ACH

Question 1

Describe the synthesis (what makes it and what catalyzes the reaction) and basic whereabouts of ACh.

Answer 1

PNS: all NMJ and parasympathetic nervous system
CNS: multiple cell bodies in cortical/subcortical regions and interneurons in striatum

Formed by Choline and Acetyl coenzyme A

• made my choline acetyletransferase (ChAT)
• chat is a great marker for ACh cause its the only one that uses it.
• No chat inhibitors found

Rate of synthesis controlled by

1. availability of precursors
2. rate of cell firing (more firing, more made)

Question 2

How is ACh packed and released?

Answer 2

Packed by VAChT vesicular ACh transporters

Pharmacology:

1. vesamicol: reserpine analog.
   - blocks VAChT to reduce ACh levels
2. Black widow spider venom: massive ACH release in PNS
   - overactivity cause pain, tremors, nausea, vomiting, salivation, sweating
3. Botulism toxin: inhibits ACH release at NMJ only
   - deadly

Question 3

How is ACH degraded?

Answer 3

No direct reuptake.

• AChE breaks it down to choline and acetic acid (within microseconds)
• ACHe is on postsynapic and presynaptic membranes

Choline reuptaken by terminal via choline transporter.

Pharmacology
1. Hemicholinium-3 (HC-3) blocks choline transporters, reducing rate of ACh production BECAUSE its not allowing the choline to be reused! opposite to most other transport blockers :)

Question 4

Describe AChE inhibitors.

Answer 4

Blocking AChE increases ACH buildup in synapse (more postsynaptic activation)

Example: Physostigmine: crosses blood brain barrier
- offset cognitive decline in Alzeimers for a short time (cause of loss of ACH neurons)

Irreversible inhibiton of AChE (with covalent bonds)

• insecticides (weak versions)
• nerve gases (toxic) do the same as black widow venom (SARIN)
• Antitodes: offset effects until body can make new enzymes
• lead to muscle paralysis and death by asphyxiation.

Question 5

Describe the nicotinic ACH subtype

Answer 5

Ionotropic
Agonist: nicotine
Opens Na and Ca channels to enter the cell and depolarize membrane.
- fast response (excitatory) in CNS and PNS

5 subunits

• 10 variations of alpha, 4 of beta. different combos in muscles and brain.
• vary in terms of binding sites (i.e. sensitivity for ACH cause some may require more)

Question 6

Describe continuous activation of nicotinic receptors?

Answer 6

1. Initally desensitizes receptors (channel is closed when agonist is bound) but recovers after its unstimulated.
2. Long term activation leads to DEPOLARIZATION BLOCK - resting membrane potential is LOST.
   - cell can’t be excited till agonist is removed and membrane repolarizes. (till effect of drug wears off)
   - causes paralysis at neurons and muscle cells
   - happens at other synapses too (glutamate)

Question 7

Describe some nicotinic pharmacology

Answer 7

Agonists:

Succinylcholine: muscle relaxant used in surgery

• doesn’t like to be broken down by AChE, so it stimulates nicotinic receptors constantly and induces depolarization block.
• used IV not systemically

Antagonists:

Mecacylamine: blocks nicotinic receptors in CNS and autonomic ganglia (antidote for nicotinic poisoning in cerebral cortex) .

D-tubocurarine: blocks muscle nicotinic receptors

• little effect on CNS cause no BBB crossing and doesn’t stick to brain receptors.
• causes parlaysis
• used in blow guns by hunters.

Some people are trying to develop more specific ones for cognitive enhancers or nicotinic addiction.

Question 8

Describe the muscarinic receptor and subtypes

Answer 8

Metabotropic 
Agonist Muscarine (fly agaric mushrooms) 
5 main subtypes (CNS or body)
2nd messengers or enhance K+ channel opening 

Peripheral: cardiac and smooth muscle in many organs and insulin secreting pancreal cells

M2: cardiac ( slows heart rate when activated) and presynaptic autoreceptor in CNS

M3: smooth muscle (contraction -like digestive tract- when activated and other secretory responses -saliva and tears)
- drugs that act on muscarinic receptors have side effects like dry mouth cause blocking these receptors.

Question 9

What is some pharmacology of muscarinic receptors.

Answer 9

Agonist
Pilocarpine: cholonergic poisioning. parasympathomimetic agent. activates parasympathetic neurons (M2 and M3)
- leads to SLUGDE response (salivation, lacrimation, urination, pooping, gastro issues and emesis)
-body produces stuff. not the same as nicotinic ones.

Antagonist
Atropine, Scopolamine
- inhibit parasympatheitc effects (look like sympatheitc effects)
- given to counteract too much ACH
- dilate pupils, reduce secretions that block things (like airways), counteract cholinergic poisoning.
- dries you up, and crosses the BBB
- CNS: sleepiness, euphoria, amnesia, fatigure, dreamless sleep because no rem

Question 10

Describe ACh in the striatum.

Answer 10

Many central effects through M1 (also 3-5)

Striatum
-cholingergic interneurons.
- caudate, putamen, nucleus accumbens
- movement depends on balance between ACH and DA
I.E. parkinsons, DA is low, so ACH balance is high, which makes motor action selection hard. leads to random movements
- treated by reducing ACh early on before too many neurons are lost (low dose muscarinic agonist) instead of L-dopa

Question 11

Describe ACH in the dorsolateral pons?

Answer 11

Tegmentum
Laterodorsal + Pedunculopontine nuclei
= project to thalamus, cerebellum and other cell groups (raphe, locus, VTA)

Within VTA (midbrain) ACH is exitatory on DA cells that create burst fire patterns.

• nicotinic and M4-M5 postsynaptic receptors in the VTA mediate this.
• involved in the rewarding behaviors, alertness, attention (nicotinic ones reinforce drug abuse cause it activates dopamine neurons)

Question 12

Describe ACh in the basal forebrain.

Answer 12

Basal forebrain cholingergic system (BFCS) in lots of areas

1. Medial septum
2. Diagonal band
3. nucleus basilis
4. substantia innominata

that project to hippocampus, amygdala and cerebral cortex, and other limbic structures.
- emotional and cognitive regulation

• these neurons intermixed with other cells like Glut and Gaba using cells.
• Hard to study because if you destroy the nuclei, you’re destroying other things, but if you give systemically it makes you feel poopy so maybe thats why??, need specific neurotoxin only for ACH neurons.
• found to be very important for attention!

Question 13

How is attention measured? (assay for attention)

Answer 13

Signal Detection Task (measure of sustained attention)
- Signal trials and non-signal trials.
if you don’t get this go to slide 15 on ACH package.

Question 14

What happens to attention if you manipulate ACH?

Answer 14

Systemic adminstration: we know impairs it

Microdialysis study: ACH in frontal cortex increases when performing attention task (but not when doing other things for controls)

ACH lesion study: selective basolateral forebrain lesion (192-IgG saporin) impaired perfomance on the hits but not correct rejections. Not random responding, they just weren’t paying attention so they missed the light sometimes.

optogenetics are starting now to see what happens if you stimulate or inhibit ACH (perfomr better and worse respectively)