35 - Regulating Dopamine Levels

Question 1

Effect of dopamine in the extrapyramidal motor system

Answer 1

Dopamine (released from the substantia nigra) tonically inhibits acetylcholine (released from the corpus striatum).

Question 2

How long has L-DOPA been prescribed for?

Answer 2

~50 years

Question 3

Motor signs and symptoms of Parkinson’s disease

1 - 7

Answer 3

• Tremor
• Rigidity of limbs
• Bradykinesia
• Impairment of postural reflexes
• Facial
– Impassive, no blinking
• Speech
– Monotonous, hypophonic
• Movement
– Decreased manual dexterity

Question 4

Basic cause of Parkinson’s disease

Answer 4

Dopaminergic cell death (cause of death not known)

Question 5

Non-motor features of Parkinson’s

1 - 9

Answer 5

• Cognitive deficiencies
• Depression
• Raised anxiety levels
• Olfactory deficiencies
• Sleep disturbances
• Fatigue
• Pain
• Bowel & bladder problems
• Sexual dysfunction

Question 6

First sense often affected with Parkinson’s

Answer 6

Smell

Question 7

Proportion of dopaminergic neurons that need to die before Parkinson’s symptoms manifest

Answer 7

~80%

Question 8

Usual age of onset of Parkinson’s

Answer 8

~50 years of age

Question 9

Why might dopaminergic neurons be susceptible to death in Parkinson’s

Answer 9

Dopamine production requires Fe2+ to Fe3+ oxidation generates ROS.

Doesn’t explain why not everyone gets Parkinson’s

Question 10

Proteins shown to be involved in Parkinson’s

Answer 10

Alpha-synuclein (not broken down, accumulates, or misfolds)

Parkin

Question 11

Management of Parkinson’s
1
2
3

Answer 11

1) Palliative, not curative
2) Restore dopamine deficiency
– Increase DA synthesis
– Increase DA release
– DA receptor agonists
– Reduce DA metabolism
3) Restore dopaminergic / cholinergic
balance in striatum.
– Cholinergic antagonists

Question 12

Biosynthesis of dopamine

Answer 12

Tyrosine converted to L-DOPA by tyrosine hydroxylase.

L-DOPA to dopamine by L-DOPA decarboxylase.

Question 13

Why can’t people with Parkinson’s be given dopamine?

Answer 13

Doesn’t cross blood brain barrier.

If ingest dopamine, vomit.

Question 14

Which enzymes degrade dopamine?

Answer 14

MAO, COMT

Question 15

Amount of L-DOPA (Levodopa) metabolised in the periphery

Answer 15

~90%

Question 16

Formulation that can increase dopamine levels in Parkinson’s patients

Answer 16

L-DOPA + a peripheral dopamine decarboxylase inhibitor (EG carbidopa or benserazide).
Because over 90% of L-DOPA is metabolised in the periphery.

Question 17

Issue with prescribing L-DOPA treatment

Answer 17

Reduces symptoms, but accelerates pathology with most people.

Question 18

Common side-effect of L-DOPA treatment

Answer 18

Severe addictions.

Alterations to dopamine pathway (reward)

Question 19

Levodopa

Answer 19

– Reduces rigidity, tremors and other symptoms
– Considered first line treatment
– Fluctuations in motor control
• “on-off” phenomenon
– Tremors, cramps, immobility
– Rapid absorption on empty stomach
• Competition with other neutral amino acids (Leu,
IsoLeu)
• Short half-life (1-2 hrs)
– variable plasma concentration
– Effectiveness declines with time
• Continued degeneration of dopaminergic nerves
• Increase dose or incorporate other drugs

Question 20

Adverse effects of levodopa

Answer 20

• Peripheral
– Anorexia, nausea & vomiting
– Tachycardia & ventricular dysrhythmias
– Orthostatic hypotension
– Pupil dilation (avoid in patients with glaucoma)
• Central
– Visual & auditory hallucinations, abnormal motor
movements
– Mood changes, depression, anxiety

Question 21

Dopamine agonists

Answer 21

Bromocriptine, carbergoline.

Question 22

Drawbacks of dopamine agonists

Answer 22

L-DOPA only metabolised by neurons in substantia nigra.

Dopamine agonists stimulate dopamine receptors throughout brain.

Question 23

Advantage of dopamine agonists

Answer 23

Don’t accelerate pathology like L-DOPA does

Question 24

Side effects of dopamine agonists

Answer 24

– Similar to L-Dopa but hallucinations, confusion,
delirium, nausea and hypotension more common
– Dyskinesias less prominent
– Arrhythmias, myocardial infarction

Question 25

Selegiline

Answer 25

MAOb inhibitor.

Reduces dopamine inactivation

Question 26

COMT inhibitors

Answer 26

Reduce degradation of dopamine.

Used as an adjunct to L-DOPA

Question 27

Why can muscarinic antagoinsts used for Parkinson’s?

Answer 27

Prevents ACh stimulation of GABAnergic neurons