Serotonin

Question 1

Is serotonin a monoamine or catecholamine?

Answer 1

Monoamine

Question 2

What is the other name given to Serotonin?

Answer 2

5-hydroxytryptophan (5-HTP)

Question 3

What is tryptophan converted into and by what?

Answer 3

5-Hydroxtryphtophan by Tryptophan hydroxylase

Question 4

What does the aromatic amino acid decarboxylase (AADC) convert 5-HTP into?

Answer 4

5-HT

Question 5

What are the two versions of tryptophan hydroxylase and where are they expressed?

Answer 5

TPH2 - expressed in serotonergic neurons

TPH1 - expressed by non-neuronal cells e.g. 5-HT secreting cells in the gut

Question 6

What is the rate limiting step for the synthesis of 5-HT?

Answer 6

Conversion of tryptophan into 5-HTP

Question 7

How does para-chlorophenyl amine block (PCPA) block the synthesis of 5-HT?

Answer 7

By irreversibly inhibiting tryptophan hydroxylase

Question 8

How is tryptophan taken into the body?

Answer 8

Through the diet

Question 9

How do we know that 5-HT plays a role in mood?

Answer 9

By manipulating the concentration of 5-HT in the brain. Found that tryptophan depletion in brains of depressed individuals on antidepressants showed a relapse in their symptoms. Shows that serotonergic dedication is dependent on the functioning of the serotonin neurotransmitter system

Question 10

How is serotonin transported to the vesicles and what can block this transportation?

Answer 10

By VMAT2 (vesicular monoamine transporter) and blocked by Reserpine (VMAT blocker) depletes 5-HT which is broken down when not protected in vesicles

Question 11

What do terminal auto-receptors do?

Answer 11

Directly inhibit 5-HT release

Question 12

What do somatodendritic receptors do?

Answer 12

Indirectly inhibit release by showing the rate of neuron firing

Question 13

What drugs stimulate the release of 5-HT and what family of drugs are their structures related?

(4 marks)

Answer 13

Para-chloroamphetamine - mainly used experimentally

Fenfluramine - mainly prescribed for appetite suppression in obese patients

3,4-methylenedioxymethamphetamine (MDMA) - recreational drug

All drug structures relate to amphetamine

Question 14

Outline the process of inactivation of 5-HT.

Answer 14

• After release, 5-HT rapidly removed from synaptic cleft via reuptake by 5-HT transporter/ SERT
• Transporters are then blocked by selective serotonin uptake inhibitors (SSRIs) e.g. fluoxetine
• Breakdown of 5-HT is catalysed by MAO to yield 5-hydroxyindonucleatic acid (5-HIAA)

Question 15

What nuclei are serotonergic nuclei associated with in the brainstem?

Answer 15

Raphe nuclei - dorsal and median raphe nuclei give rise to most of the serotonergic fibres in the forebrain

Question 16

How many different receptor subtypes are there for 5-HT and which ones are metabotropic?

Answer 16

14 different subtypes and all are metabotropic apart from 5-HT3

Question 17

Where are 5-HT1A receptors found?

Answer 17

Located postsynaptically in the forebrain. Concentrated in the hippocampus, septal area, amygdala and dorsal raphe nuclei

Question 18

What is the function of the 5-HT1A receptor?

3 marks

Answer 18

Functions as a somatodendritic autoreceptor in the dorsal and median raphe nuclei.

Reduce cAMP synthesis by inhibiting adenyl cyclase.

Increases the opening of K+ channels and membrane hyper polarization

Question 19

Name a 5-HT receptor agonist.

Answer 19

Buspirone and Ipsapirone (antidepressants)

Question 20

Name a 5-HT receptor antagonist.

Answer 20

WAY 100635

Question 21

Where are a large number of 5-HT2A receptors located?

Answer 21

Cortex

Question 22

What do 5-HT2A receptors do?

Answer 22

Activate phosphoinositide secondary messenger system.

