2. Contents
• History and introduction
• Synthesis release and degradation
• Mechanism of action of acetylcholine
• Pathways, receptors and functions
• pharmacology
3. History and Functions
Acetylcholine was the first neuro transmiller to be identified
in the year 1914 by Henry Hallett Dale
It was confirmed as neurotransncitter by otto loewi, initially
gave it the name Vogusstoff, it was released from vagus nerve
It is an ester of Acetic acid & choline
Functions both in the peripheral nervous system (PNS) &
central nervous system (CNS) as a Neuro modulators
In the DNS it is a major neurotransmitter in the in the
autonomic nervous system
In the CNS Aeh and the associated neurons forms
Cholinengic system
4. Synthesis, Release, and Termination
• Actylcholine
synthesized in pre –
synaptic neuron and
released on
depolarisation
5.
6. COLINERGIC NEURONS PATHWAYS
With in CNS:-
• Projection neurons
• Inter neurons
Projection nerons
| |
BasalforeBrain
Mesopontinecomplex
Outside CNS
• Preganglionic Autonomic
• Motor neurons
• Postganglionic
parasympathetic neurons
7. Basal forebrian
Nu basalis of Horiz & vert Medial septal
Meynert Diagonal bands of BROCA nucleus
Areas of cortex Ant . Cingulate Hippo campus
& Gyrus & olfactory
Amygdala bulb
8. Mesopontine complex
Pedunculo pontine &
laterodorsal tegmeutalnucleus
of midbrain & pons
Thalamus & mid brain areas Locus caruleus
Dorsal raphe
Cranial nerve Nu
9.
10.
11. RECEPTORS
Two major classes of cholinergic receptors exist
• Muscarinic - G—protein
coupled
• Longer onset latency
both excitatory &
inhibilitory
• Nicotinic – ligand gated
ion channels
• Rapid – onset excitatory
12. Muscarinic Receptors
5 Muscarnic Subtypes have been cloaned
Again Divided into fauties
M1 Active Gaj-leading to phosphotidyl inositol
M3 turn over and increase in intacellular calicium
M5
M2 Active Gi – leading to the inhibitiou of
M4 Adenylate cyclase acts as Auto receptors and hetero receptors
13. .-
Receptors Location
Subtypes
M1 Cortex , Hippo campus
stiatum
M3 GIT , GUT , Salivay glands
M5 Peripheral & crebral
blood vessel
M2 Heart & Brian
M4 Hippo campus , cortex
situation thalamus &
cerebellum
Fuctions
Memory , Synaptic plasticity , Seizures
Smooth muscle countraetious in GIT GUT
Salivation
Anterial core bid Vaso dialation
Heart rate Temors, Hypothermia
Analgecia
Oppose the effects of D1 – Receptors in
striatum
14. • Nicotinic acetylcholine receptors, are members of the ligand-gated
ion channel super family and mediate rapid, excitatory signalling.
• They are composed of a pentameric complex of membrane protein
subunits radially arranged around a central ion pore.
• The binding of acetylcholine to this receptor induces a
conformational change that opens the channel and permits the
passage of Na+, K+, and Ca2+ ions through the channel pore,
leading to membrane depolarization.
• Nicotinic acetylcholine receptor subunits are heterogeneous and
associate in varied combinations.
• Thus, the properties of an individual complex, such as cation
permeability and the rate of desensitization, depend upon its
particular subunit composition.
15. • These various nicotinic acetylcholine receptor subunits can be
categorized into three general functional classes:
– (1) skeletal muscle subunits (α1, β1, δ and ε),
– (2) standard neuronal subunits (α2–α6 and β2–β4), and
– (3) subunits capable of forming homomeric receptors (α7–α9).
• In the periphery, nicotinic acetylcholine receptors are found in skeletal
muscle, autonomic ganglia, and the adrenal medulla.
• In the brain, they are found in many locations including the
neocortex, hippocampus, thalamus, striatum, hypothalamus,
cerebellum, substantia nigra, ventral tegmental area, and dorsal
raphe nucleus.
