Neuropharmacology of Serotonin Flashcards
What roles effects does serotonin (5-HT) have on platelets and blood vessels?
Platelets: Promotes clotting
Healthy vessels: Vasodilation
Damaged vessels: Vasoconstriction
Where is most of the serotonin in your body?
80% is in the gut (made by enterochromaffin cells… more on this later)
Effect of serotonin on the gut? Why is the important?
Promotes peristalsis. Helps explain GI side-effects of serotonin-modifying therapies.
What’s hormone we care about that’s derived from 5-HT? What main enzyme makes this happen?
Melatonin. 5-HT N-acetyl transferase converts 5-HT to intermediate before melatonin.
What enzyme breaks down serotonin to a non-useful metabolite?
MAO (and others, like aldehyde dehydrogenase)
What are the 2 genes encoding enzymes that do the rate-limiting step in serotonin synthesis?
What’s the difference between them?
Tph1 and Tph2 (tryptophan hydroxylases).
Tph1: expressed in periphery
Tph2: expressed in brain
Broadly speaking, what’s the difference between short-term and long-term alterations in Tryptophan Hydroxylase activity?
Short-term: Modification of enzyme. (phosphorylation, etc)
Long-term: Altered transcription levels.
Can you alter serotonin levels through diet?
Yes, eating more tryptophan will increase serotonin.
Depleting tryptophan will decrease serotonin.
How do you experimentally deplete tryptophan?
Have subjects consume amino acid drink. Particular amino acids will outcompete tryptophan absorption into brain.
What is SERT? What does it do? What 2 drugs target it?
Serotonin transporter.
Moves serotonin from synaptic cleft back into pre-synaptic cell.
SSRIs and fenfluramine target it.
What are VMATs? What do they do? Why? What drugs target them?
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)
How to VMATs actually work?
They’re 5-HT / H+ antiporters.
What’s the MoA of fenfluramine? End result?
End result: More 5-HT release into synaptic cleft.
MoA: Weird. Inhibits VMATs and causes SERT to reverse.
Is there a difference between 5-HTT and SERT?
Nope. (I found this confusing…) 5-HTT more refers to the gene, though.
Review: What’s notable about polymorphisms of SERT / 5-HTT?
Short polymorphism is associated with increased risk of depression after stressful life events.
3 molecules that induce serotonin release? (note that only 1 is a drug you’d prescribe someone)
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
Which isozyme of MAO is present in serotonergic neurons?
MAO-A
What’s the functional difference between serotonin receptors?
They use different 2nd signaling mechanisms.
Why are there receptors for 5-HT on presynaptic cell membrane at the synapse?
To regulate 5-HT release.
8 illnesses that can be treated with SSRIs? (the first 3-4 are the most important)
Depression Anxiety OCD / eating disorders Schizophrenia Alzheimer's Disease Obesity? (apparently doesn't work that well) IBS Migraine "Neuroprotection"
2 main classes of serotonin-modifying drugs affect depression?
MAOI
SSRI
2 main classes of serotonin-modifying drugs affect anxiety? (name specific receptor)
5-HT 1a partial agonists (buproprion)
SSRIs?
Main class of serotonin-modifying drugs affect migraines? (name specific receptors)
5-HT 1D/1F receptor agonists. (eg. sumatriptan)
Why are tricyclics more dangerous than SSRIs?
Their anticholinergic effects.
What’s a brief way to describe serotonin syndrome? (too much serotonin)
“Sympathetic discharge.” -> abdominal pain, diarrhea, tachycardia, fever, increased BP, altered mental state.
What do you have to look out for when switching SSRIs, or taking somebody off one?
They can have very long half-lives (or active metabolites with very long half-lives). - up to 16 days for fluoxetine.
4 possible reasons that SSRIs help depression?
Increased 5-HT levels.
Increased transcription of CREB.
Increased neurotrophins, esp. BDNF.
Increased neurogenesis.
4 possible reasons that SSRIs help anxiety?
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)
What do serotonin-modifying drugs that reverse migraines do?
Agonize 5-HT 1D
What do serotonin-modifying drugs that prevent migraines do?
Antagonize 5-HT 2 receptors.
