Regulating dopamine levels Flashcards
Describe the structure/pathway of the extrapyramidal motor system?
Three NTs: Ach (excitatory input), DA (tonic inhibition) and GABA
Involves substantia nigra, corpus striatum, cortex and spinal cord
Output to skeletal muscle
Which three NTs are important for motor coordination?
Ach
GABA
DA
Describe the motor signs and symptoms of Parkinson’s disease?
Tremor
Rigidity
Bradykinesia
Impaired postural reflexes
Facial: impassive, no blinking
Monotonous, hypophonic speech
Decreased dexterity
What is PD?
Multisystem neurological disorder which affects cognitive processes, emotion and autonomic function
Why are the effects of PD so widespread throughout the body?
Pathology affects the whiole brain > affects the whole individual
Describe the non-motor signs and symptoms of PD?
Cognitive deficiencies
Depression
Increased anxiety
Olfactory deficiencies
Sleep disturbance
Fatigue
Pain
Bowle and bladder problems
Sexual dysfunction
Which are the first symptoms of PD to appear?
Olfactory deficiencies
Bowel and bladder problems
Which part of the brain degenerates in PD?
Dopaminergic nerves in substantia nigra > decreased DA levels
Describe the extent of degeneration of dopaminergic neurons when symptoms of PD begin to appear?
When you start expressing motor symptoms, about 80% of the dopaminergic neurons in the substantia nigra are already dead
Which signal transduction pathway is involved in PD?
Various signal transduction mechanisms to deal with Parkinson’s
Very complex
Describe the pattern of degradation of dopaminergic neurons in PD?
Asymmetric
How is PD managed?
No therapeutic cure
Medication > palliative, symptomatic relief
Describe the rationale behind drug treatment for PD?
Restore DA deficiency:
Increase DA synthesis or release
DA receptor agonists
Reduce DA metabolism
Restore dopaminergic/cholinergic balance in striatum:
Cholinergic antagonists
Why can’t PD just be treated by injecting or orally taking DA?
DA does not cross blood brain barrier
Makes patients violently ill
Which drug can be used to increase dopamin synthesis?
How does it work?
Levodopa
L-Dopa + Peripheral DDC inhibitor > prevents metabolism
What does levodopa require in order to work?
Why is this a problem?
Some functional dopaminergic neurons (need to convert it into dopamine)
Problem because once you flood the system with DA, degeneration of dopaminergic neurons increases
Describe the outcome of treatment with levodopa?
Reduces rigidity, tremors and other symptoms
What is the first line treatment for PD?
Levodopa
What are the disadvantages of levodopa?
Rapid absorption on empty stomach > short half-life (1-2 hours) > patients must constantly medicate, and work out themselves when they need it > may overdose
Effectiveness declines over time
Why does the effectiveness of levodopa decline over time?
Continued degeneration of dopaminergic nerves
What is the result of overdosin on levodopa?
Dyskinesias
Describe the adverse effects of levodopa?
PERIPHERAL
Anorexia, nausea and vomiting
Tachycardia and ventricular dysrhythmias
Orthostatic hypotension
Pupil dilation
CENTRAL
Hallucinations
Abnormal motor movements
Mood changes, depression, anxiety
Why are there so many adverse effects associated with levodopa?
Giving extra DA to areas that don’t need it
Which dopamine agonists are used in treatment of PD?
How are they used?
Bromocriptine, cabergoline, pergolide
Bromocriptine and cabergoline: monotherapy
Pergolide: only as adjunct to L-Dopa
How does entacapone act in the treatment of PD?
Blocks COMT > reduces metabolism of L-Dopa
How does selegiline act in the treatment of PD?
MAOb inhibitor > reduces metabolism of DA
Which drugs can be used to restore the dopaminergic-cholinergic imbalance in PD?
MuscR antagonists
What is the alternative treatment to medication in PD?
Deep brain stimulation
Stimulate substantia nigra
Describe the role of a-synuclein in PD?
How are mitochondria implicated in PD?
What is the average age of onset of PD?
60
Age is largest risk factor
What is the largest risk factor for PD?
Ageing
Weakens mitochondria and reduces neurons’ ability to dispose of a-synuclein aggregates
