Block 2_1 - Serotonin

Question 1

Outline Steps in Serotonin Synthesis

• note rate limiting step, cofactors

Answer 1

1. Tryptophan (essential amino acid)

Tryptophan Hydroxylase (rate limiting step)

2. 5-hydroxytryptophan

L-aromatic amino acid decarboxylase (with pyridoxine cofactor)

3. Serotonin (5-hydroxytryptamine)

Question 2

How is serotonin synthesis different in the brain/CNS? Cofactors?

Answer 2

Tryptophan hydroxylase is not the rate limiting step because of low tryptophan levels (i.e. tryptophan concentration limits synthesis in the brain) - Requires O2 and reduced pteridine cofactor

Question 3

Serotonin is converted to what in the pineal gland?

Answer 3

Melatonin (5-methoxy-N-acetyltryptamine)

Serotonin –a–> N-Acetyl Serotonin –b–> Melatonin

a) 5 HT N-acetylase
b) 5-hydroxy indole O-methyl transferase

Question 4

Name 2 ways Serotonin is metabolized (and terminated)

Answer 4

1. Converted by monoamine oxidase (MAO) and aldehyde dehydrogenase to 5-hydroxyindole acetic acid
2. Neuronal action terminated primarily by high affinity active reuptake mechanism - serotonin transporter (SERT) - then intraneuronal conversion to 5-hydroxyindole acetic acid

Question 5

Distribution of Serotonin in the body?

Answer 5

GI System - 90%

Platelets - 8%

CNS - 2%

Question 6

Serotonin is synthesized in most tissues that contain it except _____

Answer 6

Blood Platelets

Question 7

Distribution of Serotonin in GI Mucosa

1. Cells?
2. Release?
3. May be a part of what system?

Answer 7

1. Enterochromaffin cells
2. Slow spontaneous release - turnover 1 day
3. Enteric Nervous System - small fraction of GI serotonin is in neurons
   - note: synthesis and storage is both neuronal and non-neuronal

Question 8

Distribution of Serotonin in Blood Platelets

1. Stored where?
2. uptake, storage and release is similar to what?
3. T/F serves as a site for removal of serotonin from plasma and may be involved in clotting

Answer 8

1. vesicles with ATP - similar to neurons
2. neuronal serotonin
3. True

Question 9

Distribution of Serotonin in the CNS

1. Cell bodies where?
2. Project where?
3. Turnover?
4. affected by?

Answer 9

1. midbrain raphe nuclei
2. hypothalamus, neostriatum, limbic forebrain, neocortex, medulla, spinal cord
3. rapid turnover, less than 4 hours
4. many psychoactive drugs

Question 10

Serotonin Receptor Subtype 5-HT_{1A, 1B, 1D, 1E}

G protein - Effector Pathway?

Answer 10

5-HT_{1A, 1B, 1D, 1E}

G_i - Inhibition of Adenylate Cyclase

5-HT_1A

G_i - Opening of K+ channel

G_o - closing of Ca2+ channel

Question 11

Serotonin Receptor Subtype 5-HT_{<span>2A, 2B, or 2C</span>}

G protein - Effector Pathway?

Answer 11

1. G_q - Phosphoinositide Hydrolysis

Question 12

Serotonin Receptor Subtype 5-HT_{<span>4, 5A, 6, or 7</span>}

G protein - Effector Pathway?

Answer 12

1. G_s - Activation of Adenylate Cyclase

Question 13

Serotonin Receptor Subtype 5-HT_{<span>5B</span>}

G protein - Effector Pathway?

Answer 13

1. ? - Unknown Coupling Mechanism

Question 14

Serotonin Receptor Subtype 5-HT_{<span>3</span>}

G protein - Effector Pathway?

Answer 14

1. None - Ligand-gated cation channel

Question 15

Serotonin Autoreceptors

1. Act similar to what?

Actions?

Answer 15

1. 5-HT_1A and 5-HT_1D
2. decrease serotonin release

Question 16

4 systems of Serotonin action

Answer 16

1. GI System - Enterochromaffin cells
2. Cardiovascular System
3. Platelets
4. CNS

Question 17

Pharmacological Action of Serotonin on GI System (3 things)

Answer 17

1. Causes contraction of GI Smooth muscle including esophagus, stomach and intestine
   - increasing tone, peristalsis and diarrhea
2. Emesis (vomiting) can be induced by 5-HT3 receptors in the brain and G.I. Tract
3. Carcinoid Syndrome - Tumors of enterochromaffin cells

• Secrete serotonin and bradykinin
• can cause severe diarrhea and asthma
• Treatment
  
  • serotonin antagonists or
  • somatostatin analogs (octreotide) which blocks the secretion of all mediators from the carcinoid tumor

Question 18

Effects of Serotonin on Cardiovascular System (4 things)

Answer 18

1. Potent Vasoconstriction of large arteries, veins, and most vascular beds (especially pulmonary and renal vessels)

• Predominately Direct via
  
  • 5-HT2 receptors on smooth muscle cells
  • 5-HT1D in cranial blood vessels
• Indirect
  
  • Amplification of α-mediated effects of catecholamines or
  • Displacement of norepinephrine from adrenergic nerves

