 Introduction.

Serotonin
 In animals & unicellular organisms.

 Anatomy.

 Biosynthesis.

 Metabolism.

 Function.

 Serotonin receptors & the mechanism of action.

 Pathology & Increasing serotonin levels.

 Drugs targeting the 5 –HT system.

 References & External links.

 Serotonin
Introduction
 Widely distributed amine (animals + plants).
 Serotonin (5-hydroxytryptamine, or 5-HT) is a monoamine
neurotransmitter synthesized In humans.

 Serotonin is present in
GI enterochromaffin cells (90%), platelets ,
CNS (raphe nuclei of brain stem )&
pineal gland (precursor of melatonin).

 Synthesized from tryptophan (in diet) in two steps.

 Serotonin
Introduction

- Platelets do not synthesize but take up from blood

(active uptake process in platelets and nerve
terminals).

- Cell storage in granules similar to catecholamines .

- Serotonin is also found in many mushrooms and

plants, including fruits and vegetables.
 Serotonin
In animals& In unicellular organisms
 Serotonin as a neurotransmitter is found in many animals,
including insects.
 The gastrointestinal parasite Entamoeba histolytica secretes
serotonin, causing a sustained secretory diarrhea in some
patients.
 Patients infected with Entamoeba histolytica have been found
to have highly elevated serum serotonin levels which returned
to normal following resolution of the infection.
 Entamoeba histolytica also responds to the presence of
serotonin by becoming more virulent .
 Serotonin
Anatomy in the brain
Gross Anatomy.


Micro Anatomy.

 Serotonin
Anatomy
Gross Anatomy
 The neurons of the raphe nuclei are the principal source of 5-HT release
in the brain.

 The raphe nuclei are neurons grouped into about nine pairs and
distributed along the entire length of the brainstem, centered around the
reticular formation.

 Axons from the neurons of the raphe nuclei form a

neurotransmitter system, reaching large areas of the brain.

 Axons of neurons in the caudal raphe nuclei terminate in the following

locations:
 Deep cerebellar nuclei
 Cerebellar cortex
 Spinal cord
 Serotonin
Anatomy
Gross Anatomy
On the other hand, axons of neurons in the rostral raphe nuclei terminate in
e.g.:
 Thalamus
 Striatum
 Hypothalamus
 Nucleus accumbens
 Neocortex
 Cingulate gyrus
 Cingulum
 Hippocampus
 Amygdala
Thus, activation of this serotonin system has effects on large areas of the
brain
 Serotonin
Anatomy
Microanatomy
 Serotonin is released from serotonergic
varicosities (swellings) into the extra neuronal
space, but not from synaptic terminal boutons as
other neurotransmitters.

 Serotonin diffuses over a relatively wide gap

(>20µm) to activate 5-HT receptors located on
the dendrites, cell bodies and
presynaptic terminals of adjacent neurons .
 Serotonin
Biosynthesis
 A hydroxyl-group at carbon 5 of the
carbon skeleton of L- tryptophan
without a carboxyl group gives
serotonin its descriptive chemical
name, 5-hydroxytryptamine.
Serotonin
Biosynthesis
 Serotonin
Biosynthesis
 In animals including humans, serotonin is synthesized
from the amino acid L- tryptophan by a short
metabolic pathway consisting of two enzymes:
tryptophan hydroxylase (TPH) and
amino acid decarboxylase (AAD)

 The TPH-mediated reaction is the rate-limiting step in the

pathway. TPH has been shown to exist in two forms:
TPH1, found in several tissues, and TPH2, which is a
brain-specific isoform.

 5-OHTr decarboxylase same as DOPA decarboxylase.

 Serotonin
Biosynthesis
 There is also evidence that ovarian hormones can affect
the expression of TPH in various species, suggesting a
possible mechanism for postpartum depression and
premenstrual stress syndrome .

 Serotonin biosynthesis in plants likewise begins with L-

tryptophan, which is however first decarboxylated by
tryptophan decarboxylase to give tryptamine, which is then
hydroxylated by the cytochrome P450 monooxygenase,
tryptamine 5-hydroxylase, yielding serotonin.
 Serotonin
Biosynthesis
 Serotonin taken orally does not pass into the
serotonergic pathways of the central nervous system
because it does not cross the blood-brain barrier.

 However, tryptophan and its metabolite

5-hydroxytryptophan (5-HTP), from which serotonin is
synthesized, can and do cross the blood-brain
barrier.

 These agents are available as dietary supplements

and may be effective serotonergic agents .
 Serotonin
Metabolism
 One product of serotonin breakdown is
5-Hydroxyindoleacetic acid (5 HIAA), which is
excreted in the urine.

 Serotonin and 5 HIAA are sometimes produced

in excess amounts by certain tumors or cancers,
and levels of these substances may be
measured in the urine to test for these tumors.

