Serotonin Flashcards
1
Q
How is serotonin synthesized?
A
- From essential amino acid tryptophan
-
5-Hydroxytryptophan formed by tryptophan hydroxylase — rate limiting step.
- Except in the CNS ⇒ low tryptophan levels
- Requires O2 and a reduced pteridine cofactor
-
Synthesized in most all tissues that contain it
- Except blood platelets
- Converted to melatonin in the pineal gland
2
Q
Metabolism:
A
- Converted by monoamine oxidase & aldehyde dehydrogenase ⇒ 5- hydroxyindole acetic acid
- May also be reduced to an alcohol
- Neuronal action terminated primarily by high affinity active reuptake mechanism (SERT) ⇒ intraneuronal conversion to 5- hydroxyindoleacetic acid
3
Q
Distribution:
Enterochromaffin cells of GI mucosa
A
largest store in body - 90%
- Synthesis and storage take place
- Slow spontaneous release - turnover 1 day
- May be part of “enteric nervous system”
- small fraction of GI serotonin is in neurons
4
Q
Distribution:
Blood platelets
A
8%
-
no synthesis takes place in platelets
- uptake, storage and release
- site for removal of serotonin from plasma
- may be involved in clotting
5
Q
Distribution:
CNS
A
midbrain raphe nuclei - 2%:
- project to hypothalamus, neostriatum, limbic forebrain, neocortex, medulla and spinal cord
- synthesis, storage and release occur
- **rapid turnover < **less than 4 hours
- affected by many psychoactive drugs
6
Q
Receptors:
A
At least 13 subtypes:
- Most are GPCRs
- Except 5HT3
-
5-HT1(A-E) - inhibition of adenylate cyclase.
- 5- HT1A also opens K+ channel
- 5-HT2(A-C) - PI hydrolysis
- 5-HT3 - ligand-gated Cation channel
- 5-HT4 - 7 - activation of adenylate cyclase or unknown
- Auto-receptors – decrease serotonin release – 1A and 1D like
7
Q
5-HT1 family:
A
-
5-HT1A
- Gi Inhibition of adenylate cyclase
- Gi Opening of K+ channel
- Go Closing of Ca2+ channel
-
5-HT1B, 5-HT1D, 5-HT1E
- Gi Inhibition of adenylate cyclase
8
Q
5-HT2 family:
A
5-HT2A, 5-HT2B, 5-HT2C :
- Gq
- Phosphoinositide hydrolysis
9
Q
Other serotonin recpetor subtypes:
A
-
5-HT4, 5-HT5A, 5-HT6,5-HT7:
- Gs
- Activation of adenylate cyclase
- 5-HT5B
- Unknown coupling mech.
10
Q
What is the major difference with HT3 receptors?
A
-
Ligand-gated ion channels
- not GPCRs
11
Q
What are the pharmacological actions of serotonin in the GI system?
A
-
Site of synthesis and storage
- neuronal & non-neuronal
-
Slow release
- turnover rate = 1 day
-
Contraction of G.I. smooth muscle:
- esophagus, stomach and intestine
- increases tone, peristalsis, and diarrhea
-
Emesis
- induced by 5-HT3 receptors in brain and G.I. tract
-
Carcinoid syndrome – serotonin secreting tumors
- also bradykinin
- treated with serotonin antagonists or octreotide a somatostatin analog
- can cause severe diarrhea and asthma
12
Q
What are the pharmacological actions of serotonin in the cardiovascular system?
A
Vasoconstriction or vasodilation:
-
Potent vasoconstriction in large arteries and veins in most vascular beds
- especially pulmonary and renal vessels (5-HT2)
- also cranial blood vessels (5-HT1D)
-
Vasodilation
- coronary arteries, arterioles
- skeletal muscle and cutaneous blood vessels
-
Bezold-Jarisch reflex: chemoreceptors in coronary vasculature
- powerful activator of afferent vagal nerve endings
- response is bradycardia, hypotension and hypoventilation
- Platelet aggregation
13
Q
What are the pharmacological actions of serotonin in the CNS?
A
Cell bodies in midbrain raphe nuclei:
- Sensory perception - LSD
-
Sleep – Slow wave deep sleep
- not REM sleep
- Temperature regulation
-
Neuroendocrine regulation
- release of ACTH, GH, prolactin, TSH, FSH and LH
- Learning and memory – particularly short-term.
- Pain perception – spinal and brain sites.
- Drug abuse
- Emesis – 5-HT3 receptors
- Mental Illness
14
Q
Descrbe how serotonin is involved in mental illness:
A
- Affective disorders
- SSRIs & SNRIs
- Schizophrenia
- atypical antipsychotics
- Obsessive-compulsive disorder
- SSRIs
- Anxiety disorders – 5-HT1A receptors
- Aggressive behavior
15
Q
Serotonin Agonists (4):
A
- Lysergic Acid Diethylamide
- Buspirone (BuSpar®)
- Sumatriptan (Imitrex®)
- Tegaserod
16
Q
Lysergic Acid Diethylamide (LSD):
A
- potent hallucinogen (~1μg/kg)
- Full or partial agonist at 5-HT2 receptors
- Other drugs with similar action include psilocybin, mescaline and dimethyltryptamine (DMT)
17
Q
Buspirone (BuSpar®):
A
- partial agonist at 5-HT1A receptors
- used as antianxiety agent
18
Q
Sumatriptan (Imitrex®):
A
agonist at 5-HT1D receptor
- used in the treatment of migraine headaches
- stops existing headache
- side effects: nausea and vomiting, angina, dizziness and flushing
19
Q
Tegaserod:
A
- 5-HT4 partial agonist used to treat irritable bowel syndrome with constipation in women
- stimulates G.I. motility
20
Q
Indirect agonists (2):
A
- Fluoxetine (Prozac®)
- Phenelzine
21
Q
Fluoxetine (Prozac®):
A
Serotonin specific reuptake inhibitors (SSRIs)
- blocks the active reuptake of serotonin into neurons
- increases amount of serotonin at synapse
- used in treatment of affective disorders, obsessive compulsive disorders, panic attacks, etc.
- side effects: sexual dysfunction, nausea
- Other SSRIs include sertraline, paroxetine, fluvoxamine and citalopram
22
Q
Phenelzine:
A
Monoamine oxidase inhibitors
- block metabolism of serotonin, NE and DA
- used in treatment of depression and narcolepsy
- Side effects: food induced hypertensive crisis
23
Q
Serotonin antagonists (3):
A
- Cyproheptadine
- Ondansetron (Zofran® / Zofran® ODT)
- Alosetron
24
Q
Cyproheptadine:
A
-
5-HT2 receptor antagonist
- also histamine H1 antagonist
- treatment: skin allergies & carcinoid
- particularly pruritus and urticaria
25
Q
Ondansetron (Zofran® / Zofran® ODT):
A
- 5-HT3 receptor antagonists
- very effective in treatment of chemotherapy- induced nausea and vomiting
- acts both at G.I. and brain receptors
- I.V. and oral forms available
26
Q
Alosetron:
A
- Selective 5-HT3 antagonist
- Treats women with diarrhea-predominant IBS who have failed to respond to conventional therapy
- Can produce severe GI adverse effects
- restricted prescribing program must be followed
