L14 - Dopamine: Parkinson's disease and schizophrenia Flashcards
(64 cards)
1
Q
What are the roles dopamine has in the body?
A
- major role in reward- motivated behaviour
- involved in motor control
- role in controlling release of various hormones and chemicals
2
Q
What are the different hormones and chemicals that dopamine regulates the release of?
A
- in blood vessels: noradrenaline
inhibits NA release and acts as a vasodilator - kidneys:
increases sodium excretion and urine output (hypertension) - reduces insulin production and reduces GI motility
3
Q
What are the 2 types of dopamine receptor and how are the different?
A
dopamine D1 type receptors
- Gs receptors = activation of adenylate cyclase
dopamine D2 type receptors
- Gi receptors = inhibition of adenylate cyclase
4
Q
What do the dopamine D1 type receptors consist of?
A
D1 and D5 receptors
5
Q
What do the dopamine D2 type receptors consists of?
A
D2, D3 and D4 receptors
6
Q
What downstream effect does dopamine D1 receptor activation have?
A
activation of protein kinase A
- important in neuronal activity and modulating the activity of other ion channels in the synapse
7
Q
What downstream effect does dopamine D2 receptor activation have?
A
- pre-synaptic receptors (D2) important to reduce release of further dopamine and other neurotransmitters = prevent vesicle release
- post-synaptically inhibit adenylate cyclase
8
Q
How is dopamine removed from the synapse?
A
dopamine transporter: - dopamine active transporter (DAT) broken down: - monoamine oxidase A + B (MAOa MAOb) - catechol-O-methyltransferase (COMT)
9
Q
What is the effect of dopamine active transporter (DAT)?
A
located pre- and post-synaptically
- reuptake of dopamein into the cell
10
Q
What is the effect of monoamine oxidase (MAO) and why does it affect dopamine?
A
- breaks down dopamine
- dopamine is a monoamine
11
Q
What is different about the different types of monoamine oxidase? MAOa + MAOb
A
MAOa: - liver - vascular - GIT - placenta MAOb: - brain - platelets
12
Q
Where are MAO and COMT located?
A
in the synapse
13
Q
Why does COMT have an effect on dopamine?
A
dopamine is a catecholamine
14
Q
What is the pathological role of dopamine in the CNS?
A
too little dopamine = Parkinson’s Disease
too much dopamine = Schizophrenia
15
Q
What pathways in the brain is dopamine involved in?
A
- frontal cortex
- striatum
- substantia nigra
- nucleus accumbens
16
Q
What is the pathway involved in Parkinson’s Disease?
A
nigrostriatal pathway:
- dopamine cells in the substantia nigra progressively die
- no dopamine released into striatum
- results in reduced dopamine levels in the striatum
17
Q
What are the causes of Parkinson’s Disease?
A
cause unknown:
- genetic (15%)
- mostly environmental factors (pesticide exposure, head injuries)
18
Q
What is the age of onset of Parkinson’s disease?
A
60+ years
early onset: <50 years
19
Q
What is Parkinson’s Disease?
A
progressive neurodegenerative disorders affecting movement
- low dopamine receptor activation in striatum
20
Q
What are the symptoms of Parkinson’s Disease in the early stages?
A
- barely noticeable hand tremor
- little/no facial expression
- arms don’t swing when walking
- slurred speech
21
Q
What are the motor symptoms associated with Parkinson’s Disease?
A
- resting tremor
- bradykinesia (slow movement and impaired ability to adjust body position)
- rigidity
- postural instability
22
Q
What are the non-motor symptoms associated with Parkinson’s Disease?
A
- cognitive decline leading into dementia
- autonomic dysfunction (constipation + hypotension)
- depression and anxiety
23
Q
What is the goal for the treatment of Parkinson’s disease?
A
increase dopamine receptor activation in the striatum
24
Q
What is the ‘gold standard’ treatment option for Parkinson’s Disease?
A
Levodopa (L-dopa)
25
Why is dopamine not given as a treatment for Parkinson's disease? What is given instead?
- cannot give dopamine because it can't cross the BBB and has systemic effects
- give metabolic precursor of dopamine
26
How is Levodopa given?
- given alone but with low bioavailability
| - given with dopa decarboxylase inhibitor for increased effect
27
What is drug is a dopa decarboxylase inhibitor?
Carbidopa
28
What is the effect of Carbidopa?
- inhibits the conversion of L-dopa into dopamine in the systemic circulation (it can't cross BBB)
- this causes reduces peripheral side effects (cardiovascular + GI)
- more L-dopa to the brain where it is converted to dopamine
29
What are the problems associated with chronic L-dopa treatment?
- psychological effects (delusion/hallucination)
- decreased effectiveness over time due to cells death
- dyskinesia (hyperkinetic, purposeless movement)
- on-off phenomenon (sudden unpredictable changes in mobility)
30
What is the second like treatment for Parkinson's Disease?
dopamine agonist
31
How is apomorphine (dopamine agonist) given?
- orally
| - subcutaneous injection
32
What drug is a dopamine agonist?
apomorphine
33
What are the benefits of using a dopamine agonist cf. L-dopa?
- last longer
- lower risk of dyskinesia
- when used in combination with L-dopa able to smooth on/off phenomenon
- however is less effective
34
What is the onset of action and half-life of apomorphine?
