5. Parkinsons

Question 1

whats effected in parkinons?

Answer 1

degeneration of cells in the substantia nigra decreases dopaminergic input to putamen. less excitation of direct and inhibition of indirect –> decreased thalamic drive –> bradykinesia. The indirect pathway is less effected to movement inhibition is stronger.

Question 2

whats effected in huntingtons?

Answer 2

decreased local inhibition causes increased dopamine activity leading to early degeneration of striatal cells. More inhibitory output from the GPe causes more drive of thalamus and hyperkinesia

Question 3

electrical activity in parkinsons

Answer 3

BG becomes arrhythmic and bursty. falling out of rhythm with the cortex causes it to have less ability to effect cortex.

Question 4

parkinsons symptoms

Answer 4

-hypokinesia/bradykinesia -rigidity -micrographia -tremor -reduced facial expression

Question 5

BG structures

Answer 5

-striatum (caudate nucleus and putamen striped by insula) -globus pallidus interna/externa -substantia nigra pars compacta/reticulata -sub thalamic nuscleus

Question 6

BG involved in functions:

Answer 6

motor, ocumolotor, emotional and executive - different parts of BG in each

Question 7

D1 receptors

Answer 7

direct pathway - excitatory

Question 8

D2 receptors

Answer 8

indirect pathway - inhibitory

Question 9

Striatal neurons:

Answer 9

spiny and gabaergic - receives glutamatergic and dopaminergic input from the cortex - also local gaba and ACh striatal interneuronal input -

Question 10

SN output from the

Answer 10

Pars compacta

Question 11

Parkinsons model primates

Answer 11

MTPT in primates (MOAb broken down to MPP+ which is selectively taken up by SN cells to which it is toxic)

Question 12

Parkinsons model rodents

Answer 12

They don’t make enough MPP+ so instead we use 6 hydroxydopamine -
Or 6-OHDA (relatively selective
catecholaminergic neurotoxin): taken up by NA and D transporters so NET blocked. Causes bilateral lesion and symmetrical bradykinesia. Channel rhodopsin and laser light used to stimulate direct pathway.

Question 13

Levadopa action:

Answer 13

broken down by dopamine decarboxylase to dopamine

Question 14

admin alongside L dopa:

Answer 14

MOA inhibitors, DDC inhibitors (periphery only), COMT inhibitors

Question 15

MAO inhibitors with L dopa

Answer 15

prevent dopamine breakdown in the CNS -selegilline (caused hyperness as metabolisee dto amphetamine) and rasagilline

Question 16

COMT inhibitors

Answer 16

in periphery entacapone and tolcapone. Tolcaopne can pass BBB.

Question 17

DDC inhibitors

Answer 17

carbidopa and benserazide (periphery only)

Question 18

Side effects of L dopa:

Answer 18

1. peripheral actions and dyskinesia after a couple years - difficulty in dosing
2. on/off effects - low half life causes some symptoms such as hypokinesia to reappear until next meds are taken
3. nausea - counteracted by domperidone on the area postrema
4. postural hypotension due to bad posture
5. psychological symptoms like delusions and hallucinations, more commonly insomnia nightmares and confusion

Question 19

Dopamine agonists:

Answer 19

-bromocriptine/pergolide

-amantadine
-pramipexole and ropinirole
antimuscarics

Question 20

pramipexole and ropinirole

Answer 20

-act more at D2/3 and have longer half life than Ldopa. however compulsive gambling and hypersexuality

Question 21

-bromocriptine/pergolide

Answer 21

• oral admin but nausea and vomiting limits their use and compliance

Question 22

Amantadine

Answer 22

viral infection drug but works on parkinsons

Question 23

Antimuscarinics

Answer 23

ACh can decrease dopamine release so inhibiting it can help. But many antimuscarinc side effects

Question 24

Other parkinsons treatments

Answer 24

deep brain stimulation (dangerous) sets a rhytmic pattern of firing. transplants w stem cells. Ablation of globus pallidus interna or subthalamic nucleus

Question 25

Huntingtons:

genes, prevalance, age

Answer 25

dominant inherited autosomal condition. emergeds around 30/40 and death follows 15/20yrs later. 5-10/100,000 have it.

Question 26

Huntingtons causes

Answer 26

hyperkinesia, chorea and dementia

Question 27

Huntingotns neurodegen caused by

Answer 27

decreased local inhibition and increased dopamine activity causes neurodegen of striatal neurons and less indirect inhibition and more thalamic drive

Question 28

Huntingtons drugs

Answer 28

tetrabenzine, chorpromazine, haloperidol, respiradone, olanazpine and quetiapine

Question 29

haloperidol

Answer 29

for chorea in huntingtons

Question 30

respiradone

Answer 30

for chorea in huntingtons

Question 31

olanazpine

Answer 31

for chorea in huntingtons

Question 32

quetiapine

Answer 32

for chorea in huntingtons

Question 33

Tertrabenzine

Answer 33

inhibitor of VMAT (vesicular monoamine uptake - packaging of dopamine into vesicles)

Question 34

Chorpromazine

Answer 34

dopamine antagonist usually used as an antipsychotic

Question 35

therapeutic stats effectiveness of l-dopa

Answer 35

80% have improvement. 20% fully recover. 30% still improving after 5 years.