AUTONOMIC NEUROTRANSMISSION.pptx

NEUROTRANSMISSION
IN AUTONOMIC
NERVOUS SYSTEM
Presenter:-
DR NIKHIL KAMDI
Junior resident 1
Guided by:-
DR BHUSHAN DUDHE
Assistant professor

Overview:-
• Introduction
• Anatomic and general function
• Sympathetic and parasympathetic system
• Neurohumoral transmission
• Cotransmission in autonomic nervous system
• Cholinergic transmission
• Adrenergic transmission
• Summary
17-09-2022 Neurotransmission in ANS 2

Introduction:-
• Autonomic nervous system also called the visceral, vegetative or involuntary nervous
system
• Distributed widely throughout the body
• Regulates autonomic functions that occur without conscious control
• Supply all innervated structures of the body except skeletal muscle

Introduction cont…
Differences between autonomic and somatic nervous system:-
Somatic Autonomic
1.Organ supplied Skeletal muscles All other organs
2.Distal most synapse Within CNS Outside CNS (In ganglia)
3.Nerve fibers Myelinated Preganglionic: myelinated
Postganglionic: non-myelinated
4.Peripheral plexus
formation
Absent Present
5.Primary efferent
transmitter
Acetylcholine Acetylcholine, Norepinephrine
6.Effect of nerve section
on organ supplied
Paralysis and atrophy Activity maintained, no atrophy

Anatomy and general functions:-
Afferent fibres from visceral structures are the first link in the reflex arcs of
the autonomic system
Two Main Sensory Systems
Cranial visceral sensory system
(Parasympathetic)
Spinal Visceral afferent system
(sympathetic)
 Carries mechanoreceptor and chemosensory
information
 Four cranial nerves the trigeminal (V), facial
(VII), glossopharyngeal (IX), and vagus (X)
nerves
 Pelvic sensory afferents enter at S2–S4 and
are important for the regulation of sacral
parasympathetic outflow
• Carries sensations related to temperature and
tissue injury of mechanical, chemical, or
thermal origin
• Sympathetic visceral sensory afferents arise
at the thoracic levels
All the transmitters of the primary afferent fibres have not been identified conclusively
Substance P and glutamate may mediate many afferent impulses; both are present in high
concentrations in the dorsal spinal cord
17-09-2022 Neurotransmission in ANS
5

Central Autonomic Connections:-
• Autonomic reflexes can be elicited at the level of the spinal cord
• Extensive central ramifications exist above the level of the spinal cord
• Hypothalamus and the Solitary tract Nucleus (STN) are principal loci of
integration of ANS functions

Central autonomic connection cont.….
• Stimulation of the STN and the hypothalamus activates bulbospinal pathways
and hormonal output to mediate autonomic and motor responses
• Highly integrated patterns of response generally are organized at a hypothalamic
level and involve autonomic, endocrine, and behavioral components

Divisions of the Peripheral Autonomic System:-
• Two main divisions:-
• Most organs in the body are innervated by both divisions of the ANS
• One system usually predominates in controlling the activity of a given organ
Sympathetic or thoracolumbar outflow
Parasympathetic or craniosacral outflow

Sympathetic System:-
• Preganglionic neurons origins from Thoracic and lumbar regions (T1 to L2) of the
spinal cord
• Preganglionic neurons are short in comparison to the postganglionic ones
• Axons of the postganglionic neuron extend from these ganglia to the tissues that they
innervate and regulate
• Adrenal medulla receives preganglionic fibres from the sympathetic system

Functions of the sympathetic nervous system:-
• Property of adjusting in response to stressful situations such as trauma, fear,
hypoglycaemia, cold, and exercise
• Changes experienced by the body during emergencies have been referred to as the “fight or
flight” response
• These reactions are triggered both by direct sympathetic activation of the effector organs
and by stimulation of the adrenal medulla