 No end-product negative feedback.

 Serotonin
Function

 In the central nervous system, serotonin plays

an important role as a neurotransmitter in the
modulation of anger, aggression,
body temperature, mood, sleep,
human sexuality, appetite, and metabolism,
as well as stimulating vomiting .
 Serotonin
Function
In the C.N.S
 Pain perception
 Sleep/Wakefulness
 Various behaviors normal/abnormal:
depression, schizophrenia, obsessive
compulsive behavior, etc.
 Neuroendocrine regulation – controls
hypothalamic cells involved in release
of several anterior pituitary hormones.
 Serotonin
Function

 In addition, serotonin is also a peripheral signal

mediator. It is found extensively in the human
gastrointestinal tract as about 80-90% of the body's
total serotonin is found in the enterochromaffin cells
in the gut.

 In the blood, the major storage site is platelets, which

collect serotonin for use in mediating post-injury
vasoconstriction .
 Serotonin
Function
 Precursor of melatonin
 hormone secreted by the pineal gland in
proportion to the body's exposure to light,
hormone that is essential in the regulation of
biological rhythms (sleep, mood, puberty, and
menstrual cycles).

Recent research suggests that serotonin plays
an important role in liver regeneration and acts
as a mitogen (induces cell division) throughout
the body.
 Recent research also suggests that intestinal
serotonin may inhibit bone formation
 Serotonin
Serotonin Receptors

 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.
 Serotonin
Serotonin
Receptors
 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.
 Serotonin
Serotonin Receptors
Serotonin
Serotonin Receptors
 Serotonin
Increasing serotonin levels
 Serotonin levels can not be increased by diet or supplements of
tryptophan. For example, increasing foods rich in tryptophan (eg,
meats, proteins) does not increase serotonin levels, due to
competition with other amino acids.
 What is required to increase serotonin production is an increase in
the ratio of tryptophan to phenylalanine and leucine.
 Fruits with a good ratio include dates, papaya and banana.
 Foods with a lower ratio inhibit the production of serotonin. These
include whole wheat and rye bread .
 Serotonin
Increasing serotonin levels
Much research has indicated that vigorous
aerobic exercise improves mood, believed to
be facilitated by an increase in serotonin
levels.
 Research also suggests that eating a diet
rich in whole grain carbohydrates and low in
protein will increase serotonin by secreting
insulin, which helps in amino acid
competition.
 Serotonin
Increasing serotonin levels
 Itis also believed that muscles use
many of the amino acids except
tryptophan, allowing men to have more
serotonin than women.
 Serotonin
Pathology

 Ifneurons that make serotonin —

serotonergic neurons — are abnormal
in infants, there is a risk of
sudden infant death syndrome (SIDS).
 Serotonin
Pathology
Serotonin syndrome

Overstimulation of central & peripheral

serotonin receptors.
 this may be occurred due to increasing of
stretonergic medications prescriptions.
 Serotonin
Pathology
Serotonin syndrome
 Laboratory Abnormalities
 1. Metabolic acidosis.
 2. rhabdomyolosis (disintegration of skeletal
muscle tissue as a result of electrocution or
prolonged exposure to toxins (characterized by
excretion of myoglobin in the urine)
 3.Elevated serum aminotransferase &
creatine.
 Serotonin
Pathology
Serotonin syndrome
 Serotonin
Pathology
Chronic diseases resulting
from serotonin 5-HT2B overstimulation
 overdoses of serotonin, or serotonin
agonist drugs, may cause acute or chronic
pulmonary hypertension from pulmonary
vasoconstriction, or else syndromes of
retroperitoneal fibrosis or cardiac valve
fibrosis (endocardial fibrosis) from
overstimulation of serotonic growth
receptors on fibrocytes .
 Serotonin
Pathology
Chronic diseases resulting
from serotonin 5-HT2B overstimulation
 Serotonin itself may cause a syndrome of
cardiac fibrosis when it is eaten in large
quantities in the diet (the Matoki banana of
East Africa) or when it is over-secreted by
certain mid-gut carcinoid tumors.

 The valvular fibrosis in such cases is typically

on the right side of the heart, since excess
serotonin in the serum outside platelets is
metabolized in the lungs, and does not reach
the left circulation.
 Serotonin
Drugs targeting the 5-HT system
 Severalclasses of drugs target the 5-HT
system including some antidepressants,
antipsychotics, anxiolytics, antiemetics,
and antimigraine drugs as well as the
psychedelic drugs and empathogens.
 References & External links
 From Wikipedia .com, the free encyclopedia.
 Scribd.com.
 Handbook of endocrinology.
 Textbook of biochemistry with clinical
correlations.
 Harper’s biochemistry & lehninger
biochemistry.
 Other search websites (yahoo, google & 4-
shared)

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