1. Presentator : Dr. T.Ravikanth
Moderators: Dr. Sharbandh Raj
Dr. Swaroopa Chary
2. Introduction
Synthesis.
Degradation.
Serotonin Receptors.
Pathways in Brain.
Disorders associated with malfunctioned
Serotonergic System.
Drugs affecting on serotonergic System
3. Introduction
Serotonin is a monoamine neurotransmitter.
extensively in GIT
80 to 90 percent - enterochromaffin cells in the gut,
where it is used to regulate intestinal movements.
The remainder is synthesized in 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.
4. 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.
5.
6. Majority released from gut
Responsible for smooth muscle
contractions
Release stimulated by food intake
Inhibits release of gastric acid
Softens stool
Cardiovascular system –
vasoconstrictor
Bronchioconstriction
Uterine contractions
7. Peripheral
Peristalsis
Vomiting
Platelet aggregation and haemostasis
Inflammatory mediator
Sensitisation of
nociceptors
8. Central
Control of appetite
Sleep
Mood
Hallucinations
Stereotyped
behaviour
Pain perception
Vomiting
9.
10. (Rate OH
COOH limiting) COOH
Tryptophan
C NH2 hydroxylase C NH2
N N
In diet. Active
Tryptophan CNS transport 5-Hydroxytryptophan
5-OH Tryptophan
decarboxylase
C COOH
OH H
N
C NH2
5-Hydroxy Indole N
Acetic Acid 5-OH Indole
Acetaldehyde 5-Hydroxytryptamine
15. 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.
24. •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 adenylate cyclase.
•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.
25. 5–HT2
7 trans–membrane domains
G protein linked
Phospholipase C dependant
Subtypes
5–HT2A, 5–HT2B, 5–HT2C
26.
27.
28. 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
30. •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 predominantly as
anti-emetic drugs.
31. 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 is metoclopramide
used for treating gastrointestinal disorders.
Little is known about the function and
pharmacology of 5-HT5, 5-HT6 and 5-HT7
receptors.
35. 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.
36. 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.
39. 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 on platelets.
40. 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 therapeutic effects 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
41. 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.
42. There is weak evidence for the significant
involvement of serotonin in ADHD.
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.
43. 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.
44. 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.
45. Seretonin in ANOREXIA NERVOSA
Three neurotransmitters involved in regulating eating
behavior in the paraventricular nucleus of the
hypothalamus.
Serotonin,
Dopamine,
Norepinephrine.
Seretonin in BULIMIA NERVOSA
Because antidepressants often benefit patients with
bulimia nervosa and because serotonin has been linked to
satiety, serotonin and norepinephrine have been
implicated.
46. 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.
47. 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
heart problems. 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.
