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Acetylcholine- Chapter 7
Supplementary figures from Basic Neurobiochemistry by Siegel, et al (1999)
Acetylcholine (ACh) formed from choline and acetyl coenzyme A (acetyl CoA) in axon
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
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
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
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
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
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)

Organization of the Cholinergic System

In PNS, involved in signaling in sympathetic and parasympathetic (SANPAA)

In CNS, cholinergic neurons clustered in a few areas (Fig 6.7)
Some in striatum are stimulated by DA neurons in nigrostriatal pathway
(anticholinergics like orphenadrine reduce Parkinsons symptoms)
Basal forebrain cholinergic system (BFCS): in nucleus basalis, substantia
innominata, medial septal nucleus- these project throughout forbrain, limbic
system, and hippocampus. Implicated in loss of cognitive function with aging
(Bartus, 1982).
BFCS plays role in cognitive functioning: (giving a muscarinic antagonist like
atropine or scopolamine disrupts learning tasks)
Lesion studies using 192 IgG-saporin (from an immunoglobin and saporin which is from
soapwart (Fig 6.8)
192 IgG-saporin binds to ACh transporters and is taken up into axon terminal,
then kills cell
Animals treated with it show defecits in learning, memory, and attention, but only
after 75%+ loss of cells

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
Found in neuromuscular junctions, and brain
Some in brain are on axon terminals- when excited they increase Ca++ in
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
It is resistant to breakdown by AChE, so it stays bound to receptors causing
depolarization block
Muscarinic: metabotropic receptors, M1 to M5

Some activate IP3, others inhibit cAMP

Many cause opening of K+ channels (hyperpolarize cells)
Widely distributed in brain (neocortex, hippocampus, thalamus, striatum, basal
Some evidence also shows M5 might be involved in rewarding effects of
morphine (Basile, 2002)
Found outside the brain in the heart and smooth muscle in many organs
Cause decrease in HR by opening K+ channels, increase smooth muscle
activity and contraction
Activation of muscarinic receptors also causes sweating, salivation, lacrimation,
and pupil dilation
Muscarine is major agonist, as are pilocarpine and arecoline
These are parasympathomimetic agents- lead to parasymp activation
Atropine and scopolamine are antagonists, from plants like Atropa belladonna
These are parasympatholytic agents- inhibit parasymp activation

Alzheimers Disease (Box 6.2)

Progressive disease resulting in dementia (impairment of cognitive functions, language,
and abstract thinking)
Brains of Alzheimers patients lose brain tissue, with wider sulci and enlarged ventricles
On microscopic level, -amyloid protein (AP) that forms plaques and neurofibrillary
tangles inside neurons are present
Neurofibrillary tangles due to excess phosphorylation of tau protein, causing it to
clump and become toxic to cells
Microscopic analysis shows massive neuronal loss in cortex and hippocampus
Likely due to AP accumulation when precursor molecule (amyloid precursor
protein) is incorretly metabolized
Basal forebrain cholinergic neurons projecting to cortex and hippocampus are also
heavily damaged
AChE inhibitor drugs have been tried to increase ACh levels, but show little
New remedies likely going to target enzymes that cause bAP formation
Acetylcholine and Cognitive Function
Previous research has shown ACh plays major role in cognitive processing
Evidence: atropine and scopolamine (anti-muscarinics) produce amnesic effects
in humans, and was often used during labor to ease trauma to mother, called
twilight sleep
Animal use of drugs impaired ability of rats to acquire and maintain many types
of learning tasks
Seems these drugs interfere with memory consolidation, especially with ACh role
in hippocampus in encoding episodic memories
Others concluded that deficits in attention and sensory discrimination are the
most selective consequences of blocking muscarinic receptor activity
Studies using muscarinic blockers revealed roles of ACh in cognitive function
However, this ignores nicotinic receptor involvement
Anti-muscarinics were administered systemically, which makes it impossible to
determine where in the brain the critical cholinergic pathways were located
Need to localize key cholinergic neurons, so lesion studies were used
Gross destruction of tissue in the basal forebrain caused various types of deficits
in learning and memory

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
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
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