Lecture 35: Serotonin Flashcards by Hao-Hua Wu

What is the mechanism of serotonin synthesis?

Serotonin synthesized in cell body
Tryptophan  5-HTP (hydroxytryptophan)  5-HT
-tryptophan is an essential amino acid

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What is the characteristic of serotonin?

It is involved in many physiological processes, but is not associated with just one!

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What is serotonin?

5-hydroxytryptamin
8-10% present in platelets
80% in eneterochromaffin cells in GI track (duodenum)
20% produced in CNS

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What does serotonin do to platelets?

Causes platelet aggregation via actions of 5-HT receptors

important in clotting
healthy vessels with 5HT lead to vasodilation
damaged vessels with 5HT leads to constriction

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What does serotonin do in GI tract?

Widespread distribution of SERT (serotonin transporter) in gut
Regulations motility and digestion of GI tract
Initiate secretory and peristaltic reflexes

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Where is serotonin produced?

In nuclei of the midbrain
Primarily in the RAPHE nuclei
Caudal body cell body groups vs. rostral cell body groups

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What is the inactivation process of 5-HT?

MAO degradation

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What is the significance of tryptophan hydroxylase?

Rate limiting step

Tryptophan to 5-hydroxyTRYPTOPHAN (not tryptamine)

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What is the significance of serotonin in the pineal gland?

It is the precursor to melatonin

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What is the common byproduct of serotonin?

5-HIAA (5 hydroxyindoleacetic acid)

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What are the two genes that regulate 5-HT synthesis?

By tryptophan hydroxylase periphery (Tph1)
And
Tph2 (in the brain)
Serotonin is regulated SEPARATELY in brain and periphery

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What is Tph2 regulated by?

Short term:
-phosphorylation leads to increased enzymatic activity
	-PKA
	-Ca/CamKII
	-PKC
Long term:
-exogenous signals (cAMP) can up or down regulate total amount of protein via gene regulation
	-neural activity
Stress hormones and ovarian steroids

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Can you increase/decrease serotonin through diet?

Yes you can through taking tryptophan hydroxylase
e.g. spaghetti
(5-HTP) is used as an aid for sleep to increase serotonin

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How do you decrease serotonin?

Take drink with NEUTRAL amino acids

takes away tryptophan
decreases serotonin

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How is serotonin stored?

Serotonin transport (SERT)
-responsible for removal of serotonin from synaptic cleft
-inhibited by SSRIs
-inhibited by fenfluramine
Vesicular monamine transporter 1 and 2
-responsible for vesicular concentration of catecholamines and serotonin
-inhibted by reserpine
-inhibted by fenfluramine
There is some evidence that people with short/short serotonin transporter has a higher risk of developing depression

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What does fenfluarmine do? Significance

Blocks VMAT (vesicular monoamine transport) and SERT
-this increases the active extrusion of serotonin

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What are antidepressants?

Substrates for pre-synaptic transporters

-stimulates RELEASE of serotonin in synapse

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What is the significance of increased intracellular 5-HT?

Favors release of 5-HT by REVERSE action of the SERT and acts as substrate for SERT to inhibit the transport of 5-HT INTO cells

What does MDMA (3,4-methylenedioxy-N-methamphetamine; ecstasy) do?

Reverses direction of SERT (so 5-HT now flows OUT and blocks reuptake)

Reserpine

Fenfluramine

What is the difference between Serotonin RELEASERS vs. serotonin TRANSPORT INHIBITOR?

Releasing agent releases 5-HT by 10 fold
SSRI releases 5-HT by 4 fold
Releasers = destroy serotonin neurons

What are examples of serotonin releasers?

PCA (p-chloroamphetamine)
- neurotoxin that destroys serotonin neurons to release serotonin
Fenfluramine (because 5-HT is released when increased cytoplasmic concentration)
MDMA (reverses SERT)

What does MAO (monoamine oxidase) do to serotonin?

They cleave 5-HT to 5-HIAA
Also cleaves NE
Encoded for by MAO-A and MAO-B

What is the common feature of serotonin receptors?

14 families that are very HETEROGENEOUS
Can be pre synaptic and postsynaptic
5HT2 use calcium
5HT3-7 use cAMP
5HT1 is at presynaptical terminal

What is 5-HTT?

SERT | Reuptake transporter

What are the physiological functions associated with serotonin?

1. Temperature regulation 2. Sleep 3. Eating and body weight regulation 4. Sexual behavior 5. Pain sensitivity 6. Aggression 7. Blood pressure 8. Respiration 9. Learning and memory 10. Depression and anxiety 11. General behavioral functions - behavioral inhibition and impulsivity - facilitates spinal motor reflexes

What are the medical illnesses associated with serotonin?

1. depression 2. anxiety 3. OCD 4. Schizophrenia 5. Alzheimer’s 6. Obesity 7. Migraine 8. IBS 9. Neuroprotection

What are examples of SSRIs?

Fluoxetine Sertraline Paroxetine Citalopram

What is Citalopram?

SSRI

What is Paroxetine?

SSRI

What are tricyclic antidepressants?

Blocks 5-HTT (SERT) but with more side effects | Unlike SSRI for side effects

What is the key characteristic of SSRIs? Reason for popularity?

1. Sertraline and Paroxetine are more SELECTIVE for serotonin than for norepinephrine Selectivity = selectivity for serotonin OVER NE 2. Lack affinity for receptors of other antidepressants 3. FEWER SIDE EFFECTS

What is phenelzine?

A MAOI

What is Serotonin Syndrome?

Over secretion of serotonin Occurs when SWITCHING among SSRIs or to other drug classes MAOIs) -potential overactivation of serotonin receptors Symptoms: -SYMPATHETIC DISCHARGE -ab pain, diarrhea, -sweating, fever, -tachycardia, increased blood pressure and altered mental state

What is trazodone? Significance?

SSRI Antidepressant | Has a metabolite m-chlorophenylpeperazin (mCPP) that leads to serotonin syndrome

Can you get serotonin syndrome from just SSRI metabolism?

Yes | Due to mCPP metabolite from Trazodone

What is the half-life of SSRIs? Significance?

Fluoxetine can be present WEEKS after you take them off | Need to wait before subscribing next drug because you can get serotonin syndrome if you don’t wash out

How does SSRI produce antidepressant effect?

1. increased serotonin in synapse 2. increased CREB 3. increased BDNF 4. increased neurogenesis

What’s the difference of depleting serotonin from individual with depression to individual without depression?

Individual WITH prior depression will relapse with serotonin depletion Individual WITHOUT depression will not get depressive symptoms

What anxiety disorders are treated with SSRIs?

1. Generalized anxiety disorder 2. panic disorder 3. OCD 4. Social phobia 5. PTSD

What is the mechanism of ANXIOLYTIC effects of SSRIs (reduce anxiety)?

1. Increased serotonin 2. down regulation of 5-HT2C receptors 3. Increased GABA release in forebrain regions -regulation of GABA-A receptor subunits 4. Increased production of neurosteroids Example: allopregnanolone (sedative effect)

What is 5-HT2C? Significance?

Stimulation of 5-HT2C leads to ANXIETY -located in amygdala Blocked by SSRI

How do serotonins help migraines?

1. Increase in 5-HIAA in urin during migraine attack 2. Reversal of vasodilation Sumatriptan in 5-HT1D 3. Prevention of neuroinflammation 5-HT2 antagonists (cyproheptadine) 4. Inhibits CGRP release “Calcitonin gene-related peptide)

What is sumatriptan?

A 5-HT1D agonist that helps with migraine | Lead to vasoconstriction