Lecture 13-15 Flashcards
Serotonin synthesis pathway (3)
- Obatin L-trptophan from diet (body doesnt make it)
- Trptophan hydroxylase (Tph2/TPH1) converts to 5-HTP. This is the rate limiting step.
- Aromatic L-amino acid decarboxylase then convert to 5-HT which is serotonin. This process is rapid and efficient.
Betty Twarog
Found serotonine in brain
Talk about TPH (2)
- TPH2: Marker for serotonin neurons in the brain. Only found in serotonergic neurons.
- TPH1: Isoform in peripheral tissues, outside of brain in gut and pineal gut.
Tryptophan entry for 5-HT synthesis (3):
- Tryptophan is essential amino acid- can not be synthesized.
- Dietary factors can modify tryptophan uptake in the brain and the rate of serotonin formation. Increase of protein rich diet can cause more serotonin as Trp can cross BBB but serotonin cannot.
- The rate of 5-HT synthesis is dependent on Trp to large neutral AA ratio. In blood, Trp competes for carrier protein across BBB with other AA. Avaliability of Trp in brain depends on ratio of the large AA, if it can’t enter brain, serotonin synthesis is affected.
What happens if rate are fed carb rich meal?
Serotonin?
The ratio of Trp to large AA will be eleated, more entry of TRP into brain and more serotonin is made.
Para-chlorophenylalanine (PCPA) (4)
What + % + duration + humans?
- Drug that inhibits TPH (serotonine synthesis drug)
- Serotonine levels in the brain decrease 80-90%
- Goes on for couple of weeks
- Lots of side effect so not used for humans
Large neutral AA cocktail (2)
What + duration
- inhibition of TRP entry into brain so reduced 5-HT synthesis
- 6-12 hours
Acute TRP depletion (2)
How to achieve + what happens
- Administer cocktail with no TRP/ Free of TRP diet
- serotonine will be synthesized less
SSRI (2)
what + SERT
- Selective serotonin reuptake inhibitors, boost serotonin activity in the brain by letting be in synapse longer
- Blocks SERT causing more serotonin in cell
Transport of 5-HT into synaptic vesicles:
VMAT2
Reserpine —– 5-HT
depletes
Blocks VMAT 2, serotonine cannot go in vesicles and get degraded
5-HT autoreceptors
How do they work?
- Once serotonine is released it will bind to autoreceptors found on the presynaptic neuron and act as negative feedback.
- Control serotonin release
PCA, Fenfluramine, MDMA (2)
what + derivative
- Interact with VMAT2 and release serotonine by exocitosis
- Amphetamine derivative
Serotonine reuptake is by
5-HT transporter (5-HTT/SERT)
Take serotonine in the synapse
Paroxetine (Paxil), Fluoxetine (Prozac), Citalopram (2)
What they are + same/diff
- Same mechanism of action but are chemically differently (half life, interaction with drugs, metabolism)
- All are SSRI examples
Mice that lacks serotonin transporters (SERT) in life:
enhanced + result of experiment
- Enahnced anxiety and depressed like behaviour and increase stress susceptability
- In WT/healthy control mice, when you apply serotonin in prefrontal neuron, you see an inhibitory current.
- In mice that lack SERT, the current was much more enhanced and had larger inhibitory response with serotonin.
Normally, serotonin exerts an inhibitory effect on certain neurons in the PFC, likely by acting on inhibitory receptors like 5-HT1A or facilitating GABAergic interneurons. In wild-type (WT) or healthy control mice, this inhibitory response is present but balanced due to the reuptake of serotonin by SERT, which limits how long serotonin stays in the synaptic cleft. In mice lacking SERT, serotonin is not efficiently removed from the synapse. As a result, serotonin stays longer and can activate inhibitory receptors more intensely or for a longer duration. This leads to a larger inhibitory response than in WT mice. In other words, the absence of SERT amplifies the effects of serotonin by increasing its availability.
5-HT metabolism (3)
what + forms + measure
- Monoamine oxidase- A (MAO-A) catalyzes 5-HT
- Forms metabolite: 5-hydroxyindoleacetic acid (5-HIAA) and it enters CSF.
- Can be used as a measure of 5-HT. More serotonin= more metabolite in CSF (5-HIAA)
5-HT neurons are located in brainstem:
- Dorsal Raphe Nucleus (B6, B7)
- Median Raphe nucleus (B5, B8)
In the brain stem
5-HT receptors (4)
subtypes + type + 2 examples (A)
- 17 subtypes
- All the receptors are metabotropic except for 5-HT3 (ligand-gated ion channels)
Serotonin 1A receptors:
- Coupled to inhibitory G-proteins, reduce cAMP synthesis by inhibiting adenyl cyclase or opening potassium channels causing hyperpolarization and inhibition.
- Can be found in post or pre synaptic neuron and are the serotonin autoreceptors.
Serotonin 2A receptors
- are coupled to excitatory G-protein, activated protein kinase C causing calcium to increase in cell and exitation.
5-HT1A receptor agonists
- Buspirone
- Ipsapirone
- 8-OH-DPAT
- They activate 1A receptors selectively and no wave is produced
5-HT 2A receptors agonists
- Excitatory Gq receptors that activate protein-kinase C and increase Ca2+ ion
- DOI and TCB-2 (can cause hallucination and also affects 2C receptors)
WAY 100635
- selective 5-HT1AR antagonist
- produces inhibitory wave
TCB- 2 (2)
what + stress
- with TCB-2 cell firing is enhanced as it is excitatory
- Under stress conditions (ex: socially stressed) TCB-2 can no longer increase activity in cortical neurons.
