Parkinsons

Question 1

How is dopamine made

Answer 1

tyrosine -> tyrosine hydroxylase and dopa decarboxylase

Question 2

How is dopamine metabolised

Answer 2

MAO-B in synaptic terminal

Question 3

How is Dopamine put into vescicles

Answer 3

VMAT

Question 4

How is dopamine reuptake into the presynaptic terminal

Answer 4

DAT- dopamine/Na symporter (sodium in)

Question 5

What are the 2 types of dopamine receptors

Answer 5

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

Question 6

what are some agonists of the dopamine receptors

Answer 6

dopamine
bromocriptine (non-selective)
apomorphine (n-s)
cabergoline/pergolide (D2 more than D1)
Ropinirole (D2 selective)
Aripiprazole (Partial agonist D2 like)

Question 7

what are some antagonists of the dopamine receptors

Answer 7

Haloperidol
sulpiride
domperidone
metoclopramide

Question 8

What is the nigrostriatal pathway

Answer 8

where most dopamine is located
control movement (parkinsons)

Question 9

What is the mesolimbic pathway

Answer 9

behavioural + rewards pathway
schizophrenia (+ve)
drugs of abuse

Question 10

what is the Mesocortical pathway

Answer 10

Cognition and thoughts
Schizophrenia (-ve)

Question 11

What is the tuberohypopheseal pathway

Answer 11

controls secretion of hormones from pituitary
DA inhibits prolactin

Question 12

Where are D1 most expressed

Answer 12

Most expressed dopamine receptors
High density in mesolimbic and nigrostriatal

Question 13

Where are D2 receptors most expressed

Answer 13

Nigrostriatal, mesolimbic, tuberohypopheseal pathway (controls prolactin), and CTZ (medulla) - vomiting (antiemetics)

Question 14

what is parkinsons

Answer 14

loss of dopaminergic neurones in nigrostriatal pathway
aggregations - lewy bodies

Question 15

What are the pathways in the nigrostriatal pathway.
explain effects of dopamine.
What is lost in PD?

Answer 15

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

Question 16

what does dopamine do to cholinergic pathways in striatum

Answer 16

dopamine inhibits ACh release in striatum
Lack of dopamine in PD means ACh unopposed - hyperactivity of cholinergic synapses -> tremor

Question 17

What are Lewy bodies

Answer 17

Misfolding leads to aggregation and plaque forming
Removal via proteosomal pathways reduced in PD
death of dopaminergic neurones

Question 18

how does mitochondrial damage play a role in PD

Answer 18

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
*

Question 19

Levodopa- explain how it helps PD

Answer 19

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.

Question 20

What drugs are used to limit the metabolism of dopamine in the Brain to extend therapeutic effect

Answer 20

Selegiline
Rasagiline
= MAO-B inhibitors
less metabolism via MAO-B

Question 21

How do dopamine agonists help PD

Answer 21

Directly stimulate dopamine receptors - pramipexole, ropinirole, rotigotine = more D2

Bromocriptine and apomorphine less selective therefore more s/e