SEROTONIN &

THEIR ANTAGONISTS By

Rajneesh Kumar Singh

M.Pharm. (Pharmacology)

SEROTONIN

Serotonin is a naturally occurring amine synthesized from the

tryptophan & commonly found in plants ,some fruits ,animal tissues &

insect venoms. In human being , it is found in enterochromaffin cells in

g.i.t & CNS .

Serotonin containing neurons are mainly found in limbic system,

raphae nucleus, cortex, hypothalamus, amygdala, caudal nucleus , mid

–brain, vomiting centre & spinal cord .

These regulate sleep, body temperature & mood .

A hormone melatonin is derived from serotonin .

SYNTHESIS AND DEGRADATION

PHARMACOLOGICAL ACTIONS OF SEROTONIN (5-HT)

• Action on GIT 5-HT act as a local hormone & to regulate

peristelsis movement.• Action on CNS It act as neurotransmitter in CNS • Action on CVS 5-HT produces positive ionotropic EFFECT

& chromotropic effect in myocardium .• Action on smooth muscles 5-HT constrict the smooth muscles of

bronchia and GIT .

PHARMACOLOGICAL ACTIONS

Action on blood vessels 5-HT dilate the blood vessels of skeletal muscles,

coronary arteries & capillary of skin .

Action on platelets It enhance the aggregation of platelets &

haemostatis.

DEPRESSION Possible problems include low brain cell

production of serotonin, a lack of receptor sites able to receive the serotonin that is made, inability of serotonin to reach the receptor sites, or a shortage in tryptophan, the chemical from which serotonin is made.

If any of these biochemical glitches occur, researchers believe it can lead to depression, as well as obsessive-compulsive disorder, anxiety, panic, and even excess anger.

5-HT RECEPTORSThe 5-HT receptors are the receptors for

serotonin. They are located on the cell membrane of nerve cells and other cell types in animals, and mediate the effects of serotonin as the endogenous ligand.

With the exception of the 5-HT3 receptor, a ligand-gated ion channel, all other 5-HT receptors are G protein-coupled, seven transmembrane(or heptahelical) receptors that activate an intracellular second messenger cascade.

5-HT Receptors

5-HT1-receptors occur mainly in

CNS (all subtypes) and some blood vessels (5-HT1D subtype).

Effects are neural inhibition and vasoconstriction. Act by inhibiting adenylate cyclase.

5-HT2-receptors occur in CNS and many peripheral sites (especially blood vessels, platelets, autonomic neurons). Neuronal and smooth muscle effects are excitatory. Some blood vessels dilated as a result of nitric oxide release from endothelial cells. 5-HT2-receptors acts through phospholipase C/inositol trisphosphate pathway.

5-HT3-receptors occur in peripheral nervous system, especially nociceptive afferent neurons and enteric neurons, and in CNS. Effects are excitatory, mediated via direct receptor-coupled ion channel.

5-HT4-receptors occur mainly in the enteric nervous system (also in CNS). Effects are excitatory, causing increased gastrointestinal motility. Act by stimulating adenylate cyclase.

Little is known so far about the function and pharmacology of 5-HT5-7-receptors.

MECHANISM OF ACTION5-HT1A receptor-induced membrane

hyperpolarization and reduction in input resistance results from an increase in K+ conductance.

Slow depolarization induced by 5-HT2A-receptor activation in areas such as the prefrontal cortex, nucleus accumbens, and facial motor nucleus involves a decrease in K+ conductance.

A second, distinct mechanism involving Ca2+-activated membrane currents enhances neuronal excitability and potentiates the response to excitatory signals such as glutamate.

The fast depolarization elicited by 5-HT3 receptors reflects direct gating of an ion channel intrinsic to the receptor structure itself.

The 5-HT3 receptor-induced inward current has the characteristics of a cation-selective, ligand-operated channel. Membrane depolarization is mediated by simultaneous increases in Na+ and K+ conductance.

PATHOPHYSIOLOGICAL ROLES

NeurotransmitterPrecursor of melatoninNeuroendocrine functions Nausea and vomitingMigraine Haemostasis HypertensionIntestinal motility etc.

DRUGS AFFECTING 5-HT SYSTEM

5-HT PRECURSORS:Tryptophan increase brain 5-HT & produce

behavioral effects.

