SEROTONIN RECEPTORSFaraza Javed

Mphil Pharmacology

Serotonin Receptors

Serotonin receptors or 5- Hdroxytryptamine

is a monoamine neurotransmitter.

Serotonin is found in GIT Platelets CNS

Approximately 90% of the human body's total serotonin is located in the enterochromaffin cells in the alimentary canal (gut), where it is used to regulate intestinal movements.

The remainder is synthesized in serotonergic neurons of the CNS, where it has various functions. These include the regulation of mood, appetite, and sleep.

Serotonin secreted from the enterochromaffin cells eventually finds its way out of tissues into the blood. There, it is actively taken up by blood platelets, which store it. When the platelets bind to a clot, they release serotonin, where it serves as a vasoconstrictor and helps to regulate hemostasis and blood clotting.

Biosynthesis

Biosynthesis of serotonin begins with hydroylation of an essential amino acid L-Tryptophan. L-Tryptophan is transported through the BBB into the brain using the neutral amino acid transmitter on which competes with other aminoacids- phenylalanine, leucine and methionine. Tryptophanhydoxylase is the 1st step and speed limiting factor of 5-HT synthesis.

This enzyme was found in the brain only in serotogenic neuron. It enable the

conversion of tryptophan into 5- hydroxy tryptophan, followed by the

decarboxylation mediated by L- amino acid decarboxylase onto 5- hydroxytryptamine

(serotonin).

Receptors Types

5-HT1 Receptors

This group consist of 5 receptor subtypes:o 5-HT1Ao 5-HT1Bo 5-HT1Do 5-HT1Eo 5-HT1F

5-HT1A Receptors

This is the most extensively distributed of all 5-HT receptors. In CNS, these

receptors are present in high density in cerebral cortex, hippocampus, septum, amygdala and raphe nucelus, but they are proven in small amounts in basal

ganglia and thalamus as well.

They are involved in the inhibition of discharge of neurons, regulation of

production of behaviour and eating. They play an important role in the emergence of anxiety. They also exert some effects on

CV system.

Receptors Effects & Function

Agonist Antagonist

5-HT1A CNS: Agression, Anxiety, Appitite, Memory, MoodCVS: Vasoconstriction, BP, HR

Buspiron, Ergotamine, Yohimbine,

Alprenolol,Pindolol, Propranolol

5-HT1B Receptors

o They are present in CNS where they induce presynaptic inhibition and behavioural effects. They exhibit vascular effects as well, such as pulmonary vasoconstriction.

o Discovery of antimigraine properties of Sumatriptan (non-selective 5-HT1D/1B agonist) increased intrest in this sub type of receptors.

Receptor Effects & Function

Agonist Antagonist

5-HT1B CNS: Aggression, Anxiety, Learing, Locomotion, Memory, MoodVessels:Pulmonary Vasoconstriction

Ergotamine, Dihydroergotamine, Sumatriptan, Zolmitriptan

Yohimbine, Propranolol, Pindolol

o Expression of 5-HT1D receptor is very low as compared to 5-HT1B and their clinical significance still largely unknown.

o The function of 5-HT1E receptor is unknown but it is hypothesized that they are involved in regulation of memory.

o 5-HT1F receptor has possible role in vascular contraction. Distribution in brain appears limited.

Recetors Effects & Function

Agonist Antagonist

5-HT1D CNS: Locomotion, Anxiety

Sumatriptan, Ergotamine, Yohimbine

Methiothepin

5-HT1E CNS: Memory -- --

5HT1F BV: Vasoconstriction

-- --

5-HT2 Receptors

This class has 3 sub types:

o 5-HT2Ao 5-HT2Bo 5-HT2C

5-HT2A Receptors

This receptor type is expressed in many central and peripheral tissues. This subtype show increased platelet aggregation and increased capillary permeability following exposure to serotonin. In CNS, these receptors are mainly present in basal ganglia.

5-HT2A antagonist are being developed for the treatment of schizophrenia.

5-HT2B Receptors

Activation of 5-HT2B receptors leads to the contraction of smooth muscle of fundus. Direct injection of selective agonist BW723C86 in amygdala have anxiolytic effcets in rats.

Antagonist of these receptors are relatively new and may find clinical application in the treatment and prevention of Migraine.

5-HT2C Receptors

These receptors may found in hippocampus and substantia nigra. Due to lack of selective ligands for 5HT2C receptors the knowledge of its action remains unclear.

Receptors Effcets & Function

Agonist Antagonist

5-HT2A CNS: Anxiety, Imagination, Learning, PerceptionSM: ContractionPlatelet: Aggregation

Yohimbine Aripiprazole, Clozapine, Olanzapine, Trazodone

5-HT2B CNS: AnxietyGIT: GI Motility

Norfenfluramine Agomelatine

5-HT2C CNS: Mood, Sleep, Anxiety

-- Clozapine,Olanzapine

5-HT3 Receptors

With the exception of the 5-HT receptor, a ligand-gated ion channel, all other serotonin receptors are G protein-coupled receptors that activate an intracellular second messenger cascade to produce an excitatory or inhibitory response. The 5-HT receptor antagonist suppress vomiting and nausea by inhibiting serotonin binding to the 5-HT receptors.

5-HT4 Receptors

These receptors are found on CNS and Myenteric neurons. Prucalopride (brand name Resolor, developed by Johnson & Johnson) is a drug acting as a selective, high affinity 5-HT receptor agonist which targets the impaired motility associated with chronic constipation, thus normalising bowel movements.

5-HT5 Receptors

Rodents have been shown to possess two functional 5-HT5 receptor subtype, 5-HT5A and 5-HT5B. Pharmacological function of these receptors are unknown. Based on their localization, it has been speculated that they may be involved in motor control, anxiety, learning, adaptive behaviour and brain development.

5-HT6 Receptors

The exact clinical significance of these receptors remain still unclear. Selective antagonist of this type of serotonin receptor have an impact on behaviour and seem to improve the spatiel memory of laboratory animal.

5-HT7 Receptors

5-HT7 receptors are expressed abundantly in the vessels and are responsible for persistant vasodilation of anesthesized experimental animal. 5-HT7 receptors are also expressed in CNS and in smooth muscles (in GIT tract).

Future Aspects

Serotonin is unique among the monoamines in that its effects are subserved by distinct G-protein-coupled receptors and one ligand-gated ion channel. In the last two decades, a vast amount of new information has become available concerning the various 5-HT receptor types and subtypes, and their characteristics. It still remains to be seen which functions some of the many subtypes play in health or disease.

The challenge for the next years of serotonin research is to clear to what extent diversity in receptors fulfils specific physiological or pathophysiological roles.

The research may then assist in designing drugs with an adequate profile at the target organ and specific disease.