Parkinsons Flashcards
How is dopamine made
tyrosine -> tyrosine hydroxylase and dopa decarboxylase
How is dopamine metabolised
MAO-B in synaptic terminal
How is Dopamine put into vescicles
VMAT
How is dopamine reuptake into the presynaptic terminal
DAT- dopamine/Na symporter (sodium in)
What are the 2 types of dopamine receptors
D1 and D2 like
all GPCRs
D1 -> GaS to incr. cAMP by adenylyl cyclase
PKA phosphorylates which inhibits proteins (DARP32) which dephosphorylate other proteins
EXCITATORY - mostly post synaptically
D2 like -> Gai/o decr. cAMP
the BY subunits open K+ channels and inhibit Voltage-gated Ca2+ channels. Hyperpolarisation = decreased excitation
INHIBITORY - post and pre synaptic
what are some agonists of the dopamine receptors
dopamine
bromocriptine (non-selective)
apomorphine (n-s)
cabergoline/pergolide (D2 more than D1)
Ropinirole (D2 selective)
Aripiprazole (Partial agonist D2 like)
what are some antagonists of the dopamine receptors
Haloperidol
sulpiride
domperidone
metoclopramide
What is the nigrostriatal pathway
where most dopamine is located
control movement (parkinsons)
What is the mesolimbic pathway
behavioural + rewards pathway
schizophrenia (+ve)
drugs of abuse
what is the Mesocortical pathway
Cognition and thoughts
Schizophrenia (-ve)
What is the tuberohypopheseal pathway
controls secretion of hormones from pituitary
DA inhibits prolactin
Where are D1 most expressed
Most expressed dopamine receptors
High density in mesolimbic and nigrostriatal
Where are D2 receptors most expressed
Nigrostriatal, mesolimbic, tuberohypopheseal pathway (controls prolactin), and CTZ (medulla) - vomiting (antiemetics)
what is parkinsons
loss of dopaminergic neurones in nigrostriatal pathway
aggregations - lewy bodies
What are the pathways in the nigrostriatal pathway.
explain effects of dopamine.
What is lost in PD?
Indirect - inhibits
direct- allows movement
DA + direct = excitatory as D1
DA + indirect = inhibitory D2
Dopaminergic neurones between the SN (substantia nigra)
and striatum lost in PD
what does dopamine do to cholinergic pathways in striatum
dopamine inhibits ACh release in striatum
Lack of dopamine in PD means ACh unopposed - hyperactivity of cholinergic synapses -> tremor
What are Lewy bodies
Misfolding leads to aggregation and plaque forming
Removal via proteosomal pathways reduced in PD
death of dopaminergic neurones
how does mitochondrial damage play a role in PD
dopaminergic neurones req. lots of energy
damage to mitochondria-
*chemicals that induce PD also cause mitochondrial stress and dysfunction
*Parkin and PINK1 (mutated leads to PD) involved in Mitochondrial turn over- mutation = cells aren’t recycled
*Mitochondrial damage leads to death of dopaminergic neurones
*Generates Oxidative stress
*
Levodopa- explain how it helps PD
Loss of dopaminergic neurones in PD therefore this compensates
Crosses BBB- broken down by dopadecarboxylase to dopamine
Given with a peripheral Dopa-decarboxylase inhibitor (Carbidopa/ benserazide) as cant cross BBB- stops dopamine in periphery - more dopamine in brain, prevents side effects of dopamine in periphery
Can also be broken down by catachol-o-methyl transferase (COMT) can be inhibited by entacapone
Increases levodopa to cross BBB.
Dopamine can then work at D1 and D2 like pathways in nigrostriatal pathways for therapeutic effects.
What drugs are used to limit the metabolism of dopamine in the Brain to extend therapeutic effect
Selegiline
Rasagiline
= MAO-B inhibitors
less metabolism via MAO-B
How do dopamine agonists help PD
Directly stimulate dopamine receptors - pramipexole, ropinirole, rotigotine = more D2
Bromocriptine and apomorphine less selective therefore more s/e
