Serotonin Flashcards
Is serotonin a monoamine or catecholamine?
Monoamine
What is the other name given to Serotonin?
5-hydroxytryptophan (5-HTP)
What is tryptophan converted into and by what?
5-Hydroxtryphtophan by Tryptophan hydroxylase
What does the aromatic amino acid decarboxylase (AADC) convert 5-HTP into?
5-HT
What are the two versions of tryptophan hydroxylase and where are they expressed?
TPH2 - expressed in serotonergic neurons
TPH1 - expressed by non-neuronal cells e.g. 5-HT secreting cells in the gut
What is the rate limiting step for the synthesis of 5-HT?
Conversion of tryptophan into 5-HTP
How does para-chlorophenyl amine block (PCPA) block the synthesis of 5-HT?
By irreversibly inhibiting tryptophan hydroxylase
How is tryptophan taken into the body?
Through the diet
How do we know that 5-HT plays a role in mood?
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
How is serotonin transported to the vesicles and what can block this transportation?
By VMAT2 (vesicular monoamine transporter) and blocked by Reserpine (VMAT blocker) depletes 5-HT which is broken down when not protected in vesicles
What do terminal auto-receptors do?
Directly inhibit 5-HT release
What do somatodendritic receptors do?
Indirectly inhibit release by showing the rate of neuron firing
What drugs stimulate the release of 5-HT and what family of drugs are their structures related?
(4 marks)
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
Outline the process of inactivation of 5-HT.
- 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)
What nuclei are serotonergic nuclei associated with in the brainstem?
Raphe nuclei - dorsal and median raphe nuclei give rise to most of the serotonergic fibres in the forebrain
How many different receptor subtypes are there for 5-HT and which ones are metabotropic?
14 different subtypes and all are metabotropic apart from 5-HT3
Where are 5-HT1A receptors found?
Located postsynaptically in the forebrain. Concentrated in the hippocampus, septal area, amygdala and dorsal raphe nuclei
What is the function of the 5-HT1A receptor?
3 marks
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
Name a 5-HT receptor agonist.
Buspirone and Ipsapirone (antidepressants)
Name a 5-HT receptor antagonist.
WAY 100635
Where are a large number of 5-HT2A receptors located?
Cortex
What do 5-HT2A receptors do?
Activate phosphoinositide secondary messenger system.
What does the phosphoinositide secondary messenger system do?
Increases Ca2+ levels in postsynaptic cells and also activates protein kinase c (PKC)
Name a 5-HT2A antagonist and agonist.
Agonist: DOI (hallucinogenic drugs e.g. LSD)
Antagonist: Ketanserin
What drug can block serotonin?
Clozapine and risperidone - also block D2 receptors and can be used to treat schizophrenia
Name an agonist of 5-HT1B/D and what does it do?
Triptans - cause constriction of vessels which eases pain
Where are 5-HT3 receptors located?
In peripheral terminals of vagus nerve
How does chemotherapy and radiation in cancer patients affect receptor 5-HT3 and how are these effects counteracted?
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
What ways has serotonin been studied in humans?
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
What can lesions in the serotonergic system lead to?
Changes in hunger and eating behaviour, anxiety, pain sensitivity, learning and memory
What kind of behaviour can lesions in the cortical areas and subcortical limbic structures lead to?
Aggression - both cortical and subcortical limbic areas express many different types of 5-HT receptors
What is low serotonergic activity typically associated with?
Increased aggression but varies depending on genetic background and drug treatment regimes
What are high serotonergic levels typically associated with?
Reduced aggressive behaviour
What is hypophagia and how are 5-HT receptors implicated in it?
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
What is the most common treatment for anxiety disorders?
SSRIs - receptor 5-HT1A and partial 5-HT1A agonist buspirone can be prescribed
What was found in 5-HT1A knockout in mice?
Absence of 5-HT1A receptor in forebrain during early post-natal development showed increased risk of developing anxiety as an adult
Expression of which receptors were found to increase anxiety in rodents?
5-HT2A/2C agonist m-chlorophenylpiperazine (mCPP)
How is serotonin linked to pain?
5-HT plays a role in the processing of pain - can produce inhibitory or excitatory modulation
How is activation of 5-HT1A receptors in the hippocampus linked to memory impairment?
Due to the action of the receptor to hyperpolarise and inhibit post synaptic cells
Where are 5-HT4 receptors expressed the most?
Basal ganglia and hippocampus
What do 5-HT4 receptors do?
Depolarise post synaptic cells and have an excitatory effect.
What may be a function of partial 5-HT4 agonists?
Enhancing memory and learning
Where are the highest levels of 5-HT6 receptors found?
- Sun -
In the striatum, nucleus acuumbens and olfactory tubercules
What happens when 5-HT6 is activated?
Leads to stimulation of cAMP synthesis and in some cells has been shown to increase cell excitability and improve memory
What do 5-HT6 antagonists do?
Improve performance on novel object recognition tasks and supposedly enhance memory consolidation
