By :- Ali Al-Alwani
Group:-117 i-6

Introduction
Synthesis.
Degradation.
Serotonin Receptors.
Pathways in Brain.
Disorders associated with malfunctioned
Serotonergic System.
Drugs affecting on serotonergic System

Types of neurotransmitters: Although over 50 signal
molecules in the nervous system have been identified,
norepinephrine (and the closely related epinephrine),
acetylcholine, dopamine, serotonin, histamine,
glutamate, and γ-aminobutyric acid are most commonly
involved in the actions of therapeutically useful drugs.

Serotonin is a monoamine neurotransmitter.
It has a popular image as a contributor to feelings of well-being
and happiness
extensively in GIT
80 to 90 percent - enterochromaffin cells in the gut,
where it is used to regulate intestinal movements.
The remainder is synthesizedin serotonergic neurons
in the central nervous system.
Despite the abundance of peripheral serotonin, its
inability to cross the BBB necessitates the synthesis of
serotonin within the brain.
Serotonin is synthesized from the amino acid
tryptophan, which is derived from the diet.
Introduction

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 disgorge
serotonin, where it serves as a vasoconstrictor and
helps to regulate hemostasis and blood clotting.
Serotonin also is a growth factor for some types of
cells, which may give it a role in wound healing.

Majority released from gut
Responsible for smooth muscle
contractions
Release stimulated by foodintake
Inhibits release of gastric acid
Softens stool
Cardiovascular system –
vasoconstrictor
Bronchioconstriction
Uterine contractions

Peripheral
Peristalsis
Vomiting
Platelet aggregation and haemostasis
Inflammatory mediator
Sensitisation of
nociceptors

Central
Control of appetite
Sleep
Mood
Hallucinations
Stereotyped
behaviour
Pain perception
Vomiting

Actions of 5-HT
 Potent depolarizer of Nerve endings – exerts direct as well as
Arteries
areconstricted (direct) or dilated (EDRF) – depends
on vascular bed and basal tone
Also releases Adrenaline – affects ganglionic
transmission – CVS reflexes
Overall, large arteries and veins are constricted but in
microcirculation arterioles dilate and veins constrict
Constriction of veins – escape offluid
indirect effects
 Tachyphylaxis

Actions of 5-HT - CVS
 Heart: Isolated heart stimulation - direct ionotropic andchronotropic
effects
◦ Intact animal Heart: Bradycardia due to stimulation coronary
chemoreflex (Bezold Jarrisch reflex) – through vagaus Nerve
◦ Overall bradycardia, hypotension and apnoea
 Blood Pressure: Triphasic response on BP
◦ Early sharp fall: Coronary chemoreflex
◦ Brief rise in BP: vasoconstriction and increased cardiac output
◦ Prolonged fallin BP: arteriolar dilatation and extravasation of
fluid
 (Not involved in Physiological Regulation of BP) – Preeclmpsia
 Ketanserin – 5-HT antagonist (5-HT2)

Actions of 5-HT – contd.
Platelet: 5-HT2A action – changes in shape and size
of platelets– but weak aggregator
CNS: Poor entry to BBB – however
it’s atransmitter – INHIBITORY
◦ Direct Injection: Hunger, sleepiness,
behavioural changes

5-HT Physiological Roles – contd.
 Haemostasis: Platelet aggregation and clot
formation enhancer
 Raynaud`s phenomenon: Vasospastic
 Variant angina: Coronary vasospasm or
Variant angina
 Hypertension: Not clearly known – reduced
uptake and clearance of 5-HT - Ketanserin
 Intestinal Motility: Regulates local
reflex andperistalsis in gut
 Carcinoid syndrome: Massive release –
hypermotility and bronchoconstriction
 5-HTs – N O THERAPEUTIC USE

Pathphysiological Roles – 5-HT
 Neurotransmitter: Raphe nuclei, substancia nigra and
other sites….. Send serotonergic to limbic system,
cortex, neostriatum and also to Spinal chord –
regulates sleep, temperature regulation, thought
process, cognitive, behaviour and mood, appetite,
vomiting and pain perception
 Precursor of Melatonin: Pineal gland
 Neuroendocrine Function: Hypothalamic
hormones toAnterior Pituitary – serotonergic(!)
 Nausea and Vomiting: Cytotoxic drugs and
radiotherapy –receptor of gut 5HT3
 Migraine: Vasoconstrictor phase of migraine –
Methysergide andSumatriptan

N N
COOH
C NH2
COOH
C NH2
OH
N
C NH2
OH H
Tryptophan 5-Hydroxytryptophan
5-Hydroxytryptamine
N
C COOH
5-OH Indole
Acetaldehyde
5-Hydroxy Indole
Acetic Acid
Tryptophan
hydroxylase
5-OH Tryptophan
decarboxylase
(Rate limiting)
In diet. Active
CNS transport

B
MAO A orB
(SERT)

Serotonin receptors

14 distinct serotonin receptor
subtypes
The 5-HT1 receptors = largest subfamily
The most intensively studied of these has been the
5-HT1A receptor.
This subtype is found on both postsynaptic membranes of
forebrain neurons primarily in the hippocampus, cortex,
and septum and on serotonergic neurons.
It also functions as a somatodendritic autoreceptor.

