Lecture 11 - Serotonin Flashcards
How does LH act as a model for depression
•Serotonin is up-regulated in the Hippocampus during LH
•it kind of works as a model for depression, e.g. being subdued
- it’s an unavoidable stress cause of depression
•Issues with it:
X - but cant compare this to humans
X - exhaustive depression doesnt happen to all animals, and even if it does, they only stay like this for 1-2 ays
- animals often get over this, but it depends on the environment
What does gut motility mean in this sense?
Gut motility is like your digestive muscles and stuff like that, like swallowing and contracting muscles to process food through tubes and stuff
Outline serotonin and the gut
Around 90% of serotonin is in your gut neurons
- associated with motility and appetite
- Some anti-depressants are used to treat irritable bowel syndrome, where there is increased bowel motility
- IBS oten get gas, constipation, diarrhea - and anti-anxiety/ anti-depressants can help with this
Why do anti-depressants help with IBS?
- In IBS, gut is highly sensitive to the effects of stress, if you are in fight mode, you turn off your digestion - energy goes to heart and lungs, so you dont need to worry about eating
- If you are stressed for a long period of time, gut system becomes a bit dodgy
- Cortisol acting on gut systems trying to slow it down = reactive increase in motility
Outline serotonin in the raphe nucleus
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In CNS, serotonin is known as 5-HT
- 5-HT neurons are found in 7-8 Nuclei, called the Raphe Nuclei
- it is a red nuclei that sits in the brain stem, makes up part of the reticular formation
- Associated with the regulation of sleep/wake cycle (Circadian rhythm) - depression involves issues with sleep regulation
- Caudal (towards tail) Raphe Nuclei
- projects into cerebellum and spinal cord - suppression of pain pereception
- associated with bodys own pain killers (enkephalins and endorphines - Rostral (towards head) Raphe Nuclei
- Projects into entire CNS
- important for mood, cognition, memory
How is serotonin and the raphe nuclei involved in sleep
VIA THE SUPRACHIASMATIC NUCLEI (SCN)
- The raphe nuclei and SCN are reciprocally connected
1. SCN input to raphe nuclei alters 5-HT levels for sleep/ wake states
- Raphe Nuclei feeds back to SCN depending on vigiliance/ alertness
- produces serotonin
- part of reticular formation: Critical for regulating sleep and alertness
This reciprocal feedback provides adaptable yet stable basis for circadian rhythms
What is the SCN
The Suprachiasmatic Nucleus (SCN)
- Located just above optic chiasm
- received direct input fromr etina to allow external light to drive circadian rhythms
- this produces melatonin, which makes you sleepy
How is this system involved in SAD
Serotonin is inolved in Seasonal Affective Disorder
- so you can use lights to regulate circadian rhythms
How is 5-HT associated with mood
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- 5-HT probably just alters mood intensity (rather than mood states directly)
- Lisa Feldman Barret - intensities vs type of mood
- its likely 5-HT just alters intensity, not what emotion is felt
- cant give an epinephrine shot and they will become happy/ angry - depends on environment - Used to treat depression
- Sleep and depression closely related - 5-HT involved here
- SAD - 5-HT involved here too (SCN & Raphe)
- Linked to Generalised Anxiety Disorder
- and some phobias
Outline Generalised Anxiety Disorder
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Excessive worry that interefers with activities of daily life
- for more than 6 months
Rumination, agitation, over arousal about more than one topic, it keeps you awake at night
Not easy to treat, as it’s hard to stope people ruminating, trying to tell them not to think about this makes them think about it
- need to teach them about thought stopping
How do resources and social status interact with Serotonin
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Serotonin levels are higher with increased resources and better social status (complex form of a resource)
- Better social status (e.g. in monkeys), means you have better access to resources (e.g. food) = higher serotonin
- You are happier when you are higher status
- C Elegans
- very basic animals
- if you give them food, serotonin goes up - Lobsters
- Injected with serotonin = dominant, aggressive
- can be reversed by serotonin antagonists - Crayfish
- Social experience (status) alters responses to serotonin for fight-flight response in Crayfish
- fight or flight involved in social status, and this in turn influences serotonin
Outline serotonin in moneys and neglected monkeys and stuff
- Neglected/ Abused rhesus monkeys = lower 5-HT
- quite neurotic babies, dont tend to live very long (impulsive and risk taking), get into social trouble (abused by others)
- grow up to themselves become abusive parents
- might be related to learned behaviour
