Dopaminergic pathways of the brain and drugs used to treat Parkinson’s Disease and Schizophrenia

Question 1

What are the 4 main dopaminergic pathways in the brain?

Answer 1

Nigrostriatal
Mesolimbic
Tuberoinfundibular system
Mesocortical pathway

Question 2

Where are each of these pathways found?

Answer 2

Nigrostriatal– projecting from the substantia nigra pars compacta to the striatum
Mesolimbic– projecting from the ventral tegmental area to the nucleus accumbens, frontal cortex, limbic cortex and olfactory tubercle
Tuburoinfundibular system– projecting from the arcuate nucleus in the hypothalamus to the median eminence and pituitary gland
Mesocortical- VTA to cerebrum

Question 3

What are the roles of these pathways?

Answer 3

Nigrostriatal – control of movement
Mesolimbic – involved in emotion
Tuburoinfundibular system – regulate hormone secretion
Mesocortical- executive functions and complex behavioural patterns

Question 4

What are the two families of dopamine receptors and which receptors fall into each of these families?

Answer 4

D1 family – D1 + D5

D2 family – D2, D3 + D4

Question 5

Describe dopamine synthesis.

Answer 5

Tyrosine is converted by tyrosine hydroxylase to L-DOPA

DOPA is converted by DOPA decarboxylase to Dopamine

Question 6

Is Parkinson’s disease more common in males or females?

Answer 6

Males – 4:1

Question 7

What are the possible causes of idiopathic Parkinson’s disease?

Answer 7

Possibly a combination of environmental, oxidative stress, altered protein metabolism and risk genes

Question 8

What are the cardinal signs of Parkinson’ disease?

Answer 8

Resting tremor (pill-rolling tremor)
Rigidity (stiffness – limbs feel weak and heavy)
Bradykinesia (slowness of movement)
Postural abnormality

Question 9

What are the presenting symptoms of Parkinson’s disease?

Answer 9

Pill-rolling resting tremor
Difficulty with fine movements (micrographia)
Poverty of blinking
Hypomimic face
Monotony of speech and loss of volume of voice
Disorders of posture – flexion of the neck and trunk
Lack of arm swing
Loss of balance – lack of righting reflex, retropulsion
Short steps, shuffling gait

Question 10

Describe the initial distribution of symptoms across the body.

Answer 10

Unilateral onset
Symptoms spread to both sides
Generally symptoms worsen with some patients becoming severely disabled

Question 11

What are some non-motor symptoms of Parkinson’s disease?

Answer 11

Depression  
Pain  
Taste/smell disturbances  
Cognitive decline/dementia  
Autonomic dysfunction (constipation, postural hypotension, urinary frequency/urgency, impotence, increased sweating)

Question 12

What is the main area of the brain that is affected by Parkinson’s disease?

Answer 12

Substantia nigra

Question 13

Describe the neuropathology of Parkinson’s disease.

Answer 13

There is a severe loss of dopaminergic projection cells in substantia nigra. Lewy bodies and neurites are found in these cell bodies and axons.

Question 14

What are the stages of Parkinson’s disease?

Answer 14

1-2 = dorsal motor nucleus of vagus, raphe nucleus, locus coeruleus  
3 = substantia nigra pars compacta  
4 = amygdala, nucleus of Meynert, hippocampus  
5-6 = cingulate cortex, temporal cortex, frontal cortex, parietal cortex, occipital cortex

Question 15

What is the main biochemical change seen in Parkinson’s disease?

Answer 15

Marked reduction in the caudate nucleus/putamen dopamine content

Question 16

What proportion of dopaminergic neurones of the nigrostriatal dopaminergic pathway must be lost before symptoms occur?

Answer 16

80-85% of dopaminergic neurones and 70% of striatal dopamine must be depleted before symptoms appear

Question 17

What is the reason for this?

Answer 17

There are compensatory mechanisms e.g. neurone overactivity and increase in dopamine receptors

Question 18

What other type of drug has to be given with L-DOPA in dopamine replacement therapy and why?

