CNS pharmacology IV Flashcards
What are the 2 types of depression?
1) UNIPOLAR
2) BIPOLAR
What are the drugs used to treat depression?
Different depending on which type: unipolar or bipolar
What is unipolar depression?
Mood swings always in the same direction
What is unipolar depression characterised by?
Typical symptoms
What are the causes of unipolar depression?
Reactive causes (75%) - Specific triggers lead to the disease (eg. stressful situation)
Endogenous causes (25%)
- No obvious cause
- May be genetic components that underlie the disease
What is bipolar depression?
Low mood ALTERNATE with excessive positive feelings (mania)
What are the 3 causes of depression?
- Stressful situation
- Genetics
- May be secondary to other illnesses (eg. Cushing’s disease)
What are the 4 brain regions implicated?
1) Nucleus accumbens and cingulate nucleus
2) Amigdala
3) Hippocampus
What is the amigdala part of in brain?
The LIMBIC SYSTEM
What is the amigdala involved in?
Fear responses in patients
What is the hippocampus involved in?
Important in controlling memory and learning
Where are the hormones Leptin and Ghrelin produced?
What are they involved in?
Produced in the periphery
Involved in feeding
What do the hormones Leptin and Ghrelin lead to changes in?
Stress signalling
How can postnatal depression effect the babies of the mother?
- Depressed behaviour of the mother leads to epigenetic changes in the baby
- Permanent susceptibility to depression through adult life
How can we study the brain changes in depression and the effects of anti-depressants be studied?
Cause prolonged stress to model animals and then treat them with anti-depressants and see how they react
How long does it take for anti-depressants to work in humans?
How can this be shown in animal models?
Takes several weeks
Seen in animal models that have been experiencing CHRONIC stressful situations (animal stressed in the unpredictable way each day)
What happens to mice that experience chronic stress?
Changes in the brain chemistry that is observed in the human conditions
How are the intermediate neuro chemical effects of antidepressants observed?
Observed in acute stressful situations (forced swim test, suspension test)
What is an obvious physical measure of depression?
High levels of blood CORTISOL
What is cortisol?
A stress hormone
What are the chemical causes of depression?
1) Depletion of the MONOAMINES in the brain
2) NDMA (glutamatergic) nerodegeneration
What are the 2 monoamine neurotransmitters that are involved in depression?
Serotonin (5-HT) and noradrenaline (NA)
As drugs that influence monoamine transmission (to treat depression) take several weeks to benefit, what does this show?
What did further research show?
- Must involve long term trophic effects
- Must somehow alter TRANSCRIPTION and RECEPTOR LEVELS in the effected neurons
Further research: revealed the possible role of BDNF and its receptor TrkB
What controls the levels of BDNF signalling?
Serotonin
What happens to the NA, 5-HT signalling in a depressed individual?
What does this lead to?
Reduced signalling through their receptors, leading to detrimental GENE TRANSCRIPTION
Leads to:
- Loss of neurons through apoptosis
- Loss of a number of active synapses
Normally, what do the 5-HT/NA receptors normally control?
Beneficial gene transcription
What happens to glutamate signalling in depression?
Excess activated of the NDMA receptors
Associated with neuronal loss
What is Ketamine?
What effects does it show in humans?
An anaesthetic
Shows effects in patients that are resistance to drugs in the NA-HT area
How does stress impact depression?
Through the effects on neurotransmission
How does our understanding of the different neurotransmitter systems involved in depression?
Comes through the understanding of drugs that either CAUSE or ELEVATE depression
What does iproniazid do?
What type of drug is this?
Elevates depression
An MAOI
What does reserpine do?
How?
Causes depression
Through the depletion of the monoamine transmitter stores
What do Tricyclic Acids?
Inhibit the re-uptake of 5-HT and/or NA
Effective in treating depression
What are the 3 main classes of antidepressants?
1) MAOIs
2) TCAs (tricyclic antidepressants)
3) Selective serotonin re uptake inhibitors
What is MAO involved in?
Where are they found?
The breakdown of amine neurotransmitters
Found on the inside and the outside of the neurons
What are amine neurotransmitters?
- Dopamine
- Noradrenaline
- Adrenaline
- Histamine
- Serotonin
What are the 2 different type of MAOs?