- but also perhaps due to low serotonin - Nice adoptive mums
- babies Become very sensitive to social structures
- if they get a super mum who is very nurturing and reassuring, their offspring becomed sensitised to social structures and can climb up the ladder very high
- but its not due to aggression, its because they are sensitive to social engagement, learning from their mums, so they can use other animals to create social structure - v good at working with others to get higher up in the structure
- If you are born with low serotonin, you should go down the route of aggression, but then getting a super adoptive mum, this can be reversed
What are the findings of nurture and nature and baby monkeys
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- In Macaques a pattern of low 5-HT and high stress (high levels of cortisol) = key predictor of aggresion, and maternal style when they group
- this in turns affects 5-HT in offspring, and their behaviour - Interactions between genetic polymorphisms in 5-HT metabolism (nurture) and rearing style (nurture) on behaviour & Cognitive function:
- if you give them a super mum (usually adoptive) they can overcome this and become smart/ sensitive to social interactions
What are the 2 categories of serotonin related drug s
- Aspecific - focus more on overall levels, compared to specific receptor subtypes
- not very specific to receptor subtypes
- most are aspecific - Receptor- Specific
Outline Aspecific serotonin related drugs
They just change overall levels of 5-HT, mostly not specific to receptor subtypes
- Incudes many recreational drugs, but these usually affect other monamine levels, like the catecholamines (DA, NE)
Side effects:
- due to appetite & Gut stuff: can put on weight
- interacts with hormone levels, impacting your libido, potentially quite a lot - so it can affect your relationships, how you view yourself etc
Therefore, to counter act this, researchers have tried to find receptor-specific drugs
Outline Receptor-Specific serotonin related drugs
Outline Aspecific serotonin related drugs
Can either be full or partial:
- Agnosists - help the effect of 5-HT
vs - Antagonists - block the effect of 5-HT
- Can either be fully, or partially
- So if level is low, can act as a helper, as an agonist
- but if level is too high, they then act as an antagonists - reduces it down, but still higher than the level it would be normally
- prevent it from being too low, but also from being too high
- Keeps it at a balnced level, but still more than enough
- They block the receptor
- not always the most effective, and if levels are low, still give some effect
- these Target 1 or more receptor, with varying affinities
How do drugs affect 5-HT
Several methods:
- BY AFFECTING BIOSYNTHESIS
- e.g. Tryptophan is a precursos for Serotonin
- but depends on levels of other amino acids at BB - Changing 5-HT clearance (reuptake) at pre-synpatic neuron
- Affecting its breakdown (MAO) in the cell
Outline Biosynthesis - tryptophan**
- method 1 of effecting 5-HT in the brain
- Tryptophan is an essential amino acid - found in bananas, salmon, dates, herring
- Doesnt immediately effect the brain, it depends on the BBB
- There is a Tryptophan Blood Brain transporter that transports it across the barrier, but it is also used by other amino acids, so might be busy
The rate limiting step is step 2
- Convering Tryptophan to 5-HTP (5-Hydroxy-L-Tryptophan) by TPH (Tryptophan Hyrdroxylase)
1. L-Tryptophan via TPH 2. 5-Hyrdroxy-L-Tryptophan (5-HTP) 3. Serotonin 4. 5-Hydroxyindoleacetic acid (5-HIAA)
What have findings about Tryptophan transporter found?
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- Mood induction experiments - using Branched-Chain Amino acids (BCAA) - block tryptophan blood-brain transporter
- this reduces 5-HT and induces depression
- not all the time - Receipine?***
- reduces all amino acids and can induce depression
- not in all people, not everyone is at risk of these effects
Outline a balanced diet and impact on 5-HT
- Tryptophan, Phenylalanine and Leucine (p&L in soy) all use the same BCAA transporter to cross the BBB
- If there is an increase in the ratio between these 3 -> cause increased 5-HT
- If there is an imblanaced of Phenylalanine and Leucine, it will prioritise getting them in ahead of Tryptophan
- therefore, you need to get a balanced diet, so all 3 of these are in balanced, and all 3 go through, and serotonin is increased in the brain
- have a good ratio of foods, e.g. dates, bananas etc
What does BCAA stand for?
Branched-Chain Amino acids (BCAA)
What does the BBB do?
BBB keeps out toxins, infections and stuff you dont want in your brain
- transporters decide what can come and what has to stay out
In the foetus and an older brain (especially Az) - BBB doesnt function as well
What do more complex foods do?
- more complex food effects via insulin
- insulin is important in the brain
What can selective amino acid depletion cause?