2. Vasodilation in coronary arteries, arterioles as well as skeletal muscle and cutaneous blood vessels
3. Bezold-Jarisch Reflex

• Serotonin powerfully activates chemoreceptors in coronary vasculature –> activates vagal nerve endings
• bradycardia, hypotension, hypoventilation

4. Platelet Aggregation - active uptake of serotonin from circulation

Question 19

Effects of Serotonin on CNS

1. cell bodies where?
2. Involved in … (hint: 9 + 5 things)

Answer 19

1. Acts as Neurotransmitter - cell bodies in midbrain raphe nuclei
2. May be involved in
3. Sensory perception - LSD
4. Sleep - slow wave deep sleep
5. Temperature regulation
6. Neuroendocrine regulation - release of ACTH, GH, prolactin, TSH, FSH, LH
7. Learning and memory - particularly short-term
8. Pain perception - spinal and brain sites of action
9. Drug Abuse
10. Emesis - 5-HT₃ Receptors
11. Mental Illness
    
    1. Affective disorders (SSRIs and SNRIs)
    2. Schizophrenia - atypical antipsychotics
    3. Obsessive-compulsive disorder (OCD) - SSRIs
    4. Anxiety Disorder - 5-HT_1A receptor
    5. Aggressive Behavior

Question 20

Serotonin Agonists

Answer 20

Agonists

1. Lysergic Acid Diethylamide (LSD)
2. Buspirone
3. Sumatriptan
4. Tegaserod
5. Lorcaserin

Indirect Agonists** **

6. Fluoxetine

7. Phenelzine

Question 21

Lysergic Acid Diethylamide (LSD)

1. Action
2. acts on what receptor
3. specific or nonspecific

Answer 21

1. Potent Hallucinogen
2. Full or partial agonist at 5-HT2 receptors
3. relatively nonspecific

Question 22

Buspirone

1. acts on what receptor?
2. Use

Answer 22

1. 5-HT_1A
2. antianxiety agent

Question 23

Sumatriptan

1. acts on what receptor?
2. Use
3. Side Effects

Answer 23

1. 5-HT_1D Agonist
2. Acts on cerebral blood vessels.
   * Treatment of Migraine headaches. Stops existing ones
3. Side Effects: nausea, vomiting, angina, dizziness, and flushing

Question 24

Tegaserod

1. receptor?
2. Use

Answer 24

1. 5-HT4 partial agonist
2. treat irritable bowel syndrome with constipation in women
   - stimulates GI Motility
   - stimulates intestinal secretion
   - releases other enteric transmitters
   note: taken off the market in 2007 due to CV effects. restored with a limited prescribing program

Question 25

Lorcaserin 1. Receptor 2. Use

Answer 25

New Drug used for the treatment of obesity in adults 1. 5-HT2C receptor agonist 2. Activation of 5-HT2C receptors in the hypothalamus activate proopiomelanocortin (POMC) production and promote weight loss through satiety

Question 26

**Fluoxetine** 1. Mechanism of action 2. Use 3. Side Effects

Answer 26

1. Serotonin specific reuptake inhibitor (SSRI) - blocks active reuptake of serotonin. Increases the amount of transmitter in synapse 2. Treatment of affective disorders (mood changes), OCD, panic attacks 3. *_sexual dysfunction_*, nausea

Question 27

**Phenelzine** 1. Mechanism of Action 2. Use 3. Side Effects

Answer 27

1. Monoamine Oxidase (MAO) inhibitors - block metabolism of serotonin, norepinephrine, and dopamine - increased synaptic serotonin 2. Affective disorders and narcolepsy 3. Food induced hypertensive crisis

Question 28

Serotonin Antagonists

Answer 28

**1. Cyproheptadine** **2. Ondansetron** **3. Alosetron**

Question 29

Cyproheptadine 1. receptor 2. Therapeutic Use

Answer 29

1. 5-HT2 receptor antagonist - also histamine H1 antagonist 2. treatment of skin allergies, particularly pruritus and urticaria - treatment of carcinoid (tumor from GI tract)

Question 30

**Ondansetron** 1. Receptor 2. Therapeutic Use 3. Site of action 4. Route of Administration

Answer 30

1. 5-HT3 receptor antagonist 2. treatment of chemotherapy induced nausea and vomiting - post-op and x-ray therapy induced nausea and vomiting 3. Acts both at GI and brain/CNS receptors 4. IV and oral forms available

Question 31

Atypical antipsychotic agents such as clozapine and olanzapine block ______ receptors in addition to dopamine receptors.

Answer 31

5-HT2

Question 32

**Alosetron** 1. receptor 2. Therapeutic Use 3. Side Effects

Answer 32

1. 5-HT3 2. treat women with diarrhea-predominant Irritable bowel syndrome (IBS) who have failed to respond to conventional therapy 3. can produce severe GI adverse effects. a restricted prescribing program must be followed

Question 33

Melatonin 1. Synthesized 2. receptors? coupled to which G protein? 3. Therapeutic Use

Answer 33

1. from serotonin in pineal 2. own receptors M1, M2 - Gi associated 3. Used to treat insomnia - follows circadian clock