By Duy Thai, 1997 Pharmacology Semester 1 page 1 of 6

SEROTONIN

• Serotonin – a.k.a. 5 hydroxytryptamine (5HT)

• Complex, astonishingly diverse biology
• Very medically important
• Is the subject of intense research
• There have been heaps of serotonin receptors discovered (7 families to date) with new ones popping up
and the mechanisms of the current ones being elucidated.

Synthesis and metabolism

Tryptophan (from diet)

Tryptophan hydroxylase

5 Hydroxytryptophan

Aromatic amino acid decarboxylase

5 Hydroxytryptamine

Monoamine oxidase +
N acetyl serotonin aldehyde dehydrogenase

Melatonin (in pineal) 5 hydroxy indole acetic acid

Involved in setting our (5 HIAA)
circadian rhythms Elevated levels of this
indicate hypersecretion of
serotonin

Location of serotonin: uptake vs synthesis

• Gastrointestinal tract
• 90% of the body's total 5HT is found in the GIT
• It is synthesised and stored (in secretory granules) in the enterochromaffin cells
• It is also made in some nerves (serotonergic nerves) which make up a minor component of the myenteric
plexus.
• Blood
• Platelets take up serotonin very efficiently so that there are only trace amounts of 5HT in the blood.
• Serotonin is taken up via a Na+ dependent carrier mediated uptake. This upstake can create
concentration gradients of 1000:1 (serotonin in platelets:blood)
• It is bound tightly to granules found in the platelets.
• It is not synthesised by the platelets.
• It has a very slow turnover
• CNS
• Serotonin is synthesised de novo by tryptaminergic neurons. This is because serotonin cannot pass
through the blood brain barrier and so neurons must be able to produce it.
• Serotonin is stored in vesicles.
• Serotonin is also taken up in the axons of serotonergic neurons as a means of terminating its action in the
synaptic cleft.
By Duy Thai, 1997 Pharmacology Semester 1 page 2 of 6

Serotonin receptor subtypes

• All 5HT receptors are 7 transmembrane spanning receptors EXCEPT 5HT3
• 5HT1
• Has 5 members (5HT1A, B, D, E, F)
• The receptor is G coupled
• Decreases the amount of cAMP (by inhibiting adenylate cyclase)
• 5HT1A
• Activates receptor operated K+ channels Both these factors affect ion conductions
• Inhibits voltage gated Ca2+ channels in the brain
• 5HT1D
• Expressed in substantia nigra
• Expressed in basal ganglia
• May regulate dopamine nerves by presynaptic modulation
• 5HT1D receptors are also found on pial and coronary vessels (causing
vasoconstriction) - important because sometimes use of 5HT1D agonist (sumatriptan)
for migranes may also cause coronary vasoconstriction, and in people with coronary
atherosclerosis, a reduction in luminal radius will result in coronary ischaemia.
• 5HT1A and 5HT1D
• Are also inhibitory autoreceptors
• 5HT1A is a somatodendritic inhibitory autoreceptor on serotonergic nerves in the
raphe nucleus of the brainstem
• 5HT1D is a presynaptic inhibitory autoreceptor
• Autoreceptos are found on the raphe nuclei in the brainstem.
• The presence of these inhibitory autoreceptors acts as safeguards to prevent
overactivity of these nerves.
⊗
⊗
5HT1A
5HT1D
5HT Target

Presynaptic
Diffusion to affect other neurons
Somatodendritic
• In the brain, serotonin acts at a distance from its target (most neurotransmitters are released close to the
target receptor and act locally). By acting at a distance, serotonin is able to diffuse out of the synaptic cleft
and affect other nearby nerves. Hence, serotonin can act as both a neurotransmitter and neuromodulator.
• 5HT2
• Has 3 members (5HT2A, B, C)
• G coupled
• Activates phospholipase C
• 5HT2A
• Found everywhere in the brain
• Found on platelets (plays a role in platelet aggregation)
• Found on smooth muscle cells (contraction)
• 5HT2B
• Found in the stomach fundus (contraction of the smooth muscle found there)
• 5HT2C
• Found in the choroid plexus (unknown function)
By Duy Thai, 1997 Pharmacology Semester 1 page 3 of 6

• 5HT3 (Special one!!!)