If you have selective amino acid depletion, this can also cause muscle mass depletion
- affects your behaviour here too
Outline reuptake inhibitors
- second way of influencing 5-HT levels in brain
- A very specific system
- best way to act on serotonin
Do this by:
Targeting the specific transporter for 5-HT on presynaptic (5-HT+) neurons
- best way to get it out of the synpase, to stop it from repeatedly activating the post-synaptic all the time
- reuptake is usually the main clearance mechanism - so makes sense that it is effective to target this
Outline Fenfluramine as an exmple of reuptake inhibitors
Example = Fenfluramine
- very specific for 5-HT
- liscensed as an anti-obesity medication in US 1973 - as it reduced appetite
- Also acts as a strong agonist for 5-HT2B receptor which is a receptor subtype
- was banned because this receptor sat on the heart valve and caused heart valve abnormalities, withdrawn 1997
- it was good that it worked on specific receptors, but it was a shame that these receptors were involved in other stuff that was very important
Outline MDMA
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•Increases levels of all 3 monamines at one time
- DA, NE, 5-HT
•Causes changes in mood, affect, eating, sleepiness
• Can conterversionally be linked with:
- Cognitive issues
- Panic attacks (especially in anxious/ panic attack prone)
- Short or long term memory problems
- perhaps dementia (oxidative stress)
•Death relate to bad contamination, e.g. baking powder, arsenice, flower etc
Outline how MDMA might be used in therapies
Some could say it could be used in some therapies
- e.g. PTSD - can be used to increase trust, bonding with others
X - but it is still a class A drug, its illegal to use - imprisonment/ fines
Was used in psychotherapy before being declared as illegal
What did Ricaurte (2002) find about MDMA and parknisons
***** is this right?
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This study showed neuronal damage and Parkinsons in rats withdrawal from MDMA
- but they were also injected meth, which is very toxic in its own right, especially for DA neurons
Outline overlap with other DA reuptake inhibitors
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Most 5-T reuptake transporters (SERT) inhibitors also inhibit the other monoamine transports (DA/NE)
SNDRI: Serotonin, Norepinephrine, Dopamine reuptake inhibitors - cocaine, amphetamines, MDMA
Drug effects depend on receptor subtype, levels and balance of other NT’s
- depends on whats in their brain at that point, how they slept, what they had for dinner etc - hard to control in humans
- also depends on the environment
Outline SNDRI’s
Serotonin, Norepinephrine, Dopamine reuptake inhibitors
- include Cocain, amphetamines, MDMA
- Cocaine and Amphetamines influence Dopamine
Causes: •Euphoria •Motor Activity •Loss of appetite - due to impact of DA, perhaps also 5-HT and NE •Psychosis •Dont need to sleep
They affect all monamine transporters to varying degrees
Outline Tricyclic antidepressants (TCA)
they inhibit: 5-HT and NE reuptake
- discovered in the 50s, named after their chemical structure
Used to treat: depression, GAD, OCD etc
Side effects:
•Osteoporosis - increased chance
•Manic epdisodes (provoked)
Mostly now replaced with SSRi’s because of the bad side effects of TCA
- might try TCA’s if SSRI’s dont work
E.g: Imipramine, Doxepin
Outline SSRI’s
- Selective Serotonin Reuptake Inhibitors
- Widely used to treat: Depression, anxiety, OCD, ED’s and PTSD. As well as premenstrual dysphoric disorder
- changes in DSM-5 means there is an increased range of stuff treatable with SSRI’s
First class of drugs designed to target specific molecule (SERT) - rational design
E.g.: Fluoxetine (Prozac), Citalopram (Celexa)
- Prozac advertised for lots of things
Hard to come off these drugs
Outline how it is hard to come off of SSRI’s
Hard to come off these drugs
- Firstly, you have lots of side effects
•Weight Loss*** (THOUGHT IT WAS GAIN?), •Libido, Sleep/wake cycle
- But if you do stop, you can get really bad rebound anxiety and depression
- so what you need to do is ask for liquid Prozac and slightly decrease the dose
- cant just stop it immediately, as your body has adapted to it, and depends on it now
Do SSRI’s mainly work by increasing 5-HT?
NO - They dont just increase levels in the synapse immediately,
- because they do not work immediately (1 month - 6 weeks)
- Cocaine/ MDMA also block reuptake receptors, but these work immediately
SO COULD BE:
Either SSRI’s block reuptake, the cell in the raphe nucleus notices how theres reduced serotonin and ups production, and this takes a bit of time
OR
Could be: receptor down regulation -if there is too much serotonin in the synapse, the receptors go down - but that would me that low serotonin is not the issue
- too much serotonin = less receptors
- indicates that low levels serotonin might not be an issue, because reducing serotonin doesnt always cause depression, you need some vulnerability, which maybe why it only works in 60%
- Also, they only work in 60% people
- and placebo works quite well, perhaps even in 40% - suggesting SSRI only has a 20% effectiveness
- and but inducing low 5-HT doesnt always lead to depression (e.g. reserpine depletes monamine stores, but only leads to depressio nin some)
IT MIGHT BE:
- to avoid an over sensitive system/ over arousal/ burnout
SO MAYBE SSRI’s Work in via neurogenesis
Could SSRI’s act via neurogenesis?
