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Acetylcholine- Chapter 7
Supplementary figures from Basic Neurobiochemistry by Siegel, et al (1999)
Acetylcholine
Acetylcholine (ACh) formed from choline and acetyl coenzyme A (acetyl CoA) in axon
terminals
This synthesis is catalyzed by the enzyme choline acetyltransferase (ChAT) (Fig 6.1)
Adds acetyl group (-COCH3) to choline from acetyl CoA to make ACh
Cholinergic neurons make more ACh when choline and acetyl CoA are present, or when
neurons are stimulated to fire at high rate
Drugs/Toxins that Affect ACh
Vesicles in axon terminal are loaded with ACh by vesicular ACh transporters (VAChT) (Fig
6.2)
VAChT can be blocked by vesamicol
Many animal and bacterial toxins also affect release of ACh
Black widow (Latrodectus mactans) toxin causes massive ACh release in PNS
neurons
Leads to muscle pain in trunk, tremors, nausea, vomiting, salivation,
sweating, and sometimes death
Botulinum toxin interferes with SNAP-25 SNARE protein to prevent vesicular
release
Leads to muscle paralysis
Breakdown of ACh
Levels of Ach controlled by acetylcholinesterase (AChE)- breaks down ACh into choline
and acetic acid (Fig 6.3)
Found presynaptic neuron, membrane of postsynaptic neurons, and in synaptic cleft
(neuromuscular junction only for rapid inactivation)
In synaptic cleft, excess choline taken back up by presynaptic neuron via choline
transporter
Hemicholinium-3 black choline transporter, and ACh production declines
Hemicholinium-3 wont cross BBB, but if injected into brain, it markedly reduces
tasks involving visual attention pathways, attention in general, and cognitive
functions
Some drugs block AChE and prevent inactivation of ACh
Physostigmine (Eserine) from Calabar beans can cross BBB and have direct
effects on CNS
Causes slurred speech, mental confusion, hallucinations, loss of reflexes,
convulsions, and sometimes coma or death
Neostigmine (Prostigmin) and pyridostigmine (Mestinon) are synthetic versions of
physostigmine that do not cross BBB
Used mostly to treat myasthenia gravis (autoimmune disease where
persons own antibody attach to, block, and eventually destroy ACh
receptors (Fig 6.4)
Loss of receptors leads to muscle weakness and fatigue
Physostigmine, neostigmine,and pyridostigmine are reversible AChE inhibitors- once
drug is gone AChE goes back to normal
Other AChE inhibitors are irreversible- often used as insecticides
Nerve gases, such as sarin and soman work via this mechanism
Nerve gases cross the BBB quickly, causing excess ACh accumulation in CNS and
PNS, leading to sweating, salivating, convulsions, asphyxiation, and death
Can prevent nerve gas poisoning by taking pyridostigmine bromide (PBreversible AChE inhibitor) before nerve gas exposure; apparently it binds to AChE
and prevents permanent destruction by nerve gases
PB does seem to have some adverse effects- if animal/person is under stress,
more PB crosses BBB and may be a factor in one kind of Gulf War Syndrome
(confusion-ataxia which includes cognitive impairment, dizziness, loss of balance
and coordination) (Fig 6.5)
Cholinergic Receptors
Nicotinic- ionotropic receptors with five subunits (2, 1, 1, 1) (Fig 6.10)
Nicotine is agonist, D-tubocurarine is antagonist
Two molecules of ACh must bind to s at same time to open channel for Na+ and
Ca++
Found in neuromuscular junctions, and brain
Some in brain are on axon terminals- when excited they increase Ca++ in
terminal
Nicotinic receptors on muscle are less sensitive- take larger dose of ACh or
nicotine to activate
If continuously exposed to ACh, nicotinic receptors become desensitized (channel
wont open even with ACh bound to s) (Fig 6.11)
Those receptors not desensitized undergo depolarization block (Vm inside
cell is too positive to let much Na+ in)
If continuously exposed to ACh, nicotinic receptors become desensitized (channel
wont open ever with ACh bound to as)
Those receptors not desensitized undergo depolarization block (Vm inside
cell is too positive to let much Na+ in)
Succinylcholine (agonist) is powerful muscle relaxant sometimes used during
surgery
It is resistant to breakdown by AChE, so it stays bound to receptors causing
depolarization block
Muscarinic: metabotropic receptors, M1 to M5
Still difficulties, because neurons of the basal forebrain cholinergic system (BFCS)
are heavily intertwined with neurons that use other neurotransmitters, all of
which are killed by excitotoxic lesions
Solved this problem by using 192 IgG-saporin, which binds specifically to surface
proteins of BFCS neurons, and not other neurons
Saporin gets taken into the cell, and kills it- so can limit lesion to only
cholinergic neurons
Some experimenters report deficits in learning and memory using 192 IgG-saporin of
the BFCS, but more consistent effects are found with studies that focus on attentional
processes
ACh seems to be important in the facilitation of sensory cues by stimulating
cholinergic receptors of the prefrontal cortex (See figure 7.2)
Fig A: shows results of microdialysis experiment where substantial increase
in ACh release in frontoparietal cortex in animals performing a signal
detection task requiring sustained attention (Sarter and Parikh, 2005)
The ACh release was far greater than the release that occurred in
animals performing other tasks that dont impose the same
attentional demands
Figure B: Shows effects of basal forebrain 192 IgG-saporin lesions on
performance of the same signal detection task
Shows that lesions produced large reductions in the ability of
animals to detect the signal when it was presented, but had no
effect on the percentage of correct rejections (responses on the
lever associated with nonsignal presentation)
Over 30 years ago, Raymond Bartus proposed that cognitive deficits that accompany
aging are due to dysfunction of the BFCS
Spurred interest into the BFCS in regards to aging, but also regarding Alzheimers
disease
This lead to development of AChE inhibitor drugs to treat Alzheimers
Damage to the BFCS is only part of the problem, because widespread loss of
other cells and synaptic connections throughout the cerebral cortex and
hippocampus also occurs
Still interest in developing novel agents like a4b2 or a7 nicotinic receptor
agonists, which might improve Alzheimers dementia, but also cognitive deficits
associated with schizophrenia and other disorders