• Contains one member
• It is a 4 transmembrane spanning ligand gated ion channel
• It gates the ions Na+ and K+
• Found on peripheral sensory (afferent) nerves
• Located on vagal and splanchnic afferents
These regions play an important role in
• Also in the nucleus tractus solitarius
emesis
• Also found in the area postrema
• Are neuroexcitatory
• 5HT4
• One member
• G coupled
• Increases cAMP
• Neuroexciatory
• Locations:
• Found in the hippocampus
• Found in the gut:
• Myenteric plexus
• Smooth muscle cells Facilitate the peristaltic reflex
• Secretory cells (promote secretion)
• 5HT5
• 2 members (A, B)
• Unknown transduction
• 5HT6
• 1 member
Unknown functions, mostly in CNS (5HT7 in also present in
• G coupled
the GIT as well)
• Increases cAMP
• 5HT7
• 1 member
• G coupled
• Increases cAMP
• New drugs may be developed to target these receptors to affect mood, anxiety, schizophrenia and a whole range of
neurological disorders.

5HT and human disease

• Carcinoid syndrome
• Overproduction of serotonin as a result of a tumor of enterochromaffin cells
• Results in hypotension/cardiovascular system disorders
• Flushing (due to vasodilation)
• Bronchospasm
• Diarrhoea
• Treatment of carcinoid tumors involves the following drugs:
• Fenclanine
• A serotonin synthesis inhibitor
• Tends to be the preferred treatment.
• Cyproheptadine
• Block 5HT receptors (as well as H1 receptors)
• Serotonin is also involved in the following:
• Migrane
• Emesis (vomiting)
• Anxiety
• Phycosis/Schizophrenia
• Appetite Diversity of effects due to lots of receptor subtypes
• Depression
• Obsessive compulsive disorders
• Gastrointestinal disorders
By Duy Thai, 1997 Pharmacology Semester 1 page 4 of 6

Biology of serotonin: its physiological effects

• Platelet aggregation (role of serotonin in hemostasis)
• Serotonin is not synthesised by platelets
• It is taken up by platelets and stored in high concentration is dense core granules.
• Normally, platelets are continuously making contact with the endothelium but do not stick or become
activates since the intact endothelium produced anti-aggregatory factors such as EDRF. When the
endothelium is damaged, platelets become activated.
• The injured endothelium triggers the release of serotonin from platelets (along with ADP,
thrombin, thromboxaneA2)
• These factors all promote platelet aggregation.
• Serotonin acting on 5HT2A receptors:
• On other platelets enhances platelet aggregation.
• On vascular smooth muscle causes direct vasoconstriction
• Serotonin acting on 5HT1 receptors causes vasodilation via EDRF (endothelial derived relaxing
factor or NO)
• If the vessel wall is intact, serotonin can only get access to the endothelial cells and so
will promote the release of the anti-aggregatory EDRF by acting on 5HT1 receptors.
• However, if the endothelial layer is damaged, two things happen:
1. The endothelium stops making EDRF
2. Exposure of the underlying smooth muscle means serotonin can now act on
5HT2A receptors and cause vasoconstriction.
• Serotonin may have a role in the pathogenesis of:
• Atherosclerosis
• Coronary vasospasm (if platelets release serotonin abnormally)
• Raynauds syndrome
• Constriction of vessels in hands and periphery, leading to cold extremities.
• Serotonin in the cardiovascular system
• Causes direct contraction of arteries (EDRF modulates this effect) by acting on 5HT2A receptors on
smooth muscle.
• May also cause constriction of other blood vessels:
• Splanchnic
• Renal
• Pulmonary
• Cerebral
• Will also contract bronchial smooth muscle, leading to bronchial constriction.
• Direct stimulation of vagal nerve endings to the heart.
• Results in Bezold-Jarisch reflex (5HT3 mediated)
• Bradycardia and hypotension
• Amplifies the effects of:
• Histamine
• Noradrenaline
• Angiotensin II
• Increases the rate of SA node, thus increasing the heart rate (5HT4 mediated)
• Serotonin in the gut
• There are 5HT receptor types in the gut, and so serotonin may have many different actions, enhancing or
inhibiting motility.
• 5HT4 increases motility (peristalsis) hence increasing transit time (5HT4 is found on myenteric plexus
nerves)
• Enteric serotonin released from nerves in the myenteric plexus may regulate tone.
• Serotonin acting on 5HT3 receptors on afferent nerves (sensory nerves from the gut) may stimulate
emesis.
• The major source of serotonin in the gut is from enterochromaffin cells.
• The release of serotonin from the enterochromaffin cells is probably due to stretching of the gut
wall.
• Serotonin can then act on 5HT3 receptors on the sensory nerves or on 5HT4 receptors in the
myenteric plexus to regulate peristalsis.
By Duy Thai, 1997 Pharmacology Semester 1 page 5 of 6