Answer 18

Peripheral DOPA decarboxylase inhibitor

This prevents the conversion of L-DOPA to dopamine by peripheral DOPA decarboxylase (this can cause nausea and vomiting)

Question 19

State two different preparation of dopamine replacement therapy.

Answer 19

Carbodopa + L-DOPA Benserazide + L-DOPA

Question 20

What symptoms does L-DOPA treat?

Answer 20

Hypokinesia
Tremor
Rigidity

Question 21

What are the acute side effects of L-DOPA?

Answer 21

Nausea (prevented by domperidone)  
Hypotension 
Psychological effects (schizophrenia like syndrome with dellusions, hallucinations, confusion, disorientation and nightmares)

Question 22

What are the chronic side effects of L-DOPA?

Answer 22

Dyskinesias (abnormal movement of limbs and face – can occur within 2 years of treatment – disappear with reduced dose)
Rapid fluctuations in clinical state (off periods may last for minutes to hours

Question 23

Name 2 dopamine agonists.

Answer 23

Bromocriptine

Pergolide

Question 24

Which receptors does bromocriptine act on?

Answer 24

D2 receptor

Question 25

What are the benefits of dopamine agonists over L-DOPA?

Answer 25

``` Longer duration of action Smoother and more sustained response Actions independent of dopaminergic neurones Incidence of dyskinesias is less NOTE: L-DOPA is still the gold standard ```

Question 26

What are the adverse effects of dopamine agonists?

Answer 26

Common – confusion, dizziness, nausea/vomiting, hallucinations Rare – constipation, headache, dyskinesia

Question 27

What structure used to be present in older dopamine agonists that caused quite serious clinical problems?

Answer 27

Ergot ring | This caused fibrosis of heart valves

Question 28

What has been the consequence of the removal of this structure within dopamine agonists?

Answer 28

Development of addictive behaviour e.g. gambling

Question 29

Name two MAO inhibitors.

Answer 29

Deprenyl | Rasagiline

Question 30

What are the effects of Deprenyl?

Answer 30

Selective for MAO-B (this predominates in dopaminergic areas of CNS) Does NOT have the peripheral side effects of non-selective MAO inhibitors Can be given in combination with L-DOPA (reduce dose of L-DOPA by 30-50%)

Question 31

Name two COMT inhibitors.

Answer 31

Tolocapone (CNS + PNS) | Entacapone (PNS)

Question 32

What are the effects of COMT inhibition in the CNS?

Answer 32

Prevents breakdown of dopamine in the brain

Question 33

What are the side effects of COMT inhibitors?

Answer 33

Cardiovascular complications

Question 34

What are the symptoms of schizophrenia?

Answer 34

Positive Symptoms (overt symptoms that should NOT be present)  Hallucinations  Delusions  Disorganised thoughts Negative Symptoms (lack of characteristics that SHOULD be present)  Reduced speech  Lack of emotional and facial expression  Diminished ability to begin and sustain activity  Decreased ability to find pleasure in everyday life  Social withdrawal Cognitive deficits  Memory  Attention  Planning  Decision making

Question 35

What appears to have quite a strong contribution to the development of schizophrenia?

Answer 35

Genetics

Question 36

Once schizophrenia has been diagnosed, what are the four main outcomes for patients?

Answer 36

1 – illness resolves completely, with or without treatment and never returns (10-20%) 2 – illness recurs repeatedly with full recovery between episodes (30-35%) 3 – illness recurs repeatedly with incomplete recovery and a persistent defective state develops, becoming more profound with each successive relapse (30-35%) 4 – illness pursues down a downhill course from the beginning (10-20%) NOTE: most cases are relapsing and remitting

Question 37

Describe the involvement of dopamine in schizophrenia.

Answer 37

Positive symptoms – results from excessive dopamine transmission in the mesolimbic and striatal region (D2-mediated) Negative symptoms – results from dopamine deficit in the pre-frontal region (D1-mediated)

Question 38

What evidence has arisen that supports this hypothesis?

