acetylcholine

What nervous systems in ACh a key part of?

Both peripheral and central

Where is ACh used in the peripheral NS?

All neuromuscular junctions and as part of the parasympathetic NS

Where is AHc used in the CNS?

Multiple cell body regions enervate cortical/subcortical regions and ACh interneurons are found in the striatum

What two molecules form ACh?

Choline and acetyl coenzyme A (acetyl CoA)

What enzyme turns choline and acetyl CoA into ACh?

Choline acetyltransferase (ChAT)

Why would we stain for choline acetyltransferase (ChAT)?

Because ChAT is only in neurons that use ACh

What two factors control the rate of ACh synethesis?

Availability of precursors and the rate of cell firing

What molecule is a ChAT antagonist?

No selective inhibitors of ChAT have been found

What transporter packages ACh into vesicles?

VAChT

What drug blocks VAChT?

Vesamicol

What is the cellular effect of Vesamicol?

Reduces ACh levels

What two naturally-occuring toxins work on the ACh system?

Black widow spider venom and botulinum toxin (botox)

What effect does black widow spider venom have on ACh?

Causes massive ACh release in the PNS

What bodily effects does black widow spider venom have?

Cholinergic over activity causes muscle pain, tremors, nausea, vomiting, salivation, copious sweating, and even muscle paralysis

What effect does botox have on ACh?

Inhibits ACh release selectively in neuromuscular junctions - prevents muscular contractions

Why is the inhibition of cholinergic activity deadly?

Because it can cause muscular paralysis of areas like the diaphragm, which prevents respiration

Does ACh undergo direct reuptake?

No, it doesn’t undergo direct reuptake

What enzyme controls ACh levels?

Acetylcholinesterase (AChE)

How does acetylcholinesterase (AChE) control ACh levels?

Rapidly breaks it down into choline and acetic acid (in microseconds)

Where is AChE located?

On postsynaptic membranes and in presynaptic cells that metabolize excess ACh

What happens to ACh after it’s broken down into choline and acetic acid?

Most choline is taken back into cholinergic nerve terminals by a choline transporter

What does hemicholinium-3 (HC-3) do?

Blocks choline transporter, reducing the rate of ACh production

What molecule is a choline transporter antagonist?

Hemicholinium-3 (HC-3)

What happens when you block AChE (and ACh inactivation)?

Increases postsynaptic effects of ACh

What are the effects of physostigmine?

Blocks AChE and increases postsynaptic effects of ACh

What drug blocks AChE?

Physostigmine

What disease is physostigmine sometimes used to treat?

Alzheimer’s (specifically the cognitive declines)

What compounds cause irreversible inhibition of AChE?

Weak versions are used as insecticides while toxic varieties are used as nerve gases (ex. Sarin)

What are the effects of Sarin?

Causes irreversible inhibition of AChE - ACh accumulation and overstimulation of cholinergic synapses leads to muscle paralysis and death by asphyxiation

What is the antidote to Sarin or other irreversible AChE blockers?

Cholinergic antagonist

What are the two types of ACh receptors?

Nicotinic and muscarinic

What is the agonist for nicotinic receptors?

Nicotine

What happens when nicotinic receptors are activated?

Channel opens and NA+ and Ca²+ enter the cell and depolarize the memberane

What responses are mediated by nicotinic receptors?

Fast excitatory responses in the CNS and PNS

What are the five subunits of nicotinic receptors?

α, β, γ, δ, and ε

How many variations of alpha subunits exist?

10

How many variations of beta subunits exist?

4

Different subtypes of receptors can vary in terms of…

• Number of bindings sites

• Affinity for ACh

• Ion flow through channel

• Open/closing kinetics

• Allosteric binding sites

• Location in brain

Continuous short-term activation of nicotinic receptors can cause…

Receptor desensitization (channel remains closed even when agonist is bound) - recovers after short time with no stimulation

Continuous long-term activation of nicotinic receptors can cause…

Depolarization block - cell can’t be excited until agonist is removed and membrane repolarizes

What is depolarization block?

When persistent depolarization of a cell causes the resting potential to be lost

What is the agonist for nicotinic receptors?

Succinylcholine

What are the effects of succinylcholine?

Nicotinic agonist - used as a muscle relaxant in some surgical procedures

How does succinylcholine work?

Resistant to breakdown by AChE; this continuously stimulates the nicotinic receptors and indices a depolarization block of the muscle cells

What are the two antagonists for nicotinic receptors?

Mecamylamine and d-tubocurarine

How do mecamylamine and d-tubocurarine work?

