ACETYLCHOLINE

Presentation
By
Dr.RAJIN
Chair:Dr.Anil Prabhakaran
 Structure

 Synthesis, release & regulation

 Pathways

 Receptors

 Clinical considerations
 HISTORY
 Acetylcholine (ACh) was first identified in
the year 1914 by Henry Hallett Dale for
its actions on heart tissue.
 It was confirmed as a neurotransmitter
by Otto Loewi who initially gave it the
name vagusstoff because it was released
from the vagus nerve. Both received the
1936 Nobel Prize in Physiology or
Medicine for their work.
 Acetylcholine was also the
firstneurotransmitter to be identified
MOLECULAR STRUCTURE

CH3 O

CH3 N+ CH2 CH2 O C CH2

CH3
 Acetylcholine is an ester of acetic
acid and choline with chemical
formula CH3COOCH2CH2N+(CH3)3. This structure is
reflected in the systematic name, 2-acetoxy-N,N,N-
trimethylethanamine

 Acetylcholine has functions both in the peripheral

nervous system (PNS) and in the central nervous
system (CNS) as a neuromodulator.
 In the PNS, acetylcholine activates muscles, and is a
major neurotransmitter in the autonomic nervous system.
 In the CNS, acetylcholine and the associated neurons
form a neurotransmitter system, the cholinergic system,
which tends to cause excitatory action.
 Storage & Release
 Mainly Taken up from blood
 Stored in synaptic vesicles through
the action of vesicular acetyl choline
transporter
 Degraded by acetylcholine esterases
in post synaptic terminal
 Choline transporters transport the
released choline back to presynaptic
terminal.
Cholinergic neurons

Acetyl.CoA
+
choline

ACh

choline
ACh

ASE

Postsynaptic tissue
 Cholinergic neurons
within CNS Outside CNS

1. projection 1. Pre ganglionic

neurons autonomic
2. inter neurons neurons
2. Motor neurons
3. Post ganglionic
parasympathetic
neurons
 Projection neurons

Basal forebrain Mesopontine

complex complex
 Basal forebrain complex

Nu. basalis of
Medial septal
MEYNERT nucleus
Horiz. & vert.
Diagonal bands of
BROCA

Areas of cortex
&
Ant, cingulale hippocampus
amygdala
Gyrus &
Olfactory bulb
 Mesopontine complex

Pedunculopontine &
Laterodorsal tegmental nu.
of midbrain & pons

Thalamus & Locus ceruleus,

Midbrain Dorsal raphe,
areas Cranial nerve nu
Copyright © 2004 Allyn and Bacon
 RECEPTORS
A. Muscarinic B. Nicotinic
5 subtypes have been 3 functional classes
cloned 1. Skeletal ms.
1. M1 Subunits
2. M2 2. Standard neuronal
3. M3 subunits
4. M4 3. Subunit capable of

5. M5 forming homomeric
receptors
 M1 receptor
 Gq protein coupled
 Increases phosphatidine inositol
turnover
 Location: forebrain including cortex,
hippocampus, striatum
 Functions: memory ( involving
interaction between cortex &
hippocampus)
 : seizures
 M2 receptors
 Gi protein coupled .
 Decreases adenylate cyclase
 Location: heart,brain
 Functions: mediates tremor,
hypothermia & analgesia induced by
muscarinic receptors
 M3 receptor
 Gq protein coupled
 Increases phosphatidine inositol
turnover
 Location: smooth muscles of GIT &
GUT, salivary glands,many areas of
CNS
 Functions: no major role in CNS
 M4 receptors
 Gi protein coupled
 Decreases adenylate cyclase
 Location: hippocampus, cortex,
striatum, thalamus, cerebellum
 Functions: opposes the effects of D1
receptors in the striatum
 M5 receptors
 Gq protein coupled
 Increases phosphatidine inositol
turnover
 Location: peripheral & cerebral blood
vessels
 Functions: ? Mediate cholinergic
cerebral arterial vasodilation
 NICOTINIC RECEPTORS
 Ligand gated ion channel

