Serotonin

Question 1

How is serotonin synthesized?

Answer 1

• 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

Question 2

Metabolism:

Answer 2

• 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

Question 3

Distribution:
Enterochromaffin cells of GI mucosa

Answer 3

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

Question 4

Distribution:

Blood platelets

Answer 4

8%

• no synthesis takes place in platelets
  
  • uptake, storage and release
• site for removal of serotonin from plasma
  
  • may be involved in clotting

Question 5

Distribution:

CNS

Answer 5

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

Question 6

Receptors:

Answer 6

At least 13 subtypes:

• Most are GPCRs
  
  • Except 5HT₃

1. 5-HT_1(A-E) - inhibition of adenylate cyclase.
   
   • 5- HT_1A also opens K+ channel
2. 5-HT_2(A-C) - PI hydrolysis
3. 5-HT₃ - ligand-gated Cation channel
4. 5-HT_{4 - 7} - activation of adenylate cyclase or unknown
5. Auto-receptors – decrease serotonin release – 1A and 1D like

Question 7

5-HT1 family:

Answer 7

1. 5-HT_1A
   
   • G_i Inhibition of adenylate cyclase
   • G_i Opening of K⁺ channel
   • G_o Closing of Ca^₂₊ channel
2. 5-HT_1B, 5-HT_1D, 5-HT_1E
   
   • G_i Inhibition of adenylate cyclase

Question 8

5-HT₂ family:

Answer 8

5-HT_2A, 5-HT_2B, 5-HT_2C :

• G_q
• Phosphoinositide hydrolysis

Question 9

Other serotonin recpetor subtypes:

Answer 9

• 5-HT_4, 5-HT_5A, 5-HT₆,5-HT_7:
  
  • Gs
  • Activation of adenylate cyclase
• 5-HT_5B
  
  • Unknown coupling mech.

Question 10

What is the major difference with HT₃ receptors?

Answer 10

• Ligand-gated ion channels
  
  • ​not GPCRs

Question 11

What are the pharmacological actions of serotonin in the GI system?

Answer 11

• 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

Question 12

What are the pharmacological actions of serotonin in the cardiovascular system?

Answer 12

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-HT_1D)
• 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

Question 13

What are the pharmacological actions of serotonin in the CNS?

Answer 13

Cell bodies in midbrain raphe nuclei:

1. Sensory perception - LSD
2. Sleep – Slow wave deep sleep
   
   • not REM sleep
3. Temperature regulation
4. Neuroendocrine regulation
   
   • release of ACTH, GH, prolactin, TSH, FSH and LH
5. Learning and memory – particularly short-term.
6. Pain perception – spinal and brain sites.
7. Drug abuse
8. Emesis – 5-HT3 receptors
9. Mental Illness

Question 14

Descrbe how serotonin is involved in mental illness:

Answer 14

1. Affective disorders
   
   • SSRIs & SNRIs
2. Schizophrenia
   
   • atypical antipsychotics
3. Obsessive-compulsive disorder
   
   • SSRIs
4. Anxiety disorders – 5-HT1A receptors
5. Aggressive behavior

Question 15

Serotonin Agonists (4):

Answer 15

1. Lysergic Acid Diethylamide
2. Buspirone (BuSpar®)
3. Sumatriptan (Imitrex®)
4. Tegaserod

Question 16

Lysergic Acid Diethylamide (LSD):

Answer 16

• potent hallucinogen (~1μg/kg)
• Full or partial agonist at 5-HT₂ receptors
• Other drugs with similar action include psilocybin, mescaline and dimethyltryptamine (DMT)

Question 17

Buspirone (BuSpar®):

Answer 17

• partial agonist at 5-HT_1A receptors
• used as antianxiety agent

Question 18

Sumatriptan (Imitrex®):

Answer 18

agonist at 5-HT_1D receptor

• used in the treatment of migraine headaches
  
  • ​stops existing headache
• side effects: nausea and vomiting, angina, dizziness and flushing

Question 19

Tegaserod:

Answer 19

• 5-HT₄ partial agonist used to treat irritable bowel syndrome with constipation in women
• stimulates G.I. motility

Question 20

Indirect agonists (2):

Answer 20

1. Fluoxetine (Prozac®)
2. Phenelzine

Question 21

Fluoxetine (Prozac®):

Answer 21

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

Question 22

Phenelzine:

Answer 22

Monoamine oxidase inhibitors

• block metabolism of serotonin, NE and DA
• used in treatment of depression and narcolepsy
• Side effects: food induced hypertensive crisis

Question 23

Serotonin antagonists (3):

Answer 23

• Cyproheptadine
• Ondansetron (Zofran® / Zofran® ODT)
• Alosetron

Question 24

Cyproheptadine:

Answer 24

• 5-HT₂ receptor antagonist
  
  • also histamine H₁ antagonist
• treatment: skin allergies & carcinoid
  
  • particularly pruritus and urticaria

Question 25

**Ondansetron** (Zofran® / Zofran® ODT)**:**

Answer 25

* **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

Question 26

**Alosetron:**

Answer 26

* **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