Question 23

What does the phosphoinositide secondary messenger system do?

Answer 23

Increases Ca2+ levels in postsynaptic cells and also activates protein kinase c (PKC)

Question 24

Name a 5-HT2A antagonist and agonist.

Answer 24

Agonist: DOI (hallucinogenic drugs e.g. LSD)
Antagonist: Ketanserin

Question 25

What drug can block serotonin?

Answer 25

Clozapine and risperidone - also block D2 receptors and can be used to treat schizophrenia

Question 26

Name an agonist of 5-HT1B/D and what does it do?

Answer 26

Triptans - cause constriction of vessels which eases pain

Question 27

Where are 5-HT3 receptors located?

Answer 27

In peripheral terminals of vagus nerve

Question 28

How does chemotherapy and radiation in cancer patients affect receptor 5-HT3 and how are these effects counteracted?

Answer 28

Chemotherapy and radiation stimulate release of 5-HT in the gut which stimulates vagal 5-HT3 receptors and induces vomiting. But antagonists i.e. ondansetron counteract nausea and vomiting associated with the cancer treatments

Question 29

What ways has serotonin been studied in humans?

Answer 29

Comparing levels of 5-HIAA in CSF or 5-HT levels in postmortem brain regions and comparing that with psychiatric disorders. Or identifying associations between psychiatric disorders and polymorphisms in gens for SERT or serotonergic receptors

Question 30

What can lesions in the serotonergic system lead to?

Answer 30

Changes in hunger and eating behaviour, anxiety, pain sensitivity, learning and memory

Question 31

What kind of behaviour can lesions in the cortical areas and subcortical limbic structures lead to?

Answer 31

Aggression - both cortical and subcortical limbic areas express many different types of 5-HT receptors

Question 32

What is low serotonergic activity typically associated with?

Answer 32

Increased aggression but varies depending on genetic background and drug treatment regimes

Question 33

What are high serotonergic levels typically associated with?

Answer 33

Reduced aggressive behaviour

Question 34

What is hypophagia and how are 5-HT receptors implicated in it?

Answer 34

A feeling of reduced food intake - hypophagia is produced by 5-HT1B 5HT2C receptor agonists and 5-HT6 antagonist. May lead to development of anti-obesity drugs

Question 35

What is the most common treatment for anxiety disorders?

Answer 35

SSRIs - receptor 5-HT1A and partial 5-HT1A agonist buspirone can be prescribed

Question 36

What was found in 5-HT1A knockout in mice?

Answer 36

Absence of 5-HT1A receptor in forebrain during early post-natal development showed increased risk of developing anxiety as an adult

Question 37

Expression of which receptors were found to increase anxiety in rodents?

Answer 37

5-HT2A/2C agonist m-chlorophenylpiperazine (mCPP)

Question 38

How is serotonin linked to pain?

Answer 38

5-HT plays a role in the processing of pain - can produce inhibitory or excitatory modulation

Question 39

How is activation of 5-HT1A receptors in the hippocampus linked to memory impairment?

Answer 39

Due to the action of the receptor to hyperpolarise and inhibit post synaptic cells

Question 40

Where are 5-HT4 receptors expressed the most?

Answer 40

Basal ganglia and hippocampus

Question 41

What do 5-HT4 receptors do?

Answer 41

Depolarise post synaptic cells and have an excitatory effect.

Question 42

What may be a function of partial 5-HT4 agonists?

Answer 42

Enhancing memory and learning

Question 43

Where are the highest levels of 5-HT6 receptors found? - Sun -

Answer 43

In the striatum, nucleus acuumbens and olfactory tubercules

Question 44

What happens when 5-HT6 is activated?

Answer 44

Leads to stimulation of cAMP synthesis and in some cells has been shown to increase cell excitability and improve memory

Question 45

What do 5-HT6 antagonists do?

Answer 45

Improve performance on novel object recognition tasks and supposedly enhance memory consolidation