• Serotonin in the central nervous system

• Serotonin has 2 roles in the CNS
• As a neurotransmitter
• Serotonin is produced de novo by neurons because it cannot pass through the blood
brain barrier.
• As a neuromodulator
• Serotonin diffuses out of the synaptic cleft to affect nearby nerves.
• The principle cell bodies where serotonin is synthesised are in the raphe nucleus of the brainstem, which
project up to the brain and also down to the spine.
• Serotonin may be involved in:
• The sleep/wake cycle (depletion of serotonin with p-chlorophenylalanine can cause insomnia)
• Aggression
• Serotonin acting on 5HT1B receptors (???) may cause aggression in some people. This
is evidenced by drugs which prolong serotonin action (fluoxitine - Prozac). Prozac is
found to cause some people to have aggression.
• Anxiety/depression
• Mediated by 5HT1A, 2A, 2C, 3

What happens at a serotonergic synapse

Tryptophan

5HT
p-chlorophenylalanine Iproniazid
(fenclonine)

Reserpine

Granule 5HIAA

MAO

5HT1D 5HT

8 OH DPAT reuptake
5HT
Neuromodulation
Fluoxetine

• p-chlorophenylalanine (fenclonine)
• Inhibits the synthesis of serotonin
• reserpine
• Inhibits the uptake of serotonin into storage vesicles
• Promotes direct release of serotonin from the nerve
• iproniazid
• Inhibits the enzyme MAO, which is used to degrade serotonin
• 8-OH-DPAT
• Presynaptic modulation via 5HT1D receptor (the drug is an agonist)
• Inhibits the exocytosis of vesicles storing serotonin
• Fluoxetine
• Prevents the reuptake of serotonin, thus prolonging the action of serotonin
By Duy Thai, 1997 Pharmacology Semester 1 page 6 of 6

Theories of migrane
• A primary neuronal disturbance causes hyperactivity of NA and serotonin releasing neurons.
• NA and serotonin may cause cerebral vasoconstriction, explaining the initial visual disturbances.
• Serotonin may also cause perivascular inflammation, the inflamed vessels release prostaglandins and bradykinin
which sensitise nociceptive nerve terminals.
• Inflammation may cause vasodilation and the distention may stimulate afferent nerves which are sensitised to pain,
thus we get a headache.
• Drugs used to treat migranes:
• Sumatriptan
• Acts on the 5HT1D inhibitory autoreceptor to prevent the release of serotonin from serotonergic
nerved.
• Aspirin
• Inhibits the formation of prostaglandins which have a role in mediating pain
• Ergotamine
• Causes vasoconstriction of the cerebral vasculature.

Theories of emesis
• All pathways of emesis finally reach the medullary emetic center.
Higher centers
(psycogenic induced
vomiting)
Solitary tract
nucleus
Medulla emetic 5HT3, D2, M, H1
center
Cerebellum 5HT3, D2, M
H1, M
CNX CNV, CNIX
Area postrema
chemoreceptor
trigger zone
5HT3, D2, M
Inner ear
Pharynx

Cytotoxics,
emetics Gut
5HT3

Radiation

• 3 receptors may be involved in the pathway towards vomiting:

• H1 (histamine) receptor
• 5HT3 (serotonin) receptor
• D2 (dopamine) receptor
• M (muscarinic) receptor
• Drugs which are antagonists of these receptors have proved useful in the treatment of emesis.
• H1 Difenhydramine
• 5HT3 Ondansetron
• D2 Metaclopromide
• M Scopolamine

Clinically important drugs

• Know the drugs on the handout!!!