serotonin and similar tryptamines is discussed at length by Shulgin (1997).

Functions of Serotonin


Serotonin has a wide and complex variety of functions in both the peripheral and central nervous systems.

Studies of serotonin in the nematode Caenorhabditis elegans indicate that serotonin plays a major role in appetite and satiety (the feeling of being "full" after food). In this regard, serotonin is an appetite suppressant, and this effect is well-documented in serotonergics such as MDMA, where users generally have a poor appetite for the duration of the drug's effects.

The large concentrations of serotonin in the G.I tract's endochromaffin cells react to irritants and pathogens in food content, resulting in diarrhea, nausea and vomitting.

The efficacy of selective serotonin agonists such as sumatripan for treating migraines indicate a role of serotonin in neuropathic-spectrum pain.

As mentioned, serotonin, when deficient, is thought to be the main causative factor for major depressive disorder and associated anxiety, as well as transient depressive states, obsessive-compulsive behaviour and the depressive swings in bipolar disorder. Serotonin's action on appetite is also documented in the efficacy of SSRIs in treating anoxeria and bulimia nervosa. Combinations of atypical antipsychotics, which largely antagonise dopamine, with a serotonin antagonist at the 5-HT2 receptor showed a marked increase in suppression of negative symptoms of schizophrenia, indicating a role of serotonin in psychoses. This hypothesis is strengthened by the action of hallucinogenics such as LSD, which have a non-selective action at several serotonin receptors, particularly 5-HT2A, resulting in psychotomimetic effects.

Serotonin also functions in sleep and arousal. There is effectively no serotonergic neurotransmission during REM sleep, while transmission is highest during waking arousal. A gradual hyperpolarisation of serotonin action seems to occur during the phase-dependent transition from arousal to deep sleep.
Sexual arousal and sexual dysfunction also seem to be somewhat dependent on serotonin. Antidepressant drugs that increase serotonin levels cause sexual dysfunction in a high percentage of patients.


Serotonin Receptors


A wide variety of serotonin, or 5-HT receptors are expressed in the human brain. They are all G protein-coupled receptors, with the exception of the 5-HT3 receptor, which is a ligand-gated ion channel. These receptors are proteins, and in the CNS they are found on the cell membranes of neurons. 5-HT receptors are also found in endochromaffin cells of the GI tract, in the peripheral nervous system (PNS), on platelets, in blood vessels and on peripheral neurons projecting from smooth muscle.

Serotonin is the endogenous ligand for these receptors, but they are also targets for hundreds of psychoactive and medicinally relevant drugs.

In all, there are seven 5-HT receptors; 5-HT1, 5-HT2, 5-HT3, etc.

The 5-HT1 receptor has five subtypes. 5-HT2 has three subtypes, and 5-HT5 has two subtypes.

References


[1]Merck Index, fifteenth edition (2013)
[2]Calculated from Atomic Weights of the Elements, 2007

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