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Serotonin - Receptors and effects

Serotonin receptors are classified into 7 types, 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5-HT7. Each type can have subtypes A, B and so on. These receptors are localized in brain and in peripheral organs but their distribution is not homogeneous. The majority of 5-HT receptors are postsynaptic but receptors such as 5-HT1A and 5-HT1B are mainly presynaptic and modulate serotonin release. The signalling pathways to which these receptors are coupled are known but it is hardly possible to systematize clinical effects corresponding to their stimulation.

Serotonin receptors are coupled to G proteins except 5-HT3 receptors which are receptor- channels, also called ionotropic receptors, which, in the activated state, are open and permeable to sodium and potassium cations.

As other transmitters, serotonin released in the synaptic cleft is mainly reuptaken by the presynaptic terminations by active transport with a specific carrier.

Peripheral effects

Cardiovascular action

The cardiovascular effects of serotonin are complex. They are variable depending on the dose injected, experimental conditions, animal species and vascular state.

  1. Action on vessels:
    Serotonin induces either a vasoconstriction by 5-HT2 effect, in particular of renal vessels, or a vasodilation. The response would depend on the preliminary tone of vessels and on their normal or pathological state: thus serotonin administration by intracoronary route gives a vasodilation when the coronary vessels are normal, and a vasoconstriction when they are damaged.
    Serotonin constricts veins and seems to induce venous thromboses and promotes platelet aggregating effect. It increases capillary permeability.
  2. Action on heart:
    Serotonin has a positive chronotropic action by 5-HT4 receptor stimulation and could take part in the genesis of certain rhythm disorders. It has a positive inotropic effect.
  3. Action on blood pressure:
    It is complex, according to experimental conditions, serotonin gives either hypotension, or hypertension, or no modification.

Action on smooth muscles

Serotonin induces contractions of intestine, bronchi and uterus.

  1. Digestive effects:
    1. Serotonin increases intestinal motility, probably by stimulation of 5-HT4 and 5-HT3 receptors: in human beings, injected by intravenous route, it increases duodenum and small intestine motility. This effect explains diarrhea observed in patients with carcinoid syndrome.
    2. Serotonin has an emetic effect by stimulation of 5-HT3 receptors. These receptors are located particularly on the vagal terminations in the digestive tract and in area postrema (chemoreceptor trigger zone), which is accessible to peripheral circulating serotonin. Their stimulation elicits nausea and vomiting, and 5-HT3 antagonists are used to avoid vomiting induced by antineoplastic treatments.
    3. It has an ulcerative action, its administration to animals in high doses induces gastric ulcerations.
  2. Bronchial effets :
    Serotonin has a bronchoconstrictive action; a serotonin aerosol induces dyspnea.
  3. Uterus effect:
    Serotonin induces contractions of the uterus.

Other actions

Serotonin is involved in allergic and inflammatory symptoms and in certain diseases:

  1. Carcinoid syndrome:
    The carcinoid syndrome is caused by metastatic tumors of enterochromaffin cells of the digestive tract which secrete various compounds, in particular a great quantity of serotonin. It is characterized by diarrhea, flushes (accesses of cutaneous vasodilation followed by a vasoconstriction), dyspnea and sometimes a damage to cardiac valves. The biological diagnosis of these tumors is based on the increase in serotonin concentration in blood and on the excretion of abnormal amounts of 5-hydroxy-indolacetic acid, 5-HIAA, in urines.
  2. Migraine:
    Migraine is a disease characterized by repeated accesses of headache in which vasomotor phenomena and serotonin play a determining part. In the first prodromic phase, there is a vasoconstriction, and in the second painful phase, a vasodilation. This vasodilation is reduced by vasoconstrictive drugs.
  3. Myocardial ischemia:
    Serotonin released from platelets seems to worsen the myocardial ischemia by vasoconstriction.

Central effects

Effects of serotonin on the central nervous system are numerous, complex and difficult to systematize, but of considerable importance from a pharmacological point of view because many drugs act by its intermediary.

Serotonin is involved in the regulation of sleep, mood (antidepressant action), temperature, appetite (appetite suppressant effect).

Overstimulation of 5-HT2 receptors could induce productive and negative symptoms of psychotic disorders. LSD or lysergide, agonist of 5-HT2 receptors and also of D1 and D2 dopaminergic receptors, has hallucinogenic properties.

Serotonin, thanks to its various types of presynaptic and postsynaptic receptors, modulates the activity of other transmitters. It plays a determining part in adaptation.

Notice

The mode of action of melatonin is not well known. It acts on three types of cell-surface receptors called MT1, MT2 and MT3, probably linked to G proteins.

In vitro studies showed that melatonin has antioxydant properties. It could also reduce the secretion of hypothalamic hormones.

Administered by oral route, it is well absorbed, but it has a short elimination half-life, less than one hour. It induces sleep and could have antidepressant, antimigraine and anti-nociceptive effects.


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