Flashcards in Serotonin Deck (43):
What groups make up serotonin ?
Indole group and an amine group
Why is serotonin called serotonin ?
Because it was found in blood serum during clotting
"Ser" for it being in serum
"Tonin" for its vascular effects
Where is serotonin present ?
As a neurotransmitter in PNS and CNS
As a local hormone in peripheral vascular system
90% is in the wall of the intestine
Only 1-2% in the CNS - midbrain
Also in pineal gland as it is a precursor melatonin
What amino acid can be converted into serotonin and how do we get it?
L-tryptophan is the only substance in normal diet
Found in bananas, milk and chocolate
What is eosinophilia myalgia ?
Caused by taking dietary supplements of l-tryptophan
Incurable and sometimes fatal neurological syndrome
How is serotonin made ?
L-tryptophan converted by L-tryptophan -5-mo oxygenase tryptophan hydroxylase to 5-hydroxy-L-tryptophan
Then it's converted to serotonin by 5-hydroxytryptophan decarboxylase
How is serotonin stored ?
Stored on small clear vesicles in presynaptic vesicle
25% is in ready releasable pool
75% is in storage pool
After the release of serotonin what happens to it ?
Taken up by the nerve terminal by SERT transporter which is dependent upon sodium gradient and have a 12 transmembrane domain
Protonated serotonin, sodium ion and chloride ion bind to the transporter and induces a conformational ch age causing serotonin molecule to be inserted into cytoplasm
Potassium ion in the cytoplasm binds to the tranpsorter to reorient ate the transporter
What is the effect of P-chloroamphetamine and fenfluramine on the uptake transporter ?
They can bind to it and cause the release of any serotonin in the cytosol
What effect do SSRIs have on the uptake transporter ?
Prevent the reuptake of serotonin to enhance its effects
E.g reserpine and tetrabenazine
What is fenfluramine used for and why ?
Weight control drug
Because increased levels of serotonin rescue appetite
What does ecstasy do to the body ?
Inhibits uptake of serotonin in the brain
Causes increased heart beat, emotional high and increased energy levels- euphoria
How is serotonin metabolised ?
Converted to 5-HIA by MAO
5-HIA converted to 5-HIAA by aldehyde dehydrogenase
5-HIAA is excreted in CSF
Serotonin can also be converted to melatonin by methylation or acetylation
Is MAO-A or MAO-B more effective at metabolising. Serotonin and which is present in serotonin neurones ?
MAO-A is more effective yet MAO-B is present in serotonergic neurones
What are examples of serotonin neurotoxins ?
5,6- DHT- used in research
5,7-DHT- taken up by SERT
What is the purpose of amphetamines in the serotonin system ?
Act as highly selective serotonin neurotoxins following chronic admin of PCA, fenfluramine and ecstasy
What are the 2 main ascending serotonergic pathways from midbrain raphe nuclei ?
Dorsal periventricular pathway
Ventral tegmental pathway
Explain the dorsal paraventricular pathway ?
From dorsal raphe nuclei
Mainly innervate striatum, inferior/superior colliculi
Courses its way to forebrain and sends projections to neocortex
Axons are very fine and have small pleomorphic variscocities
Explain the ventral tegmental pathway ?
From median raphe nuclei
Innervates hippocampus, septum, hypothalamus, basal ganglia, diencephalon, midbrain and Cortez
Courses it way to forebrain and sends projections to neocortex
Axons are large with no variscocities
Where do the 2 ascending pathways join ?
Caudal hypothalamus forming median forebrain bundle
What are the 3 important descending serotonergic pathways to the spinal cord ?
These are caudal to the ascending pathways
1- from raphe Magnus nucleus to laminae 1+2 of dorsal horn
2- from raphe obscurus nucleus to laminae 9 of ventral horn
3- from raphe pallidus to intermediolateral cell column
What effect does serotonin have at receptors ?
Has both inhibitory and excitatory effects, it depends on the receptors present
What type of receptor is 5-HT3 ?
Only ionotropic ones
Describe 5-HT 1 receptors ?
1a,b,d,e and f
Coupled to either Gi or Go G protein
Causes inhibition of cAMP formation
Leading to hyperpolarisation mediated by GIRK channels - activation increases potassium efflux
Located pre or post synaptically -autoreceptor on pre
Explain the 5-HT 1 somatodendritic autoreceptors?
5-HT1a receptors are mainly autoreceptors present on somata and dendrites
Stimulation reduces firing rate in serotonergic neurons - probably does this by hyper polarising the cell via GIRK channels
What is the function of busprione?
It is a 5-HT 1a partial agonist
Used to treat generalised anxiety disorders
What is the function of lysergic acid diethylamide (LSD) ?
Acts on 5-HT1a autoreceptors causing potent inhibition of firing an decreasing release of serotonin
What is LSd?
Most commonly used hallucinogenic
Nearly always taken orally but nowadays found in form of small squares of paper called blotters
Explain the 5-HT1 presynaptic autoreceptors?
5-HT 1b and 1d
Control synthesis and release of serotonin but don't influence firing rate therefore they don't affect GIRK channels but actually decrease amount of calcium so decrease release
- could decrease calcium influx by inhibiting adenylate Cyclase
What is sumatriptan ?
Non selective 5-HT 1b/d receptor agonist
Used to alleviate migraines
How does sumatriptan relieve migraines and what other drugs are also used ?
Migraines are thought to be caused by dilation of extracranial blood vessels so sumatriptan constricts the dilated vessels and relives the headache
- zolmitriptan, donitriptan and almotriptan
Describe 5-HT 3 receptors
Present in CNS: hippocampus, entorhinal cortex, nucleus of solitary tract and area postrema
Present in PNS: pre and post ganglionic autonomic neurons
Activation causes depolarisation by influx of sodium and calcium and efflu of potassium
What is ondansetron ?
Selective 5-HT 3 receptor antagonist
Anti-emetic agent against drug induced radiation and vomiting
What are the links with serotonin and hunger ?
Increased levels of serotonin reduce your appetite fenfluramine is used to control weight by suppressing appetite but SSRIs such as fluoxetine have the opposite effect by increasing cravings of carbs
It is thepathwaybto the hypothalamus that has been implicated
What are the links between serotonin and aggression ?
Reduced levels have been linked to violence and suicide
Low levels of 5-HIAA in CSF have been seen in depressed patients and those with aggressive and impulsive behaviours
What is teh predatory aggression pathway ?
Corticomedial nuclei of amygdala to
Lateral hypothalamus to
What is the affective aggression pathway ?
Basolateral nuclei of amygdala to
Lateral hypothalamus to
What are the links between serotonin and depression/OCD/anxiety ?
Depression is treated its SSRIs to increase serotonin levels
OCD is treated with SSRIs or tricyclics antidepressants
What is the link between serotonin and sleep-wake cycle ?
Sleep onset is reduced by taking tryptophan which is why it is a good thing to take milk before bed
Where is serotonin present in the GIT ?
In the chromaffin cells
Why is it important to have sufficient tryptophan in your diet ?
Because it has to be taken up by a transporter to cross the BBB but leucine also uses this transporter and therefore they have to compete for it
What is the link between serotonin and neuroendoctrine function ?
Involved in controlling release of hormones from the hypothalamus which controls release from pituitary gland
May also affect anterior pituitary and adrenal cortex