- effects in ~ 5min
- peak plasma conc. ~3min after injection
- half-life of 30min
35
What is a good use of apomorphine in combination with L-dopa?
good way to manage off-period symptoms before L-dopa has effect
36
What are the problems associated with L-dopa use in combination with dopamine receptor agonists?
- require functioning neurons = less effective in later stages of disease
- side effects
37
What are the side effects of L-dopa and dopamine receptor agonist combination use?
- hallucinations
- nausea and vomiting because triggers dopamine receptors in chemoreceptor trigger zone
NOTE: above side effects can be managed by dose
- impulse control disorder (because dopamine pathways associated with reward) = impulse shoppers and gamblers
38
What is the last treatment option for Parkinson's Disease?
enzyme inhibitors:
- monoamine oxidase (MAOb) inhibitor
- COMT inhibitor
39
How do enzyme inhibitors work in Parkinson's Disease?
- reduce the breakdown of dopamine
| - increase the duration of action of dopamine in the brain by increasing at synapse
40
When are enzymes inhibitors used in Parkinson's Disease?
- used alone in early stages
- treat anti-depressant effects in later stages (increased serotonin - monoamine)
- can be used in combination with L-dopa to increase effectiveness
41
DONT NEED TO KNOW DRUG NAMES: What drugs are enzyme inhibitors used in Parkinson's disease treatment?
- MOAb inhibitor: selegiline
| - COMT inhibitor: entacapone
42
What is Schizophrenia?
neurological disorder characterised by abnormal social behavious and failure to understand what is real
- too much dopamine receptor activation in prefrontal cortex and nucleus accumbens
43
What are the causes of Schizophrenia?
cause remains unclear
- genetic predisposition
- maternal viral infection increases risk
44
What is the life expectancy of people with schizophrenia and why?
20-30 years shorter
- unhealthy lifestyle
- smoking
- increased suicide risk
45
What are the symptoms associated with the condition schizophrenia?
- positive symptoms: delusions and hallucinations
- negative symptoms: withdrawal, lack of emotions and social functioning
- mood disorders: depression and anxiety
- cognitive defects: difficulty concentrating and following instructions
46
What are the positive symptoms of schizophrenia?
- delusions
- hallucinations
- thought disorder: wild train of though, irrational conclusions
- abnormal behaviours: stereotyped movements, aggressive behaviour
47
What are the negative symptoms of schizophrenia?
- withdrawal from social contact
- poor social functioning
- apathy
- flattening of emotional responses
48
What are the cognitive symptoms of schizophrenia?
- attention
- memory
- executive functioning (following instructions)
49
What are the mood disorder symptoms of schizophrenia?
- anxiety
- depression
- aggression
- 10% patients commit suicide
50
What is the cause for the positive symptoms experienced in schizophrenia?
increased dopamine in the nucleus accumbens
| = delusions + hallucinations
51
What is the cause for negative symptoms of schizophrenia?
decreased dopamine in the prefrontal cortex
52
What brain pathways are involved in schizophrenia and what is occurring?
- nucleus accumbens: increased dopamine
| - prefrontal cortex: decreased dopamine (due to receptor desensitisation in the nucleus accumbens ??????)
53
What are the types of drug treatments for schizophrenia?
- typical antipsychotics
| - atypical antipsychotics
54
What is the mechanism of action of typical antipsychotics?
they are antagonists or inverse agonists for dopamine D2 type receptors
55
What is a drug that is a typical antipsychotic?
haloperidol
56
What are the side effects of typical antipsychotics?
- can induce negative symptoms
- Parkinson's like symptoms
- antihistamine side effects
- anticholinergic side effects
- antiadrenergic side effects
57
Why are there wide spread side effects associated with typical antipsychotic use?
because they are non-selective and also block other receptors in the body:
- muscarinic receptors
- histamine receptors
- alpha adrenergic receptors
58
What are the wide spread side effects?
```
antihistamine side effects:
- weight gain
- drowsiness
anticholinergic:
- constipation
- blurred vision
- dry mouth
- drowsiness
antiadrenergic side effects:
- decreased blood pressure
- drowsiness
- dizziness
```
59
What is the mechanism of action for atypical antipsychotics?
- act as an antagonist for both dopamine D1 and D2 receptor types
- block serotonin (5-HT) receptors
60
What is the benefit in atypical antipsychotics to block serotonin receptors?
serotonin modulates dopamine activity by:
- increasing dopamine D2 type receptors
- increasing dopamine release
= blocking these receptors causes a decrease in dopamine in the brain
61
What is an atypical antipsychotic drug?
clozapine
62
What are the side effects of atypical antipsychotics?
```
- Parkinson's-like side effects
also blocks other receptors:
- muscarinic receptors
- histamine receptors
- alpha adrenergic receptors
```
63
Atypical antipsychotics are more commonly used now than typical antipsychotics. Why?
- lower risk of Parkinson-like side effects
| - less affinity for other receptors so less side effects
64
What are the treatment options for the different symptoms of schizophrenia?
positive symptoms: antipsychotics
negative symptoms: antidepressants
negative symptoms: no proven treatment
cognitive defects: no proven treatment