5–HT1
7 trans–membrane domains
G protein linked
cAMP dependant
Anxiolytic and antidepressant
Subtypes
 5–HT1A, 5–HT1B, 5–HT1D, 5–
HT1E, 5–HT1F
5–HT1A
Limbic system
 Regulation of emotions
Neocortex
Hypothalamus
Substantia gelatinosa
 Proprioception

CNSforum.com

•5-HT1 receptors occur primarily in the brain and cerebral
blood vessels (5-HT1D only), where they mediate neural
inhibition and vasoconstriction.
•They function mainly as inhibitory presynaptic receptors,
linked to inhibition of adenylatecyclase.
•Specific agonists at 5-HT1 receptors include
•Sumatriptan (used in migraine therapy)
•Buspirone (used in the treatment of anxiety).
•Spiperone and methiothepin are specific antagonists of 5-
HT1 receptors.

5–HT2
7trans–membrane domains
G protein linked
Phospholipase C dependant
Subtypes
 5– HT2A ,5– HT2B ,5– HT2C

5– HT2A
Periphery
 Contraction of vascular /non–vascular smooth muscle
 Platelet aggregation
 Increased capillary permeability
 Cognitive process of working memory, a function
believed to be impaired in schizophrenia.
 Modulation of the release of other neurotransmitters
and hormones
ACh, Adrenaline, Dopamine, Excitatory amino
acids, Vasopressin

5- HT2A
CNS
 Motor behaviour
 Sleep regulation
 Nociception
 Neuroexcitation

•5-HT3 receptors occur
mainly in the peripheral
nervous system,
particularly on nociceptive
afferent neurones and on
autonomic and enteric
neurones.
•The effects of these
receptors are excitatory,
mediated by receptor-
coupled ion channels.
•5-HT3 antagonists (eg
ondansetron, tropisetron)
are used predominantlyas
anti-emetic drugs.

5-HT4 receptors are found in the brain, as well
as peripheral organs like the heart, bladder and
gastrointestinal (GI) tract.
stimulating peristalsis.
A specific 5-HT4 agonist ismetoclopramide
used for treating gastrointestinal disorders.
Little is known about the function and
pharmacology of 5-HT5, 5-HT6 and 5-HT7
receptors.

Serotonin has both ascending &
decending projections.
Ascending serononergic projections
Serotonergic neurons are clustered in midline raphe
nuclei of the midbrain, pons, and medulla
Ascending projections from these nuclei course through
the medial forebrain bundle before diverging to many
target regions.
 median raphe nucleus provides the majority of the
serotonergic innervation of the limbic system, including
the hippocampus and septum,
 dorsal raphe nucleus provides the primary innervation of
the striatum and thalamus.

Decendng serononergic projection
extend down the brainstem, and through the
spinal cord.
The caudal raphe serotonergic neurons project to the
medulla, cerebellum, and spinal cord.
Serotonergic efferents to the dorsal horn of the
spinal cord have been implicated in the
suppression of nociceptive pathways.

Ascending pathway
regulates
Mood,
Anxiety,
Sleep
Decending pathway regulate the pain
sentation.

1. Mood Disorders
2. Anxiety Disorder
3. Schizophrenia
4. ADHD
5. Sexual Disorders
6. Impulse Control Disorder
7. Personality disorders
8. Carcinoid syndrome

With the huge effect that the selective serotonin reuptake
inhibitors (SSRIs) for example, fluoxetine have made on the
treatment of depression, serotonin has become the biogenic
amine neurotransmitter most commonly associated with
depression.
The identification of multiple serotonin receptor subtypes has also
increased the excitement within the research community about the
development of even more specific treatments for depression.
Depletion of serotonin may precipitate depression, and some
patients with suicidal impulses have low cerebrospinal fluid
(CSF) concentrations of serotonin metabolites and low
concentrations of serotonin uptake sites onplatelets.

