L14 - Dopamine: Parkinson's disease and schizophrenia Flashcards
What are the roles dopamine has in the body?
- major role in reward- motivated behaviour
- involved in motor control
- role in controlling release of various hormones and chemicals
What are the different hormones and chemicals that dopamine regulates the release of?
- 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
What are the 2 types of dopamine receptor and how are the different?
dopamine D1 type receptors
- Gs receptors = activation of adenylate cyclase
dopamine D2 type receptors
- Gi receptors = inhibition of adenylate cyclase
What do the dopamine D1 type receptors consist of?
D1 and D5 receptors
What do the dopamine D2 type receptors consists of?
D2, D3 and D4 receptors
What downstream effect does dopamine D1 receptor activation have?
activation of protein kinase A
- important in neuronal activity and modulating the activity of other ion channels in the synapse
What downstream effect does dopamine D2 receptor activation have?
- pre-synaptic receptors (D2) important to reduce release of further dopamine and other neurotransmitters = prevent vesicle release
- post-synaptically inhibit adenylate cyclase
How is dopamine removed from the synapse?
dopamine transporter: - dopamine active transporter (DAT) broken down: - monoamine oxidase A + B (MAOa MAOb) - catechol-O-methyltransferase (COMT)
What is the effect of dopamine active transporter (DAT)?
located pre- and post-synaptically
- reuptake of dopamein into the cell
What is the effect of monoamine oxidase (MAO) and why does it affect dopamine?
- breaks down dopamine
- dopamine is a monoamine
What is different about the different types of monoamine oxidase? MAOa + MAOb
MAOa: - liver - vascular - GIT - placenta MAOb: - brain - platelets
Where are MAO and COMT located?
in the synapse
Why does COMT have an effect on dopamine?
dopamine is a catecholamine
What is the pathological role of dopamine in the CNS?
too little dopamine = Parkinson’s Disease
too much dopamine = Schizophrenia
What pathways in the brain is dopamine involved in?
- frontal cortex
- striatum
- substantia nigra
- nucleus accumbens
What is the pathway involved in Parkinson’s Disease?
nigrostriatal pathway:
- dopamine cells in the substantia nigra progressively die
- no dopamine released into striatum
- results in reduced dopamine levels in the striatum
What are the causes of Parkinson’s Disease?
cause unknown:
- genetic (15%)
- mostly environmental factors (pesticide exposure, head injuries)
What is the age of onset of Parkinson’s disease?
60+ years
early onset: <50 years
What is Parkinson’s Disease?
progressive neurodegenerative disorders affecting movement
- low dopamine receptor activation in striatum
What are the symptoms of Parkinson’s Disease in the early stages?
- barely noticeable hand tremor
- little/no facial expression
- arms don’t swing when walking
- slurred speech
What are the motor symptoms associated with Parkinson’s Disease?
- resting tremor
- bradykinesia (slow movement and impaired ability to adjust body position)
- rigidity
- postural instability
What are the non-motor symptoms associated with Parkinson’s Disease?
- cognitive decline leading into dementia
- autonomic dysfunction (constipation + hypotension)
- depression and anxiety
What is the goal for the treatment of Parkinson’s disease?
increase dopamine receptor activation in the striatum
What is the ‘gold standard’ treatment option for Parkinson’s Disease?
Levodopa (L-dopa)
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
How is Levodopa given?
- given alone but with low bioavailability
- given with dopa decarboxylase inhibitor for increased effect
What is drug is a dopa decarboxylase inhibitor?
Carbidopa
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
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)
What is the second like treatment for Parkinson’s Disease?
dopamine agonist
How is apomorphine (dopamine agonist) given?
- orally
- subcutaneous injection
What drug is a dopamine agonist?
apomorphine
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
What is the onset of action and half-life of apomorphine?
- effects in ~ 5min
- peak plasma conc. ~3min after injection
- half-life of 30min
What is a good use of apomorphine in combination with L-dopa?
good way to manage off-period symptoms before L-dopa has effect
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
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
What is the last treatment option for Parkinson’s Disease?
enzyme inhibitors:
- monoamine oxidase (MAOb) inhibitor
- COMT inhibitor
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
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
DONT NEED TO KNOW DRUG NAMES: What drugs are enzyme inhibitors used in Parkinson’s disease treatment?
- MOAb inhibitor: selegiline
- COMT inhibitor: entacapone
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
What are the causes of Schizophrenia?
cause remains unclear
- genetic predisposition
- maternal viral infection increases risk
What is the life expectancy of people with schizophrenia and why?
20-30 years shorter
- unhealthy lifestyle
- smoking
- increased suicide risk
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
What are the positive symptoms of schizophrenia?
- delusions
- hallucinations
- thought disorder: wild train of though, irrational conclusions
- abnormal behaviours: stereotyped movements, aggressive behaviour
What are the negative symptoms of schizophrenia?
- withdrawal from social contact
- poor social functioning
- apathy
- flattening of emotional responses
What are the cognitive symptoms of schizophrenia?
- attention
- memory
- executive functioning (following instructions)
What are the mood disorder symptoms of schizophrenia?
- anxiety
- depression
- aggression
- 10% patients commit suicide
What is the cause for the positive symptoms experienced in schizophrenia?
increased dopamine in the nucleus accumbens
= delusions + hallucinations
What is the cause for negative symptoms of schizophrenia?
decreased dopamine in the prefrontal cortex
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 ??????)
What are the types of drug treatments for schizophrenia?
- typical antipsychotics
- atypical antipsychotics
What is the mechanism of action of typical antipsychotics?
they are antagonists or inverse agonists for dopamine D2 type receptors
What is a drug that is a typical antipsychotic?
haloperidol
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
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
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
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
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
What is an atypical antipsychotic drug?
clozapine
What are the side effects of atypical antipsychotics?
- Parkinson's-like side effects also blocks other receptors: - muscarinic receptors - histamine receptors - alpha adrenergic receptors
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
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