 Pentamericmembrane protein subunits

with a central ion pore

 Bindingof acetylcholine causes

conformation changes opening of
ion pore passage of Na+, K+,
Ca++
Nicotinic acetylcholine receptor subunits can be
separated into three general functional classes

(1) skeletal muscle subunits (α1, β1, δ, ε)

(2) standard neuronal subunits (α2 through α6,

β2 through β4)

(3) subunits capable of forming homomeric

receptors (α7 through α9).
 Standard neuronal subunits are
present in neocortex, hippocampus,
thalamus, striatum,hypothalamus,
cerebellum, substantia nigra, ventral
tegmental area, dorsal raphe nucleus

 Receptors contain alpha-4 beta-2

subunit or alpha-7 subunit
Functions:
 Cognitive(esp. working
memory,attention & processing speed )
 Sensory gating
 Action on mesolimbic dopaminergic
reward pathways
 Seizure
subtype Primary Proposed cinical relevance
effector
M1 Inc. PI cognition,seizures
turnover
M2 Dec AC Cardiac function
M3 Inc. PI Smooth muscle contraction
turnover
M4 Dec AC Antiparkinsonian anticholinergic
drugs
M5 Inc. PI ?
turnover
NAChR Cation Tobacco use,seizures
selective ion
channel
CLINICAL CONSIDERATIONS
 Acetylcholine and Schizophrenia

 Acetylcholine receptors are broadly distributed

throughout the brain, including the neocortex,
hippocampus, and basal ganglia.

 Cholinergic mechanisms have been implicated

in the regulation of attention, memory,
processing speed, working memory, and
sensory gating processes—processes that are
impaired in patients with schizophrenia
 Impaired sensory gating, including impaired
performance on the P50 sensory gating paradigm.

 The α7 nicotinic receptor has got role in normal

sensory gating function, smoking reverses P50
impairments in patients with schizophrenia

 In families with patients with schizophrenia, impaired

P50 performance is linked with the chromosome 15 region
that contains the gene for the α7 nicotinic receptor.

 Patients with schizophrenia have been shown to have

decreased α7 nicotinic receptors in the hippocampus.
 The α4β2 nicotinic receptor has been
shown to regulate dopamine, serotonin,
GABA, and glutamate release,
 Regulate the neurotransmitter systems that
are involved in cognition.
 Postmortem studies have demonstrated
abnormal regulation of these receptors in
patients with schizophrenia
 ACETYL CHOLINE AND MOOD DISORDER

 Cholinergic neurons have reciprocal or interactive

relationships with all three monoamine systems.

 Abnormal levels of choline, which is a precursor to

ACh, have been found at autopsy in the brains of
some depressed patients, perhaps reflecting
abnormalities in cell phospholipid composition.
 ACETYL CHOLINE AND MOOD DISORDER
 Cholinergic agonist and antagonist drugs
have differential clinical effects on
depression and mania. Agonists can produce
lethargy, anergia, and psychomotor
retardation in normal subjects, can
exacerbate symptoms in depression, and can
reduce symptoms in mania.
 Antidepressants, via their serotonergic or
adrenergic effects, may decrease cholinergic
function, although direct anticholinergic
effects are unrelated to antidepressants.
 DELIRIUM

 Acetylcholinehas got a role in REM

sleep, attention, arousal & memory

 Cholinergicagents such as
physostigmine is effective in delirium
of all causes
 ALZHEIMER’S DISEASE

 Decrease in cholineacetyl transferase

in nucleus basalis of Meynert &
several neocortical regions
 Myasthenia gravis
 Autoimmune disease
 Antibodies to the nicotinic ACh receptor.
 Weakness and fatigue in the voluntary
muscles
 Muscarinic receptors in the heart and
CNS are unaffected.
 Treatment with acetylcholinesterase
inhibitors such as edrophonium that
prolong the life of the released ACh
 ANTICHOLINERGIC DRUGS
 Trihexyphenidyl, benztropine,
biperiden, procylidine, orphenadrine