Parasympathetic system:-
• Parasympathetic preganglionic fibres arise from :-
⮚Cranial nerves III (oculomotor), VII (facial), IX (glossopharyngeal), and X(vagus)
⮚Sacral region (S2 to S4) of the spinal cord
• Vagus nerve accounts for 90% of preganglionic parasympathetic fibres in the body

Parasympathetic system cont.…
• Postganglionic neurons from this nerve innervate most of the organs in the
thoracic and abdominal cavity
• Preganglionic fibers are long and the postganglionic ones are short

Functions of the parasympathetic nervous system:-
• Parasympathetic division is involved with maintaining homeostasis within the body
• To accomplish this, it maintains essential bodily functions, such as digestive processes
• It usually acts to balance the actions of the sympathetic division
• Generally dominant over the sympathetic system in “rest and digest” situations

Difference between Sympathetic and Parasympathetic system:-

Enteric nervous system:-
• Consider to be the third division of the ANS
• Processes of mixing, propulsion, and absorption of nutrients in the GI tract are
controlled locally through ENS
• It is modulated by both the sympathetic and parasympathetic nervous systems
• Two nerve plexus ;- 1) Myenteric (Auerbach) 2) Submucosal (Meissner)

CONT ENS….
• Primary neurotransmitter providing excitatory inputs: Ach
• Ach activates M2 and M3 receptors in postjunctional cells to elicit motor
responses
• Inhibitory responses are elicited by a purine derivative (e.g ATP)) and Nitric
oxide
• ATP, substance P, 5HT are also important in mediating integrative processes

Neurohumoral Transmission
Nerve impulses elicit responses in smooth, cardiac, skeletal muscles,
exocrine glands and postsynaptic neurons by liberating specific chemical:
neurotransmitters

Evidence for Neurohumoral Transmission
1. Demonstration of the presence of a physiologically active compound and its
biosynthetic enzymes at appropriate sites
2. Recovery of the compound from the perfusate of an innervated structure during
periods of nerve stimulation but not in the absence of stimulation

3. Demonstration that the compound is capable of producing responses identical to
responses to nerve stimulation
4. Demonstration that the responses to nerve stimulation and to the administered
compound are modified in the same manner by various drugs, usually competitive
antagonists

Criteria for neurotransmitter:-
1. Should be present in the presynaptic neuron
2. Should be released in the medium following nerve stimulation
3. Its application should produce responses identical to those produced by nerve
stimulation
4. Its effects should be antagonized or potentiated by other substances which similarly
alter effects of nerve stimulation

Steps involved in neurotransmission:-
1. Impulse conduction
2. Storage and Transmitter release
3. Transmitter action on postjunctional membrane
4. Postjunctional activity
5. Termination of transmitter action

1. Impulse conduction:-
• Resting transmembrane potential -70 is established by high K+ ions permeability of
axonal membrane
• Stimulation or arrival of an electrical impulse causes a sudden increase in Na+
conductance - depolarization
• K+ ions then move out in the direction of their concentration gradient and
repolarization is achieved
• Action potential (AP) thus generated sets up local circuit current
• AP is propagated without decrement

2. Storage and Transmitter release:-
• Transmitter is stored in prejunctional nerve endings within synaptic vesicle
• Nerve impulse promotes fusion of vesicular and axonal membranes through Ca+
ions entry which fluidizes membrane
• All contents of the vesicle (transmitter, enzymes and other proteins) are extruded
by exocytosis in the junctional cleft

3.Transmitter action on postjunctional membrane:-
• Released transmitter combines with specific receptors on the postjunctional
membrane
• Increase in permeability to cations Na+ or Ca+ influx causes depolarization followed
by K+ efflux: EPSP is generated
• Increase in permeability to anions, so that Cl- ions move in and tend to hyperpolarize
the membrane : IPSP is generated