SYNTHESIS INHIBITORSp-Chlorophenylalanin selectively inhibit tryptophan

hydroxylase & reduce 5-HT level in tissue .

UPTAKE INHIBITORSTricyclic antidepressants inhibit 5-HT uptake along

with NA .Some like fluoxetine ,sertraline are selective serotonin reuptake inhibitors.

STORAGE INHIBITORS Reserpine block 5-HT uptake into storage

granules & cause depletion of all cell monoamines .

DEGRADATION INHIBITORAS

Non-selective MAO inhibitors (tranylcypromine) &selective MAO –A inhibitors (chlorgyline) increase 5-HT content by preventing its degradation.

NEURONAL DEGENRATION 5,6 Dihydroxytryptamine selectively destroys 5-HT

neurons .

5-HT RECEPTIR AGONISTS

1. D-Lysergic acid diethyl amide(LSD) Non selective 5-HT agonist Activates subtypes of 5-HT receptors including 5-

HT1A, 5HT2A/2C ,5HT5-7 .

Antagonize 5HT2A receptor in ileum .

AZAPIRONES Like buspirons ,gepirone act as partial agonist of

5HT1A Receptor in brain.

8 HYDROXYDIPROPYLAMINO TETRALINE Selective 5HT1A agonist Used as experimental tool

SUMATRIPTAN AND OTHER TRIPTAN Selective 5HT1B/1D agonists, Most effective in treatment of acute migraine attack

CISAPRIDEProkinetic drug increase g.i.t motility Selective 5HT4 agonist.

M-CholorophenylpiperazineActive metabolite of antidepressant drug

TRAZODONE.found to be agonist of 5HT1B 5HT2A/2C Receptor in

brain.

5-HT RECEPTOR ANTAGONISTS

CyproheptadineMethysergideKetanserinClozapineRisperidoneOndansetron

CYPROHEPTADINEBlock 5HT2A receptorUtilized in controlling intestinal

manifestations of carcinoid & postgastrectomy dumping syndrome

Antagonize priapism caused by 5HT uptake inhibitor like fluoxetine.

Side effects: drowsiness,dry mouth ,ataxia confusion.

METHYSERGIDEAntagonize action of 5HT on

smooth muscles including that of blood vessels

Potent 5HT2A/2C ANTAGONIST & Non selectively act on 5HT1 receptors .

Used for migraine prophylaxis

RISPERIDONE5HT2A antagonist Ameliorates negative symptoms

of schiphereniaProduce extrapyramidal side

effects on slightly higher doses

ONDANSETRON Selectively 5HT3 AntagonistRemarkable efficacy in controlling

nausea & vomiting following administration of highly emetic anticancer drugs & radiotherapy .

KETANSERINSelective 5HT2 receptor blocking

property with action on 5HT1,5HT3

& 5HT4 receptors .5HT induced

vasoconstriction ,platelets aggregation & contraction of airway smooth muscles are antagonized but not contraction of guinea pig ileum or rat stomach .

CLOZAPINE 5HT2A/2C blockerInverse agonist activity at

cerebral 5HT2A/2C ReceptorsEfficacy in resistant cases of

schizophrenia

Goodman & Gilman’s “The Pharmacological basis of

Therapeutics” Eleventh Edition, 2001. Published By McGraw-

Hill Publishing Company.

“Tripathi K D”; “Essential of Medical Pharmacology”; Fifth

edition 2003, Published by Jaypee Brothers .

“Rang H P”, “Dale M M”, “Ritter J M”, “Flower R J”; “Rang

and Dale’s Pharmacology”; Sixth edition, Published by

Churchchill Livingstone. 

REFRENCES

Bibiliography GOODMAN & GILMAN'S “THE PHARMACOLOGICAL BASIS OF THERAPEUTICS”, Eleventh Edition, 2001. Published By McGraw-Hill Publishing Company

Tripathi K..D , ”Essentials of Medical Pharmacology”, 6th Edition 2010, Published By : Jaypee Medical Publishers

RANG H.P, DALE M.M, RITTER.J, FLOWER.R,” Rang & Dales Pharmacology, Sixth Edition 2010. Published By : Churchill Livingstone.