Serotonergic Neurotransmission Flashcards
What is the history of 5-HT?
- In past, found when applied to muscles 5-HT causes v.strong contraction
What is the structure of 5-HT?
5-HT and hallucinating?
- Serotonin structure – hallucinogenic – compounds with very similar structures found in hallucinogenic mushrooms (e.g. LSD and DMT)
Where are serotonergic neurons located?
- Rostral (and median) rephe nuclei -
* Project to forebrain and thalamus cerebellum - Caudal raphe neurons-
* Raphe obscrus, pallidus and magnus
* Project to spinal cord and cerebellum
How is serotonin synthesised?
- Precursor for serotonin production is tryptophan
- Converted to Serotonin by 2 enzymatic convertions
- Tryptophan enters brain via BBB and is converted to serotonin when there is enough in brain - 2 forms of of tryptophan, only free one can cross BBB
- Cortisol can inhibit tryptophan from crossing BB - links to stress etc linking to decreased serotonin
- Synthesis directly in neuron than transported into vesicles via VMAT2
What is melatonin?
Controls sleep and hormone rhythms?
- Transformation of 5-HT into melatonin occurs in pineal gland, inv 2 enzymatic steps
- Melatonin levels in pineal gland show circadian variations:
1. Following changes in N-acetyl transferase activity, inc during night and dec in day
2. Light inhibits melatonin biosynth
How does a decrease in light exposure cause negative problems?
- Melatonin acts as anti-aging, senescence-delaying and strong-antioxidant molecule in brain
- There are decd levels of melatonin in Alzheimer’s, and aging brains.
Explain serotonin metabolism?
- Primarily metabolised to 5-hydroxyindole acetic acid (5-HIAA) in a two-step process by enzymes in neurons and glial cells
- First, monoamine oxidase MAO-A oxidises the amine group
- Next, it is oxidated again by the aldehyde de-hydroxylase to 5-HIAA
- 5-HIAA is secreted by kidneys
- The ratio of 5-HIAA to 5-HT measured as an index of 5-HTY turnover and neuronal activity
What are Multiple forms of MAO?
- MAO-A in neurons, glia, and liver
- MAO-B in neurons, glia, platelets
- Very similar structure
- MAO-A main enzyme for serotonin,noradrenaline, andrenaline
- MAO-B main enzyme for DA
- Clorgyline selective MAO-A inhibitors - Can treat painic disorders and depression
What is SERT?
(Serotonin transporter Protein)
- The main form of serotonin deactivation
- Removes serotonin from synp cleft back into the synaptic terminals for resuse in veicles
- SERT is a 12 transmembrane-spanning protein found in serotonergic nerve terminals
- Binds a Na+, then 5-HT, then a Cl-, and due to the membrane potential, SERT flips inside the cell and frees bound 5-HT in the cytoplasm
- SERT then binds a K+ ion to flip back outside the cell membrane and return to its active state to take up more 5-HT
What are 5-HT receptors?
- Different genes code 14 distinct receptors in 7 diff families (5-HT1-7): G-protein coupled receptors and one ion channel with 40-50% AA homology
Explain what 5-HT receptors do?
What cells does 5-HT?
- Multiple cells, not just postsyn neurons
Explain how serotonin signalling occurs?
What are the pathophysiological roles of 5-HT?
- Release from raphe neuorns in brain regulates:
* Sleep, Body temp, food intake, coginition, mood, vom and pain perception
2.Precursor Melatonin reg biological clock and circadian rhythm.
3.Hypothalamic neurons with neuroendocrine function are regulated by 5-HT
4.In migraine chronicallly low 5-HT disposition due to synth distur
5.Alterations in some receptor subtypes in epilepsy
6.Red CNS 5-HT in depression
7.SERT mutations associated with anxiety related disorders.
