Pharmacology of basal ganglia disease Flashcards
What is the nigrostriatal pathway?
Controlled by Dopamine neurons
Substantia nigra releases DA, which causes the initiation of movements
How does Parkinson’s arise?
Neurodegeneration of DAergic neurons in the nigrostriatal pathway
- means much less DA in the striatum and causes
- DA usually inhibits GABA, however a loss of DA means that there is overactivity of GABAergic inhibitory neurons, inhibiting thalamic relay –> difficulty initiating and stopping movement
- progresses over 5-10 years
What are the main symptoms of Parkinson’s?
Cogwheel rigidity, tremor and bradykinesia
What is Huntingdon’s disease?
- Autosomal dominant disorder
- caused by a loss of GABAergic neurons
- get hyperkinesia (jerky movements)
What are the Braak stages?
They are 6 stages of PD
- 1+2 = early degeneration, sleep and olfaction disturbances
- 3+4 = loss of 50-80% of Nigrostriatal neurons –> motor symptoms
- 5+6 = presence of Lewy bodies, emergence of psychiatric symptoms (due to compensatory activation of D1 and D2 receptors –> dementia)
What is a DaT scan?
Uses single-photon emission tomography (SPECT) and a contrast agent to highlight Dopamine transporters
What causes the hypo/bradykinesia of PD?
Increased activity of GABAergic neurons in the globus pallidus - due to decreased inhibition by Dopamine.
This gives decreased activation of cortical motor areas and so difficulty initiating movements.
What causes the tremor/rigidity of PD?
A complex disturbance of other NT systems such as NA, ACh, 5-HT and GABA.
- Cholinergic neurons are usually inhibited by DA in the striatum, therefore a lack of it will cause hyperactivity (tremor)
What causes the psychiatric changes in PD?
Pathological brain changes in later stages
- mutations of the alpha-synuclein gene leads to its misfolding, causing aggregates called Lewy bodies.
What was found in California to cause a increased prevalence of PD?
Heroin addicts
- MPTP (a metabolite of heroin) can get into neurons via DA transporters - this leads to the degeneration of the nigrostriatal tract
- MPTP is metabolised by MAOb to MPP++ (toxic)
- Causes mitochondria to produce free radicals, causing damage to the cell membrane, increasing oxidative stress
What are the main causes of PD?
- Environmental - pesticides -> mitochondrial damage –> free radicals
- Genetics
o Mutations of alpha-synuclein –> Lewy bodies
o Mutations of parkin gene
o Mutation of mitochondrial proteins - Oxidative stress, neuroinflammation
- Antipsychotics – block DA receptors in striatum at same time
5 ways to treat PD
- Block DA reuptake (cocaine)
- D2 receptor agonists
- Increase DA release
- MAOIs - stop DA breakdown
- L- DOPA
Why can you not give L-DOPA on its own?
- Have to give it with a Dopa decarboxylase inhibitor
- DC converts L-DOPA into DA
- DC is also found in the periphery so will cause peripheral side effects of increased DA in the periphery
- With an inhibitor, L-DOPA can pass through the BBB and get converted there. (DC inhibitor cannot pass through)
What are some side effects of L-DOPA?
Increases DA throughout the whole brain
- increases DA in mesolimbic pathway - causes Sz
- increases DA in nucleus accumbens - causes hypersenstivity of reward system so they can become addicted to things much easier
- increases DA in the chemoreceptor trigger zone in the area postrema - causes vomiting
What happens to the patient through long-term use of L-DOPA?
- akinesia (inability to initiate movement)
- Dyskinesia (sustained muscle contraction)
- as neurons continue to die, the patient can become dependent on LDOPA for the DA needed for their movement.
- Get on and off periods - off = poor movement when L-DOPA dose is coming to the end
- causes rapid oscillations in motility