Answer 38

Dopamine agonists can induce various psychotic reactions | Typical antipsychotics are dopamine receptor antagonists (blocking D2 receptors)

Question 39

Describe the involvement of glutamate in schizophrenia.

Answer 39

NMDA is a glutamate receptor Glutamate exerts an excitatory influence over the GABA-ergic striatal neurones and dopamine exerts an inhibitory influence These GABA-ergic striatal neurones project to the thalamus and constitute a sensory ‘gate’ Too little glutamate or too much dopamine disables this gate, allowing uninhibited sensory input to reach the cortex NOTE: you find reduced glutamate concentration and reduced glutamate receptors in post-mortem schizophrenic brains. Also NMDA receptor antagonists can produce psychotic symptoms

Question 40

What are all the susceptibility genes for schizophrenia associated with?

Answer 40

Dopamine and glutamate neurotransmission

Question 41

What type of drug are all neuroleptics?

Answer 41

Dopamine receptor antagonists (D2 receptors) | NOTE: most neuroleptics block other receptors

Question 42

Which symptoms do neuroleptic drugs treat?

Answer 42

Positive symptoms ONLY

Question 43

What are the initial effects of neuroleptic drugs?

Answer 43

Initial increase in dopamine synthesis and neuronal activity – this declines with time

Question 44

What is meant by an atypical antipsychotic?

Answer 44

Newer antipsychotics are given this term – they have fewer extrapyramidal side effects

Question 45

Name an atypical antipsychotic.

Answer 45

Clozapine- potent antagonist of 5-HT2a

Question 46

Name a typical antipsychotic.

Answer 46

Haloperidol- potent D2 antagonist

Question 47

What is an important other action of neuroleptics?

Answer 47

Anti-emetic Because they block dopamine receptors in the chemotactic trigger zone Phenothiazine is a neuroleptic that is really good at preventingnausea/vomiting caused by drugs NOTE: many neuroleptics also block histamine receptors – this is effective at controlling motion sickness

Question 48

What are the extrapyramidal side effects of antipsychotics caused by?

Answer 48

Blockade of dopamine receptors in the nigrostriatal system can induce Parkinson-like side effects

Question 49

How is dopamine metabolised

Answer 49

Removed from synaptic cleft by dopamine transporter and noradrenaline transporter then metabolised by 3 enzymes; MAO-A MAO-B COMT

Question 50

Selectivity of dopamine metabolising enzymes

Answer 50

MAO-A metabolises DA, NE and serotonin MAO-B metabolises just DA COMT metabolises all catecholamines

Question 51

What are lewy bodies and neurites made of

Answer 51

Consist of the abnormally phosphorylated neurolfilaments ubiquitin and alpha-synuclein

Question 52

What are examples of COMT inhibitors

Answer 52

Entacapone | Tolcapone

Question 53

What age do people generally have symptoms of schizophrenia beginning

Answer 53

15-35

Question 54

Life expectancy of schizophrenia patients

Answer 54

20-30 lower than normal

Question 55

Where is there a higher incidence of schizophrenia

Answer 55

Immigrants

Question 56

What tends to cause positive symptoms of schizophrenia

Answer 56

Increased mesolimbic dopaminergic activity

Question 57

What tends to cause negative symptoms of schizophrenia

Answer 57

Decreased mesocortical dopaminergic symptoms

Question 58

MOA of chlorpromazine

Answer 58

D2 receptor antagonist

Question 59

2 first generation antipsycotics

Answer 59

Chlorpromazine | Haloperldol

Question 60

4 second generation antipsycotic

Answer 60

Clozapine Risperidone Quetiapine Aripiprazole

Question 61

What is risperidone

Answer 61

Potent antagonist of 5-HT2a and d2

Question 62

What is quetiapine

Answer 62

Potent antagonist of H1 receptors

Question 63

What is aripiprazole

Answer 63

Partial agonist of D2 and 5-HT1a- affects reduced mesocortical

Question 64

Which antipyscotic drug is associated with neutropenia and agranulocytosis

Answer 64

Clozapine