Which one is the target of MAOIs? Why?
a and b subtypes
a subtype is the target of MAOIs as it is present in the CNS
b subunit is present in the PNS
How do MAOIs work?
- Inhibit MAO enzymes in the presynaptic terminal
- Build up of amines in the cytosol
- Amines leak out of the presynaptic terminal through the reversal of the transporters
What are the side effects of the MAOI equivalent to?
The increase in sympathetic drive
Why do some MAOIs have fewer side effects?
Target the a subtype more specifically (b subtype in the PNS)
What level do TCAs work at the level of?
The level of the transporters of NA and 5-HT
How do TCAs work?
- Inhibit the transport of NaA and 5-HT by binding to the transporter
- Neurotransmitters hang around in the synapse for longer
- Increased activation of the receptors on both the presynapse/postsynapse
- Increased activity through the receptors lead to their DESENSITISATION and DOWNREGULATION (takes a few weeks to be observed)
- -> leads to alterations in excitability
- Transcriptional changes
What receptor is on the NA presynapse that is activated more strongly in the presence of TCAs?
What type of synapse is this?
Alpha-2-adrenoreceptors
Inhibitory synapse
What do SSRIs show selectivity to?
Serotonergic signalling
Are tricyclic antidepressants selective?
No
Where do SSRIs work?
At the level of the transporters
What does the effectiveness of the SSRIs depend upon?
The patient - all patients have different spectrums of the disorder
What are TCAs and SSRIs drugs involved with?
5-HT
What is the major source of NA?
What is it involved in?
The amygdala
Involved in regulating mood/arousal
As well as mood and arousal, what is else is NA signalling involved with?
What does this mean?
Central regulation and blood pressure
- Can lead to unwanted side effects with long-term use of antidepressants
- Get low blood pressure
Where is NA synthesised from?
Dopamine - from the amino acid tyrosine
What is NA broken down by?
MAO and COMT
What is the difference between the pathways of dopamine and NA?
NA neurons express dopamine beta-hydroxylase
What is tyramine related to?
What disrupts tyramine processing?
Related to tyrosine
MAOI (antidepressants)
What does the Raphe nucleus use as a neurotransmitter?
Where else in the body is this neurotransmitter used?
5-HT
Also used in regulating the limbic system
Also used as a neurotransmitter in the gut
What are drugs that promote 5-HT transmission used to treat?
Depression
Anxiety
Migranes
Why does the increase in 5-HT by medicines that treat depression have peripheral side effects?
5-HT is used as a neurotransmitter in the gut
How is 5-HT synthesised?
- From an amino acid TRYPTOPHAN
- Using TRYPTOPHAN HYDROXYLASE
How is 5-HT broken down?
By MAO
How do 5-HT and NA neurons interact with each other?
They are found in the SAME brain regions
They control the release of each other
What are the selectivities of TCA and SSRI inhibitors?
VARY:
- NA-selective
- Non-selective
- 5-HT selective
What does CREB do?
How is CREB activated?
Controls the synthesis of BDNF
By the activation of serotonergic receptors in SOME parts of the brain that lead to the PHOSPHORYLATION of CREB
What does BDNF do in NORMAL patients?
How?
Stabilised synaptic connects:
- BDNF is released from the POSTSYNAPTIC site
- Acts RETEROGRADELY on the nerve terminal forming the synapse
- Action together –> strengthens the synapse
What happens in relation to BDNF in DEPRESSED patients?
- Reduced release of BDNF through the reduction in the synaptic activity
- Synapses are not maintained –> less synapses/connections
How do anti-depressant drugs strengthen signalling?
By increasing BDNF levels in the hippocampus
–> Leading to the re-establishment of the active synapses
What accounts for the small, significant ultrastructural changes associated with depression?
Loss of synapses through the loss of BDNF
What are alternative approaches to treating depression?
- Anti epileptic drugs and anti psychotics –> mood stabilisers
- ECT
When are anti epileptic drugs and anti psychotics drugs used to treat depression?
In patients that show RESISTANCE to amine based approached
Why is ECT effective?
Localised to SPECIFIC brain areas
Useful when patients are resistant to other types of drugs
Why are the drugs used to treat bipolar disorders different to drugs in unipolar disorders?
Different neuro chemical bases
What is used in the treatment of bipolar disorders?
How do they work?
Lithium
Inhibits IP3 receptors
Works on kinases