 Oral, i/m, i/v preparations available

 Use with caution in BPH & narrow

angle glaucoma
 Adverse effects:
Delirium, seizures, agitation,
hallucination, SVT, flushing mydriasis

 Impdrug interactions:
DRA, MAO-I, tricyclics

 Uses
Neuroleptic induced parkinsonism,
neuroleptic induced dystonia,
akathesia
 .,
CHOLINESTERASE INHIBITORS

 Tacrine
Inhibits AChE 120–160 mg, divided four
times daily 30% elevated transaminases and
severe GI intolerance.

 Donepezil
Inhibits AChE 5–10 mg every day.
May be associated with insomnia. Fewer GI
symptoms
.Rivastigmine
Inhibits butyryl cholinesterase
and AChE 6–12 mg, divided b.i.d. Gradual
titration may decrease GI side effects.
 Galantamine
Allosteric modulation of nicotinic
receptors, weaker AChE inhibition 24–32 mg,
divided b.i.d. Gradual titration may decrease
GI side effects. Least induction of AChE.
 Should be used cautiously with
succinyl choline

 Uses
: treat cognition impairment in
Alzheimers dementia
:vascular dementia
:traumatic brain injury
:parkinsons diseases
 Varenicline
alpha4beta2 nicotinic acetylcholine
receptor partial agonist developed from
cytisine, a drug widely used in central and
eastern Europe for smoking cessation
 Nicotine receptor partial agonists may help
smokers to quit by a combination of
maintaining moderate levels of dopamine to
counteract withdrawal symptoms (acting as
an agonist) and reducing smoking satisfaction
(acting as an antagonist). Nicotine receptor partial agonists for
smoking cessation.Cochrane Database Syst Rev. 2008 Jul 16; (3):CD006103. Epub 2008 Jul 16.
[Cochrane Database Syst Rev. 2008
 Direct acting
 Bethanechol
 Carbachol
 Cevimeline
 Pilocarpine
 Suberylcholine
 Reversible
 The following substances reversibly inhibit the
enzyme acetylcholinesterase
 Alzheimer's disease (Donepezil ,Galantamine,
Rivastigmine,Tacrine ,
 Edrophonium (myasthenic and cholinergic crisis)
 Neostigmine (myasthenia gravis)
 Physostigmine(in glaucoma and anticholinergic drug
overdoses)
 Pyridostigmine(myasthenia gravis)
 Carbamate(insecticides)
 Irreversible
 Semi-permanently inhibit the enzyme
acetylcholinesterase.
 Echothiophate ,
 Isofluorophate ,
 Organophosphate ,Insecticides ,Malathion
,Parathion ,Azinphos methyl, Chlorpyrifos
 Organophosphate-containing nerve agents (e.g.,
Sarin)
 Victims of organophosphate-containing
nerve agents commonly die of
suffocation as they cannot relax their
Thoracic diaphragm
 Reactivation of acetylcholine
esterase==== Pralidoxime
ACh receptor antagonists
====Antimuscarinic agents====
 Atropine
 Ipratropium
 Scopolamine
 Tiotropium
Ganglionic blocker
 Mecamylamine
 Hexamethonium
 Nicotine (in high doses)
 Trimethaphan
 Neuromuscular blockers
Atracurium ,Cisatracurium ,Doxacurium ,
Metocurine ,Mivacurium ,Pancuronium
,Rocuronium ,Succinylcholine ,Tubocurarine,
Vecuronium
Release isnhibitor
 Botulism toxin Botulin acts by suppressing
the release of acetylcholine.
References:
Comprehencive test book of
psychiatry 8th Ed
Essential psychopharmacology by
Stephen.M.Stahl 3rd Ed
Synopsis of psychiatry 10th Ed
Wikipedia net sources
THANK YOU