2Farma Acetylcholine

Small NTs (kleinmoleculaire NTs)

1. Acetylcholine (Ach)
2. Biogenic amines
3. Amino acids

Used in diff parts of NS

1) Motor neurons Vb. neuromuscular junction, muscles

 ->helps you move your limbs (muscle contraction)…

 

2) Deep brain structures

 Vb. striatum, nucleus basalis

 

3) Cortex: cholinergic terminals in cortex
 ->cholinerge kernen (nucleus basalis) in basale voorhersenen banen over de hele cortex: exciteert cortex (activatiefuntie, Â & geheugen)

4) Parasympathetic NS: cholinergic terminals in PNS
 ->cholinerg system in hersenstam (projectie vanuit stam naar VTA [bodem middenhersenen­] en thalamus + activerende functie nr basale voorhersenen)

 Vb. Reduced heart rate

Involved in major brain disorders

1. Myasthenia gravis

 =auto-immune disorder: affects peripheral AChR

 ->muscle ACh receptors are blocked by antibodies

 ->interferes with cholinergic transmission at neuromuscular junction=>reduces muscle contraction

2. Alzheimer’s disease (necrose nucleus basalis: memory loss)

Major cholinergic projections in brain (cholinergic system)

1) Magnocellular basal ofrebrain cholinergic system

2) Brainstem cholinergic system

Magnocellular basal forebrain cholinergic system

->medial septal nucleus (MS)

 ->vertical & horizontal limbs of the diagonal band of Broca (DB)

 ->nucleus basalis magnocellularis (nBM)

 

 1. DB projects diffusely to neocortex, basolateral amygdala and olfactory bulb
 2. MS & vertical limb of DB project to hippocampus & entorhinal cortices

Brainstem cholinergic system

projects predominantly to thalamus, also to basal forebrain

 ->pedunculopontine tegmental nucleus (PPT)

 ->laterodorsal pontine tegmentum (LDT)

~has to be the perfect balance: too much or too little is deadly

Ach synthesis

=catalyzed by enzyme choline acetyltransferase (ChAT)
 ->enzyme transfers acetyl group from acetyl CoA to choline (which then forms the Ach)

Rate of synthesis

=controlled by availability of its precursors as well as firing rate of the cell

~cholinergic neurons make more Ach when:
1. more choline and/or acetyl CoA is available
2. neurons are stimulated to fire at higher rates

Understanding of ACh

~system not yet fully understood: no development of using pharmacological agents to treat disorders yet
 ->vb Alzheimer’s choline treatment=no relief of symptoms + unpleasant side effects

ACh storage & release

~axon terminals contain vesicles (store ACh for release when nerve cell is activated)

->vesicles are loaded with ACh by a transport protein in the vesicle membrane =vesicular ACh transporter (VAChT)

->this can be blocked by a drug called Vesamicol (doesn’t affect rate of Ach synthesis, so ACh molecules remain in cytoplasm of the terminal, it just decreases vesicular ACh -> decreases the release into synaptic cleft)

Toxins

Bacterial toxins (eg black widow spider venom) leads to massive release of ACh at synapses in the PNS =>overactivity

 

Toxins like botulism poisoning (from food) potentially inhibit ACh release ->can be deadly due to muscle paralysis

Overactivity of the cholinergic system

=muscle pain in abdomen or chest, tremors, nausea & vomiting, salivation & copious sweating

ACh breakdown

Acetylcholinesterase (AChE) =enzyme controlling ACh levels
 ->present in multiple locations:
 1. Presynaptic cell (here: metabolizes excess ACh)

 2. Postsynaptic membrane (here: break down molecules after release to synaptic cleft)

 3. At neuromuscular junctions
->once broken-down: transport back up into cholinergic nerve terminal (by choline transporter in membrane)

Nicotinic ACh receptor (ionotropic)

1. Respond selectively to the agonis nicotine

2. ligand-gated (ionotropic):

 ->when ACh binds it opens: Na+ rushes in (depolarization)
 =>increasing excitability of cell
3. In muscle cell -> contraction.

4. Mediate fast excitatory responses in CNS and PNS

5. Enhances the release of NTs from the nerve terminals

Muscarinic ACh receptor (metabotropic)

1. Stimulated by muscarine
 >amanita muscarina (mushroom)

2. Metabotropic receptors (5 types M1-M5) use several different second messenger systems

3. Widely distributed: neocortex, hippocampus, thalamus, striatum, basal forebrain