They block muscle nicotinic receptors - have a hard time crossing the BBB though so don’t do much in the CNS

What is the main use of mecamylamine and d-tubocurarine?

To paralyze animals when hunting

What are other agonists/antagonists that are more selective for certain subtypes of nicotinic receptors being developed for?

As cognitive enhancers and treatments for nicotine addiction

What molecule do muscarinic receptors respond to?

Muscarine

What type of receptors are muscarinic receptors?

Metabotropic receptors

What are the muscarinic receptor subtypes?

M1-5

How do muscarinic receptors work?

Opperate vis second messengers and/or enhance K+ channel opening

Where are peripheral muscarinic receptors located?

In cardiac and smooth muscle in many organs and in insulin-secreting cells of the pancreas

What system do M2 receptors work on?

Cardiac system - also as presynaptic autoreceptors in the CNS

What bodily effects do M2 receptors have?

Slow heart rate when activated

Where are M3 receptors located?

Smooth muscles

What bodily effects do M3 receptors have?

Contraction (ex. digestive tract) and mediate other secretory responses (ex. salivation)

Why do many drugs used to treat mental disorder produce side effects like dry mouth?

Because of the blocking of peripheral muscarinic receptors

What drug is a muscarinic receptor agonist?

Pilocarpine

What bodily effects does pilocarpine have?

Acts as a parasympathomimetic agent

What would the effects of pilocarpine poisoning be?

Exaggerated parasympathetic responses (SLUDGE = salivation, lacrimation, urination, diarrhea, gastrointestinal distress, and emesis)

What drugs are muscarinic receptor antagonists?

Atropine and scopolamine

What are the bodily (PNS) effects of atropine and scopolamine?

Inhibit parasympathetic effects - dilates pupils, reduce secretions that clog airways, and counteract cholinergic poisoning

What are the brain (CNS) effects of atropine and scopolamine?

Drowsiness, euphoria, amnesia, fatigue, and dreamless sleep

What saying is use to represent that high doses of muscarinic antagonists can be toxic?

Blind as a bat (blurred vision), mad as a hatter (psychosis), red as a beet (skin flushing), hot as hades (fever), dry as a bone (reduced secretions), the bowel and bladder lose their tone, and the heart runes alone (increased heart rate)

Many central actions of ACh are mediated through which receptor?

M1

What parts of the brain contain cholinergic cell bodies?

Striatum, dorsolateral pons, and basal forebrain

The regulation of movement in the striatum depends on the balance between which NTs?

ACh and DA

What imbalance contributes to the motor symptoms in Parkinson’s?

DA is lower than ACh

When are muscarinic ACh antagonists used therapeutically?

Sometimes prescribed instead of L-DOPA in the early stages of Parkinson’s disease to restore balance between ACh and DA.

Some ACh axons project from the dorsolateral pons to which part of the brain?

Midbrain DA neurons

What is one way ACh modules DA activity in the midbrain?

ACh is excitatory on DA cells and can regulate burst-patterns of firing

What mediates the relationship between ACh and DA in the midbrain?

Activation of postsynaptic nicotinic and muscarinic (M5) receptors

What behavioural reinforcement has been associated with nicotinic and muscarinic (M5) receptors?

Reinforcing effects of certain drugs of abuse (ex. nicotine)

What is the basal forebrain cholinergic system (BFCS)?

Neurons in several brain areas that enervate the cortex, hippocampus, and other limbis structures

What occurs to ACh neurons in the BFCS?

Get intermized with other cells using different transmitters (GABA, glutamate)

What has selective destruction of cholinergic neurons in the BFCS revealed?

ACh plays a key rolei n regulating memory and cognitive functions mediated by forebrain regions by facilitating attention

What does the signal detection task measure?

Sustained attention

How does the signal detection task work?

Correct type of lever press (light or no light) gives rate a food reward. Rats are given multiple trials in quick succession at variable intervals.

What happens in signal trials of the signal detection task?

A light comes on very briefly. If the rat sees the light they should press the left lever when lever extend to get reward, incorrect right lever press = miss

What happens in non-signal trials of the signal detection task?

Rat should press right lever (correct rejection), incorrect left lever press = false alarm

What did a microdialysis study on ACh using the signal detection task find?

ACh in frontal cortex increases in rats performing attention task, but not in rate merely pressing lever for food

What effects on the signal detection task did selective destruction of basal forebrain cholinergic neurons have?

Impairs performance

What drug selectively destructs basal forebrain cholinergic neurons?

192 lgG-saporin

ACh is involved in attention, true or false?

True