Different types of acute stress result in increased 5-
HT turnover in the prefrontal cortex, nucleus
accumbens, amygdala, and lateral
hypothalamus.
 5-HT release may have anxiogenic and anxiolytic effects,
depending on the region of the forebrain involved and the receptor
subtype activated.
Anxiogenic effects are mediated via 5-HT2A receptor,
stimulation of 5-HT1A receptors is anxiolytic.
 serotonergic antidepressants have therapeuticeffects in
some anxiety disorders for example, clomipramine (Anafranil) in
OCD.
 The effectiveness of buspirone (BuSpar), a serotonin 5-HT1A
receptor agonist, in the treatment of anxiety disorders

Current hypotheses posit serotonin excess as a
cause of both positive and negative symptoms
in schizophrenia.
The robust serotonin antagonist activity of
clozapine and other second-generation
antipsychotics, coupled with the effectiveness
of clozapine to decrease positive symptoms in
chronic patients has contributed to the validity
of this proposition.

There is weak evidence for the significant
involvement of serotonin inADHD.
The support for the serotonin hypothesis comes
from the fact that some drugs (TCA & MAOI) that
affect serotonin metabolism are moderately
effective in ADHD.
However SSRIs have not been shown to be
effective.
Thus, if serotonin plays a role in ADHD, it is not
likely to have a central role but rather an
adjunctive role to one or more other
neurotransmitter systems.

SSRIs can cause
anorgasmia,
erectile dysfunction,
diminished libido.
Stimulation of
postsynaptic 5-HT2 and 5-
HT3 receptors =decreases
dopamine release from
the substantia nigra
=Sexual Dysfunction.

Low CSF serotonin metabolites often found in
certain depressions.
Also are found among people who have made
suicide attempts who are violent, impulsive,
alcoholics and it has been found among their
relatives .
Impulsive alcoholic violent offenders have
decreased 5-HIAA.

Seretonin in ANOREXIANERVOSA
Three neurotransmitters involved in regulating eating
behavior in the paraventricular nucleus of the
hypothalamus.
 Serotonin,
 Dopamine,
 Norepinephrine.
Seretonin in BULIMIANERVOSA
Because antidepressants often benefit patients with
bulimia nervosa and because serotonin has been linked to
satiety, serotonin and norepinephrine have been
implicated.

Studies of personality traits and the dopaminergic
and serotonergic systems indicate an arousal-
activating function for these neurotransmitters.
Raising serotonin levels with serotonergic agents
such as fluoxetine (Prozac) can produce
dramatic changes in some character traits of
personality.
In many persons, serotonin reduces depression,
impulsiveness, and rumination, and can produce a
sense of general well-being.

One type of tumor, called carcinoid, sometimes
secretes large amounts of serotonin into the
blood, which causes various forms of the
carcinoid syndrome of flushing, diarrhea, and
heartproblems. Because of serotonin's growth-
promoting effect on cardiac myocytes, persons
with serotonin-secreting carcinoid may suffer a
right heart (tricuspid) valve disease syndrome,
caused by proliferation of myocytes onto the
valve.

Drugs Affecting
Serotonergic System

5-HT1A : Buspirone, Ipsapirone,
Tandospirone Treat anxiety, depression
(partial agonist)
5-HT 1D/1B : Sumatriptan, Naratriptan,
Zolmitriptan
Treat migraine (partial agonist)
5-HT 2A/2C : Methysergide, Trazodone,
Risperidone, Ketanserin, Ritanserin, Mianserin
Treat migraine, depression, schizophrenia
(antagonist)

5-HT 3 : Ondansetron, Granisetron, Tropisetron,
Memantine, Mirtazapine
The enterochromaffin cells are very sensitive to
cancer chemotherapy = vomiting
Treat chemotherapy-induced emesis (antagonist)
5-HT 4 : Cisapride, Metoclopramide,
Mosapride, Dazopride, Tegaserod
Treat GI disorders (agonist)
Serotinergic
Drugs

Serotonin re–uptake
inhibitors
Citalopram, Fluoxetine, Fluvoxamine, Paroxetine,
Sertraline, Venlafaxine
Clomipramine, Imipramine
Nefazodone, Trazodone
Chlorpheniramine
Cocaine, Dextromethorphan, Pentazocine, Pethidine

Irreversible Monoamine oxidase
inhibitors (MAOIs)
Clorgyline, Isocarboxazid, Nialamide, Pargyline,
Phenelzine, Tranylcypromine
Selegiline
Furazolidone
Procarbazine

Reversible inhibitors of MAO
(RIMAs)
Brofaramine
Befloxatone, Toloxatone
Moclobemide

Kaplan and sadock ‘s comprehensive text book
of psychiatry.
Stephen M. Stahl –Essential
Psychopharmacology.
Medscape.com
Emedicine.com

Thank you