Pharmacology CNS Parkinson's

Question 1

What type of neurotransmitter is dopamine?

Answer 1

Catecholamine neurotransmitter

Question 2

How is dopamine synthesised?

Answer 2

Synthesised from the precursor tyrosine hydroxylase (TH) and Dopa decarboxylase (DDC)

Question 3

How is dopamine metabolised?

Answer 3

By MAO-B in the pre-synaptic terminal
To make sure there are the right levels of dopamine in the pre-synaptic terminal
Also metabolised by COMT (Catechol-o-methyl transferase) in non-neuronal cells

Question 4

How is dopamine packaged and moved?

Answer 4

Packaged into vesicles via VMAT (vesicular monoamine transporter)

Question 5

Describe the uptake of dopamine in neuronal cells:

Answer 5

Re-uptake via the dopamine transporter DAT
A dopamine Na+ symporter, driven by extracellular Na+, Na+ moves in down its gradient, enables dopamine to be taken up its gradient

Question 6

Describe the uptake of dopamine in non-neuronal cells:

Answer 6

Taken up into non-neuronal cells via EMT (extra neuronal monoamine transporter) e.g in the glial cell
Metabolised by MAO-A and MAO-B and COMT

Question 7

Name and describe the different dopamine receptors:

Answer 7

All GPCRs
D1 like:
-D1 -D5
D2 like:
-D2 -D3 -D4

Question 8

How do D1 like receptors work?

Answer 8

Act via Gas to increase cAMP
PKA phosphorylates DARPP-32 which inhibits protein phosphatase-1 (PP1 normally dephosphorylates proteins, so inhibition of this enhances down stream effects)
Excitatory- mainly post synaptic

Question 9

How do D2 like receptors work?

Answer 9

Act via Gai/o to decrease cAMP by inhibiting AC
The beta/gamma subunits open K+ channels (K+ out so hyperpolarisation and decrease excitability in post synaptic) so inhibits VG Ca2+ channels (decreases Ca2+ in cell so pre synaptic inhibition)
Inhibitory- both pre and post synaptic

Question 10

Name and describe the dopamine receptor agonists:

Answer 10

Bromocriptine (non-selective)
Apomorphine (non-selective)
Cabergoline (More D2 than D1 but for both)
Pergolide (More D2 than D1 but for both)
*Pramipexole (D2 like selective)
*Ropinirole (D2 like selective)
*Aripiprazole (partial agonist at D2 like)
*newer, fewer SEs

Question 10

Name and describe the dopamine receptor antagonists:

Answer 10

Haloperidol (non-selective but acts at other receptors too)
Sulpiride (D2 like)
Domperidone (D2 like)
Metoclopramide (D2 like)

Question 11

Name the 4 different dopamine pathways:

Answer 11

Nigrostriatal
Mesolimbic
Mesocortical
Tuberohypophyseal (aka tuberoinfundibular)

Question 12

Describe the Nigrostriatal pathway:

Answer 12

75% of dopamine in the brain
Cell bodies in the substantia nigra (midbrain) projecting to the striatum
Control of movement
Parkinson’s disease (pathways are lost in this)

Question 13

Describe the mesolimbic pathway:

Answer 13

From midbrain to limbic
VTA (ventral tegmental area- midbrain) to limbic areas, notably the nucleus accumbens, hippocampus and amygdala
Behavioural reward pathway
Schizophrenia (mediating +ve symptoms)
Drugs of abuse (cocaine, amphetamine- addicting stimulating reward pathway)

Question 14

Descrie the mesocortical pathway:

Answer 14

From midbrain to cortex
VTA to frontal cortex (forebrain)
Cognition and thought
Schizophrenia (-ve symptoms)

Question 15

Describe the tuberhypophyseal pathway:

Answer 15

Hypothalamus to pituitary
Control of secretion
-dopamine inhibits prolactin secretion

Question 16

Describe D1 like receptor expression:

Answer 16

D1 receptors are the most abundant
Expressed at high density in the:
-nigrostriatial (caudate nucleus, putamen)
-mesolimbic (hippocampus, nucleus accumbens, amygdala)
-mesocortical pathways (cerebral cortex)
D5 expression more restricted distribution (limbic)-hippocampus

Question 17

Describe D2 like receptor expression:

Answer 17

D2 receptors highest density in nigrostriatial, mesolimbic and tuberhypophyseal (hypothalamus) pathways
Also in the CTZ- medulla(chemo receptor trigger zone)
D3 more restricted and weaker expression
D4 weaker expression

Question 18

Describe the major pathophysiology of Parkinson’s disease:

Answer 18

Loss of dopaminergic neurons in the nigrostriatial pathway:
-60-80% are lost before symptoms occur
Lewy bodies- aggregates affecting cell survival
Mitochondrial dysfunction

Question 19

What does a PET scan look like in a person with PD and why?

Answer 19

Loss of dopaminergic neurons in the NT pathway, fewer cell bodies in the SN up to stratum so smaller PET scan

Question 20

Describe what the midbrain looks like in a healthy vs PD patient and why?