Atypical antipsychotics (4)
selective + receptors + reduce + can cause
- not selective to 5-HT receptors
- reduces schrezophenia
- also suppresses dopamine D2 receptors
- can cause parkinson
Serotonin Neurotoxins (2):
- 5,7-dihydroxytryptamine (5, 7-DHT)
- p-chloroamphetamine (PCA)
5,7-dihydroxytryptamine (5, 7-DHT) (3)
What + damage + used by
- Terminal degeneration of 5-HT in projection areas/ destroy serotonin-producing neurons in the brain
- Also damages NE so used with desipramine
- Has to be injected into the brain as it doesnt cross the BBB
p-chloroamphetamine (PCA) (2)
deriv + mechanism
- amphetamine derivative
At high doses, it depletes serotonin in the brain
- PCA acts as a releaser of serotonin (5-HT) by reversing the transporters responsible for their uptake (SERT and DAT). In high doses, PCA causes long-term depletion of serotonin levels by damaging serotonergic axons and terminals in the brain.
3,4-methylenedioxymethamphetamine (MDMA)
- ## At high dose it damages serotonin axons and 5-HT cannot be synthesized
Tph2- knockout mice (2)
what + increase + restore?
- Loss of 5-HT synthesis in the brain
- Increased mortality, weight loss, aggression in resident-intruder (territorial)
- You can partially restore 5-HT as there are no TPH2 enzymes but giving the metabolites that TPH2 usually produce (jump over that step)
Monoamine Oxidase-A (MAO-A) (3)
what it does (2) + defiency
- catalyzes 5-HT to 5-HIAA metabolite which enters the CSF
- Defiency causes increased 5-HT, NE, aggression and lower 5-HIAA in CSF
- degrades monoamines
Serotonine metabolite levels — for people with personality disorders
decrease
Brain 5-HT function (4)
- Hunger and eating behaviour (hypothalamic projections)
- Anxiety (dependent on receptors)
- Pain (neuropathic pain due to nervous tissue damage/chronic)
- Learning and memory
Brain 5-HT anxiety (4)
1A + 2A/2C + 5-HT6
- Loss of 5-HT 1A in forebrain during development increase anxiety
- mCPP (5-HT 2A/2C agonist): increase anxiety
- Loss of 5-HT 2A or 5-HT 2C: decrease anxiety
- EMD 386088 (5-HT6 agonist): decrease anxiety
Anxiety and irritability can be symptoms of —— in serotonin levels
an increase
Brain 5-HT and Pain (2)
which increace and which agonist decrease?
- 5-HT1A, 5-HT1B, 5-HT2C, 5-HT7 agonists: decrease pain
- 5-HT2A, 5-HT4A agonists: increase pain
Brain 5-HT and Learning and memory (2)
receptors + agonists
- 5-HT1A receptors: Activation increases spatial memory. Loss of function decrease spatial memory.
- 5-H4 agonists: increases learning and memory, effective in preclinical alzheimer’s models
Network Hypothesis:
- proposes that depression arises from disruptions in neural networks rather than just individual neurotransmitter imbalances.
- May not be solely based on chemical levels
5-HT in the GUT (4)
percentage + synthesized by + released after + IBS
- 90-95% is found in the gut. Rest is in the brain
- synthesized by 5-HT neurons of the enteric nervous system and enterochromaffin cells (non-neuronal enzyme Tph1)
- Released after food ingestion and taken up by SERT
- 5-HT3 antagonist (Alosetron): Treatment of servere IBS
SSRI action (2)
Acute + chronic
- Acute effects of antidepressants:
- Inhibition of reuptake through SERT, 5-HT increase in synpase, autoreceptors cause negative feedback.
- The two acute effects cancel eachother out causing little change in serotonin action. - Chronic effects of antidepressants:
- Downregulation of autoreceptors (1A)
- Less negative feedback and sertonin release increase
NE and 5-HT production zones:
Norepinephrine occurs at: Locus coeruleus
Serotonin occurs at: raphe nuclueus
Which study shows that environment has an effect on mood disorders?
- Mice treated chronically with fluoxetine in enriched environment and stress environment
- Mice in enriched environment showed positive improvement in their depression like scores with anti-depressants. Mice in stress did not benefit from AD.
If NE synthesis is prevented by deleting precursor tyrosine, patients —-.
relapse
1st generation AD is known as
Monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants
2nd generation AD is known as
SSRI
MAO deamininates —-
- Deamininates tyrosine
MAO vs MAOI vs Tricyclic AD (3)
- MAO normally regulates the amount of NT in the presynaptic terminal.
- MAOI inhibits MAO increasing the amount of NT avaliable for release.
- Tricyclic AD binds to pre-synaptic transportor and inhibit re-uptake
Most signifigant difference between 1st and 2nd generation antidepressants are:
- less side effects
no rapid onset or more signifigance.
Serotonine syndrome (2)
what + syndrome
- a potentially life-threatening drug reaction that results from having too much serotonin in your body
- Agitation, confusion, sweating, diarrhea, hypertension
Third generation of AD (2)
goal + who
- Goal is to minimize side effects, speed up onset of effectiveness
- Third-generation antidepressants are a group of antidepressant agents of variable action, not confined to serotonin reuptake inhibition.