• Most nicotinic acetylcholine receptors in mammalian brain contain
either α4 β2 or α7 subunit combinations.
-
16. • Nicotinic receptors have been implicated in cognitive function,
especially working memory, attention, and processing speed.
• Cortical and hippocampal nicotinic acetylcholine receptors appear
to be significantly decreased in Alzheimer's disease, and nicotine
administration improves attention deficits in some patients.
• The acetylcholinesterase inhibitor galantamine used in the
treatment of Alzheimer's disease also acts to positively modulate
nicotinic receptor function.
17. -
• The α7 nicotinic acetylcholine receptor subtype has been
implicated as one of many possible susceptibility genes for
schizophrenia, with lower levels of this receptor being associated
with impaired sensory gating.
• Some rare forms of the familial epilepsy syndrome autosomal
dominant nocturnal frontal lobe epilepsy (ADNFLE) are associated
with mutations in the α4 or β2 subunits of the nicotinic
acetylcholine receptor.
• Finally, the reinforcing properties of tobacco use are proposed to
involve the stimulation of nicotinic acetylcholine receptors located
in mesolimbic dopaminergic reward pathways.
18. PHARMACOLOGY
• Blocking, hindering or mimicking the action of acetylcholine has many
uses in medicine.
Drugs acting on the acetylcholine system are either agonists to the
receptors, stimulating
the system, or antagonists, inhibiting it. Acetylcholine receptor agonists
and antagonists
can either have an effect directly on the receptors or exert their effects
indirectly, e.g., by
affecting the enzyme acetylcholinesterase, which degrades the receptor
ligand. Agonists
increase the level of receptor activation, antagonists reduce it.
19. Acetylcholine and Drugs
• The most common use of anticholinergic drugs in psychiatry is in
treatment of the motor abnormalities caused by the use of classic
antipsychotic drugs (e.g., haloperidol).
• The efficacy of the drugs for that indication is determined by the
balance between acetylcholine activity and dopamine activity in the
basal ganglia.
• In healthy people, the activity of the nigrostriatal dopamine
pathway is partially balanced by the activity of cholinergic pathways
in the basal ganglia.
• Blockade of D2 receptors in the striatum upsets this balance, but
the balance can be partially restored, although at a lower set point,
by antagonism of muscarinic receptors.
20. • Blockade of muscarinic cholinergic receptors is a common
pharmacodynamic effect of many psychotropic drugs.
• Blockade of those receptors leads to the commonly seen adverse
effects of blurred vision, dry mouth, constipation, and difficulty in
initiating urination.
• Excessive blockade of CNS cholinergic receptors causes confusion
and delirium.
• Drugs that increase cholinergic activity by blocking breakdown by
acetylcholinesterase (e.g., donepezil [Aricept]) have been shown to
be effective in the treatment of dementia of the Alzheimer's type.
21. • When bound by nicotine, CNS presynaptic nicotinic receptors mediate a
large influx of calcium and, therefore, cause neurotransmitter release in
many types of neurons.
• Recent evidence has shown that nicotine increases the strength of
synaptic connections in the hippocampus, the brain region that supports
short-term memory.
• Several nicotine-like compounds that stimulate acetylcholine release are
under study as cognitive enhancers for treatment of Alzheimer's disease.
• The efficacy of Varenicline in smoking cessation is believed to be the result
of Varenicline activity at α4β2 sub-type of the nicotinic receptor where its
binding produces agonist activity, while simultaneously preventing
nicotine binding to these receptors.
• Varenicline blocks the ability of nicotine to activate α4β2 receptors and
thus to stimulate the central nervous mesolimbic dopamine system,
believed to be the neuronal mechanism underlying reinforcement and
reward experienced upon smoking.
22. Release inhibitors:-
• Botulin – suppressing the release of
acetylcholine
• Nerotoxin – bungarotoxin, crotoxin, and
notoxin prevent release of actylcholine at NM
junction
• Block acetylcholine naturally – able to work on
lowering acetylcholine levels – lipoic acid,
kavaroot, forskolin