Answer 20

Healthy midbrain has dark line in SN as cell bodies of dopaminergic neurons contain melanin so pigmented appearance
In PD midbrain, this dark colour is absent, as losing cell bodies and decrease in dopamine in synapses in stratum

Question 21

Name the 2 NT pathways that control movement:

Answer 21

2 pathways involving the basal ganglia:
-direct pathway (enables movement)
-indirect pathway (inhibits movement)

Question 22

How does dopamine promote movement in both NT pathways?

Answer 22

Dopamine control of direct and indirect pathways both lead to release of inhibition of excitatory relay neurons from thalamus to motor cortex, thus providing stimulatory input to the motor cortex

Question 23

Describe the direct NT pathway:

Answer 23

Dopamine release to D1, excitatory output, stimulate downstream neurone (inhibitory neurone)
Stimulating the inhibitory neurone which inhibits the next neurone from the PR to the thalamus so inhibits the inhibitory neurone so next neurone from thalamus is stimulated so stimulation of neurone to cortex causes movement

Question 24

Describe the indirect NT pathway:

Answer 24

Normally inhibits movement but we are inhibiting this inhibiton
Dopamine release to D2, inhibitory output, inhibit inhibitory neurone to globus palidus so next neurone is stimulated which is an inhibitory neurone in the STN (subthalamic nuclei), so inhibits the next excitatory neurone
Switches off in PR, switches off inhibitory neurone in the thalamus so switches on the excitatory neurone that goes to thalamus which causes movement

Question 25

What is the major symptom of PD and why?

Answer 25

Dopaminegric neurons between the SN and the striatum are lost in PD so no longer input so inhibits movement
Major symptom in PD is slow/ decreased movement= bradykinesia and difficulties in initiating movement

Question 26

Describe the cholinergic pathway in PD and how it leads to a symptom:

Answer 26

Cholingeric interneurons (release Ach involved in control of movement) are abundant in the striatum
Dopamine usually inhibits Ach release in the striatum
Lack of dopamine in PD leaves Ach unopposed
-hyperactivity of cholinergic synapses
Contributes to tremor

Question 27

What are Lewy bodies?

Answer 27

Intracellular aggregations of a-synuclein found in neuronal cells

Question 28

What is a-synuclein?

Answer 28

1% of protein in cytosol
A highly abundant neuronal protein at synapse involved in exocytosis of synaptic vesicles and vesicle recycling

Question 29

How does the mutation of a-synuclein cause PD?

Answer 29

Mis-folding of a-synuclein leads to aggregation and plaque formation
Removal of a-synuclein via proteosomal pathways is reduced in PD- allows to accumulate and thereofore more misfolding, aggregation and lewy bodies
Link with death of dopaminergic neurons
-mutation of a-synuclein causes early onset PD and there is in increase nº lB
-may directly cause cell death or affecting neurons

Question 30

Why does the mitochondria play an important role in PD?

Answer 30

Dopaminergic neurons require a lot of energy (more than other neurons) for their function
Damage to the mitochondria is believed to play an important role in the pathophysiology of the disease

Question 31

Name and describe ways how factors can cause mitochondrial damage and therefore PD:

Answer 31

Chemicals that induce PD (e.g roterione- pesticide, MPTP) cause mitochondrial stress and dysfunction
Mitochondrial damage leads to death of the dopaminergic neurons
Generation of oxidative stress
Secondary to this- excitatory, neuroinflammation, glia will try and help but chronic lead to neuronal cell death

Question 32

Describe a genetic factor contributing to mitochondrial damage and therefore PD:

Answer 32

Parkin and PINK1 (genes that when mutated lead to PD) involved in mitochondrial turnover- mutation means that damage mitochondria are not recycles leads to mitochondrial dysfunction

Question 33

Describe how Levodopa works in PD:

Answer 33

1st line
Precursor for dopamine

Question 34

Name 2 DDC (dopadecraboxylase) inhibitors:

Answer 34

Carbidopa
Benserazide

Question 35

How do DDC inhibitors work?

Answer 35

Always given with L-dopa
Peripheral DDC inhibitors to decrease SEs and increase L-dopa crossing the brain

Question 36

Name COMT inhibitors:

Answer 36

Entacapone
Tolcapone (rarely used)

Question 37

Describe how COMT inhibitors work:

Answer 37

Only works in the periphery
COMT metabolises L-dopa in periphery, COMTi decreases this so more L-dopa crossing BBB

Question 38

Name MOA-B inhibitors:

Answer 38

Selegiline
Rasagiline

Question 39

How do MAO-B inhibits work?

Answer 39

MAO-B metabolises dopamine
Inhibiting MAO-B means less metabolism of dopamine

Question 40

Name an add on therapy for PD:

Answer 40

Amantadine
NMDAr receptor antagonist

Question 41

Name mACHRs for PD:

Answer 41

Procyclidine
Orphenadrine
Trihexyphenidyl