Cholinergic Transmission Flashcards
Where is Ach present?
- 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
Which cholinergic systems exist in the brain?
- Interneurons within the striatum
- Basal forebrain, which innervates the cortex and hippocampus
- Dorsolateral pons which projects to the thalamus and spine
What is the biochemistry of ACh transmission?
- 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
What determines the activity of ChAT?
- Precursor availability
- Neuronal firing
What are the two functions of AChE?
- Presynaptic breakdown of excess ACh
- Postsynaptic activity to provide spatial and temporal precision
What is physostigmine?
AChE blocker capable of crossing BBB, can induce hallucinations, coma and death
What is prostigmin?
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
What are sarin and soman?
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
What is the function of the choline transporter? What is it’s blocker?
- Sustains Ach synthesis through the recylcing of choline
- Blocker is hemicholinium-3 (HC-3) which prevents presynaptic reuptake of choline
What are the 2 types of nicotinic receptors?
N1 - signalling at neuromuscular junctions
N2 - central nervous system
What are the 5 types of muscarinic receptors?
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
What is the structure of nAChRs?
All contain 5 subunits
10 α subtypes
4 β subtypes
γ, δ, ε
What is succunylcholine?
- Agonist for NMJ nAChRs
- Powerful muscle relaxant used in anasthesia which is resistant to AChE breakdown
- Patient must be kept on ventilator
Name 2 nAChR antagonists
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
What is the effect of nAChR activation on the autonomous nervous system?
- 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
What are the effects of nAChR activation on the CNS?
- Heightened tension/arousal
- Enhanced performance on cognitive and motor tasks
- Reinforcing effects through VTA-NAcc dopaminergic pathway
What are the characteristics of peripheral muscarrinic receptors?
- 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
What are other roles of M3R receptors?
- Stimulate beta-cells on pancreas and stimulate insulin secretion
- Mediate salivation and tearing
What are the agonists of muscarinic receptors?
Muscarine, pilocarpine, arecoline
Can cause tearing, salivation, sweating, diarrhea and pinpoint pupils
What are the antagonists of muscarinic receptors?
Atropine (found in nightshade)
Scopolamine which can cause drowsiness, amnesia, fatigue and pupil dilation
What is the role of muscarinic receptors in the CNS?
- Widely found in brain with high levels in the neocortex, hippocampus and thalamus
- Knockout affects reward areas, moprhine resistant rats
