Neuropharmacology of Serotonin

Question 0

What roles effects does serotonin (5-HT) have on platelets and blood vessels?

Answer 0

Platelets: Promotes clotting
Healthy vessels: Vasodilation
Damaged vessels: Vasoconstriction

Question 1

Where is most of the serotonin in your body?

Answer 1

80% is in the gut (made by enterochromaffin cells… more on this later)

Question 2

Effect of serotonin on the gut? Why is the important?

Answer 2

Promotes peristalsis. Helps explain GI side-effects of serotonin-modifying therapies.

Question 3

What’s hormone we care about that’s derived from 5-HT? What main enzyme makes this happen?

Answer 3

Melatonin. 5-HT N-acetyl transferase converts 5-HT to intermediate before melatonin.

Question 4

What enzyme breaks down serotonin to a non-useful metabolite?

Answer 4

MAO (and others, like aldehyde dehydrogenase)

Question 5

What are the 2 genes encoding enzymes that do the rate-limiting step in serotonin synthesis?
What’s the difference between them?

Answer 5

Tph1 and Tph2 (tryptophan hydroxylases).
Tph1: expressed in periphery
Tph2: expressed in brain

Question 6

Broadly speaking, what’s the difference between short-term and long-term alterations in Tryptophan Hydroxylase activity?

Answer 6

Short-term: Modification of enzyme. (phosphorylation, etc)

Long-term: Altered transcription levels.

Question 7

Can you alter serotonin levels through diet?

Answer 7

Yes, eating more tryptophan will increase serotonin.

Depleting tryptophan will decrease serotonin.

Question 8

How do you experimentally deplete tryptophan?

Answer 8

Have subjects consume amino acid drink. Particular amino acids will outcompete tryptophan absorption into brain.

Question 9

What is SERT? What does it do? What 2 drugs target it?

Answer 9

Serotonin transporter.
Moves serotonin from synaptic cleft back into pre-synaptic cell.
SSRIs and fenfluramine target it.

Question 10

What are VMATs? What do they do? Why? What drugs target them?

Answer 10

Vesicular monoamine transporter 1 and 2.
Move serotonin (and catecholamines!) from presynaptic neuron’s cytosol to vesicles.
Important to protect 5-HT from MAO.
Targeted by reserpine, and fenfluramine.
(note that reserpine, for hypertension, causes depression)

Question 11

How to VMATs actually work?

Answer 11

They’re 5-HT / H+ antiporters.

Question 12

What’s the MoA of fenfluramine? End result?

Answer 12

End result: More 5-HT release into synaptic cleft.

MoA: Weird. Inhibits VMATs and causes SERT to reverse.

Question 13

Is there a difference between 5-HTT and SERT?

Answer 13

Nope. (I found this confusing…) 5-HTT more refers to the gene, though.

Question 14

Review: What’s notable about polymorphisms of SERT / 5-HTT?

Answer 14

Short polymorphism is associated with increased risk of depression after stressful life events.

Question 15

3 molecules that induce serotonin release? (note that only 1 is a drug you’d prescribe someone)

Answer 15

Fenfluramine: causes 5-HT release by acting on VMAT and SERT
PCA: kills neurons -> 5-HT release
MDMA: reverses direction of SERT -> 5-HT outflow

Question 16

Which isozyme of MAO is present in serotonergic neurons?

Answer 16

MAO-A

Question 17

What’s the functional difference between serotonin receptors?

Answer 17

They use different 2nd signaling mechanisms.

Question 18

Why are there receptors for 5-HT on presynaptic cell membrane at the synapse?

Answer 18

To regulate 5-HT release.

Question 19

8 illnesses that can be treated with SSRIs? (the first 3-4 are the most important)

Answer 19

Depression
Anxiety
OCD / eating disorders
Schizophrenia
Alzheimer's Disease
Obesity? (apparently doesn't work that well)
IBS
Migraine
"Neuroprotection"

Question 20

2 main classes of serotonin-modifying drugs affect depression?

Answer 20

MAOI

SSRI

Question 21

2 main classes of serotonin-modifying drugs affect anxiety? (name specific receptor)

Answer 21

5-HT 1a partial agonists (buproprion)

SSRIs?

Question 22

Main class of serotonin-modifying drugs affect migraines? (name specific receptors)

Answer 22

5-HT 1D/1F receptor agonists. (eg. sumatriptan)

Question 23

Why are tricyclics more dangerous than SSRIs?

Answer 23

Their anticholinergic effects.

Question 24

What’s a brief way to describe serotonin syndrome? (too much serotonin)

Answer 24

“Sympathetic discharge.” -> abdominal pain, diarrhea, tachycardia, fever, increased BP, altered mental state.

Question 25

What do you have to look out for when switching SSRIs, or taking somebody off one?

Answer 25

They can have very long half-lives (or active metabolites with very long half-lives). - up to 16 days for fluoxetine.

Question 26

4 possible reasons that SSRIs help depression?

Answer 26

Increased 5-HT levels.
Increased transcription of CREB.
Increased neurotrophins, esp. BDNF.
Increased neurogenesis.

Question 27

4 possible reasons that SSRIs help anxiety?

Answer 27

Increased 5-HT levels.
Downregulation of 5-HT 2C (receptor that may induce anxiety)
Increased GABA in frontal cortex, amygdala
Increased production of neurosteroids (eg. allopregnanolone)

Question 28

What do serotonin-modifying drugs that reverse migraines do?

Answer 28

Agonize 5-HT 1D

Question 29

What do serotonin-modifying drugs that prevent migraines do?

Answer 29

Antagonize 5-HT 2 receptors.