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In ANIMAL RESEARCH:
- If we increase 5-HT in Hippocampus
- This increased signalling will increase the release of neurotrophic (growth) factors
- e.g. BDNK, VEGF etc - This will then stimulate the cells in the hippocampus to proliferate (multiply)
- so in all people you can still induce further maturation of hippocampal cells
This process of neurogenesis in animals, via SSRi’s, causes 2 behaviours, 2 behavioural systems are increase in these models
- Increased movement
- animals stick their tail up, walk around a lot, become very active - Eat more in a novel situation
- normally, if you put a rat in a novel situation, they wont really want to eat, because they need to figure out where they are
- But if they feel okay, despite being in this novel situation, they will eat a lot
Shows that having more cells in the hippocampus, due to the SSRI’s
- allows you for instance to have more positive, novel situations
Not sure how much you can relate this to humans
Outline Serotonin receptor classes
**INSERT THEM HERE
** What is cAMP
Cyclic AMP
Outline Serotonin receptor classes
Drugs will usually act on all of these receptors
- it’s difficult to find a drug that acts very selectively
- you could avoid unwanted effects on the Gastrointestinal tract, blood vessels - just have selective effects, potentiall on CNS
What do the 5-HT1 and 5-HT2 receptor families contain?
They each contain 3 further subtypes each:
•5-HT1A
•5-HT1B
•5-HT1C
- 5-HT2A
- 5-HT2B
- 5-HT2C
What drugs effect 5
Drugs have varying selectivity for receptor subtypes
- the wikipedia article on 5-HT receptors has very good drugs overview**
- Too many to list by receptor subtype here, will list by major drug groups instead:
- Psychadelic Drugs
- Anti-Psychotics
- Anxiolytics
- Other 5-HT receptor drugs
Outline Psychadelic drugs
Psychadelic drugs, like LSD, are MOSTLY AGONISTS FOR 5-HT2A/2C receptors
Cause: altered perception, vivid hallucinations
- LSD (Lysergic Acid Diethylamide), Magic Mushrooms (compound = Psilocybin) and Mescaline - cause this stuff by acting on 2a/ 2c receptor
- can cause bad trips, that may affect you for the rest of your lives
Might be a role for this in therapy but you need to know what you are doing
Magic mushrooms are less dangerous but can have side effects still
There has been research into microdosing with magic mushrooms
Outline research into using magic mushrooms
There has been research into microdosing with magic mushrooms , effects on 5-HT2a
- they make you more creative, engaged etc
X - still class A drugs, involved in heroin, cocaine etc
- makes it hard to investigate what the effects really are
- they might benefit therapy, but cant really get permission for it - need lots of security for this
Psychopharmeca dont want this to be found, because you cant patent a mushroom, they want it to be a chemical that only they can produce - they want one compound - so will try and keep it on the class A
Outline Antipsychotics
Tranquilise - used to treat psychiatric conditions, including psychosis e.g. sz
Most target DA receptors, but some also GABA
Atypical or 2nd generation antipsychotics meant to reduce motor side-effects and often also target 5-HT receptors
- Haldol etc aimed to combat parkinsonian symptoms, e.g. rigidity
E.g. Clozapine is a 2nd generation atypical anti-psychotic
Outline Clozapine as a 2nd generation atypical anti-psychotic
Clozapine is a 2nd generation atypical anti-psychotic
- key effects on DA receptors (D1 and D2)
- Also effects serotonin - so it causes less motor side effects
- Complex 5-HT receptor profile
Outline Anxiolytics
- Reduce anxiety and often also depression
- used to treat anxiety disorders
- Good results in depression with melatonin, it may induce neurogenesis
E.g. Busprione
- partial agonists for 5-HT1A receptor
- Also DA receptor effects: partial agonists, if your levels are low, it will up it, but not too high so you get manic
- keeps it balanced, not too low but not too high
Outline other 5-HT receptor drugs
•Migraine treatments
- e.g. triptans
•For obesity - appetite suppressants
- anorectics
•Antiemetics - against nausea and vomiting
•Gastroprokinetics (increase gut motility)
- effect gastric system directly
- Blood pressure
- Sexual Dysfunction
- Premenstrual dysphoric disorer
Outline the dopamine and serotonin pathways
Dopamine
- Substantia Nigra ->(projecting) Basal ganglia (striatal complex/ striatum)
- VTA -> Nuclues Accumbens (pleasure area)
- VTA -> projecting to frontal cortex in (in the meso cortical pathway)
Serotonin –Raphe nuclei in the brain stem – associated with sleep/ alertness
- Raphe Nuclei -> projections towards spinal cord/ cerebellum – wakefulness/ pain suppressionvia the enkephelons
- Raphe nucleus -> nucleus accumbens and striatum, and all the way into the cortexwhere it is associated with mood and memory
What receptors will drugs like LSD act on?
Agonists for 5-HT2a and 2c receptors
