Cholinergic Transmission

Question 1

Where is Ach present?

Answer 1

• Released by motor neurons and acts on skeletal muscle
• Present in parasympathetic nervous system through the vagus nerve, medulla and ganglion
• Present in the sympathetic nervous system through sympathetic ganglia in the spinal cord

Question 2

Which cholinergic systems exist in the brain?

Answer 2

• Interneurons within the striatum
• Basal forebrain, which innervates the cortex and hippocampus
• Dorsolateral pons which projects to the thalamus and spine

Question 3

What is the biochemistry of ACh transmission?

Answer 3

• Formed by the combination of choline and acetyl CoA by enzyme ChAT (choline acetyl transferase)
• Loaded into vesicle by vesicular ACh transporter (vAChT)
• Broken down in the synapse by AchE

Question 4

What determines the activity of ChAT?

Answer 4

• Precursor availability

- Neuronal firing

Question 5

What are the two functions of AChE?

Answer 5

• Presynaptic breakdown of excess ACh

- Postsynaptic activity to provide spatial and temporal precision

Question 6

What is physostigmine?

Answer 6

AChE blocker capable of crossing BBB, can induce hallucinations, coma and death

Question 7

What is prostigmin?

Answer 7

AChE blocker which cannot cross the BBB, used to treat myasthenia gravis: an autoimmune disorder which targets nicotinic receptors causing excess ACh in the synapse

Question 8

What are sarin and soman?

Answer 8

AChE blockers which can cross BBB and cause death through diaphragm paralysis, pyrisdotigmine may act as antidote (competitive reversible AChE blocker) however must be taken beforehand

Question 9

What is the function of the choline transporter? What is it’s blocker?

Answer 9

• Sustains Ach synthesis through the recylcing of choline

- Blocker is hemicholinium-3 (HC-3) which prevents presynaptic reuptake of choline

Question 10

What are the 2 types of nicotinic receptors?

Answer 10

N1 - signalling at neuromuscular junctions

N2 - central nervous system

Question 11

What are the 5 types of muscarinic receptors?

Answer 11

M1 - found in cortex and hippocampus
M2 - found in heart, forebrain and spinal cord
M3 - brain, arteries and pupis
M4 - striatum, cortex, hippocampus and spinal cord
M5- brain vasculature, basal ganglia

Question 12

What is the structure of nAChRs?

Answer 12

All contain 5 subunits
10 α subtypes
4 β subtypes
γ, δ, ε

Question 13

What is succunylcholine?

Answer 13

• Agonist for NMJ nAChRs
• Powerful muscle relaxant used in anasthesia which is resistant to AChE breakdown
• Patient must be kept on ventilator

Question 14

Name 2 nAChR antagonists

Answer 14

Inversine - blocks nAChRs both centrally and in autonomic ganglia and is used for treatment-resistant hypertension
D-tubocuranine - blocks NMJ nAChRs with low selectivity for CNS and low penetrance of BBB

Question 15

What is the effect of nAChR activation on the autonomous nervous system?

Answer 15

• Activation of nAChRs on autonomic ganglia leads to heart rate and blood pressure increase, more HCl in stomach and more bowel movement contraction
• Also stimulates adrenaline and NA release from adrenal glands to increase heart rate and blood pressure
• Increase appetite supression

Question 16

What are the effects of nAChR activation on the CNS?

Answer 16

• Heightened tension/arousal
• Enhanced performance on cognitive and motor tasks
• Reinforcing effects through VTA-NAcc dopaminergic pathway

Question 17

What are the characteristics of peripheral muscarrinic receptors?

Answer 17

• Found in the peripheral nervous system
• All metabotropic (G protein coupled)
• Can activate or inhibit
  e. g M2Rs cause hyperpolarisation of caridac muscles, M3Rs cause excitation in smooth muscles by closing K+ channels

Question 18

What are other roles of M3R receptors?

Answer 18

• Stimulate beta-cells on pancreas and stimulate insulin secretion
• Mediate salivation and tearing

Question 19

What are the agonists of muscarinic receptors?

Answer 19

Muscarine, pilocarpine, arecoline

Can cause tearing, salivation, sweating, diarrhea and pinpoint pupils

Question 20

What are the antagonists of muscarinic receptors?

Answer 20

Atropine (found in nightshade)

Scopolamine which can cause drowsiness, amnesia, fatigue and pupil dilation

Question 21

What is the role of muscarinic receptors in the CNS?

Answer 21

• Widely found in brain with high levels in the neocortex, hippocampus and thalamus
• Knockout affects reward areas, moprhine resistant rats