4. Postjunctional activity:-
• Suprathreshold EPSP generates a propagated postjunctional AP which results in nerve
impulse (in neuron), contraction (in muscle) or secretion (in gland)
• IPSP stabilizes the postjunctional membrane and resists depolarizing stimuli

5. Mechanisms of termination of transmitter action:-
 Parasympathetic neuron:
1.Acetylcholine is rapidly hydrolyzed by a specific enzyme acetylcholinesterase
2.AChE activity is inhibited, removal of the transmitter principally by diffusion
 Sympathetic neuron:
1.Noradrenaline (NA) is largely taken back into the neuron by membrane-bound
norepinephrine transporter (NET) and Etraneuronal amine transport (ENT)
2.Minor fraction diffuses away

Presynaptic modulation of neurotransmitter release:-
• Number of autocrine and paracrine factors may influences release of transmitter
• Released neurotransmitter itself influences the release
• Adenosine, Dopamine, glutamate, GABA, prostaglandins, and enkephalins

Presynaptic Receptors:-
Heteroreceptors
• Presynaptic receptors that respond to
neurotransmitters or neurohormones
released from adjacent neurons or
cells
• For example, NE can influence the
release of ACh from
parasympathetic neurons by acting
on α2A, α2B, and α2C receptors
Autoreceptors
• Receptors located on or close to
axon terminals of a neuron through
which the neuron’s own transmitter
can modify transmitter synthesis and
release
• For example, NE released from
sympathetic neurons may interact
with α2A and α2C receptors to
inhibit neurally released NE

Neurotransmitters in ANS:-

Co-transmission:-
• Classical 'one neuron- one transmitter ' model is an over simplification
• On stimulation most peripheral and central neurons have been shown to release more than
one active substance
• Other cotransmitters found are:
1. Purines (ATP, adenosine),
2. Peptides (vasoactive intestinal peptide (VIP), neuropeptide-Y, substance P,
Enkephalins, somatostatin, etc.)
3. Nitric oxide (NO) and prostaglandins

Co-transmission cont.…
• In most autonomic cholinergic neurons VIP is associated with Ach
• ATP is associated with both ACh and NA
• Transmitter at some parasympathetic sites is NO and these are called nitrergic nerves
• Cotransmitter may serve to regulate the presynaptic release of the transmitter and/or
postsynaptic sensitivity to it

Cholinergic
Neurotransmission
Synthesis of Ach
Acetyl CoA+ choline
Choline acetyl transferase
ACh
• Acetyl CoA is synthesized in
mitochondria
• Choline is transported into the
presynaptic nerve terminal by a
sodium-dependent choline
transporter (CHT)
• Blocked by Hemicholinium drug

Release of Ach
 Release of transmitter occurs
when voltage-sensitive calcium
channels in the terminal
membrane are opened, allowing
an influx of calcium ions
 It causes fusion of vesicles with
the surface membrane and
exocytotic expulsion of
acetylcholine and cotransmitters
into the junctional cleft
 This step can be blocked by
botulinum toxin

Reuptake
Acetylcholine’s action is
terminated by metabolism by
the enzyme
acetylcholinesterase

Prejunctional modulation of Ach release:-
• ACh release is subject to complex regulation by mediators, including
✔ACh itself acting on M2 and M4 autoreceptors
✔Activation of heteroreceptors (e.g., NE acting on α2A and α2C adrenergic receptors)
• Inhibitory heteroreceptors on parasympathetic terminals includes -
1.Adenosine A1 receptors
2.Histamine H3 receptors
3.Opioid receptors
4.α2A and α2C adrenergic receptors

Cholinergic Receptors:-
Nicotinic Receptors
Ligand gated ion channels
Increase in permeability to Na+
and Ca2+
Depolarization and excitation
Muscarinic Receptors
G-Protein Coupled Receptors
Not necessarily linked to
changes in ion permeability
May be excitatory or inhibitory

Subtypes of nicotinic receptors:-
Muscle Type Nm Neuronal Type Nn
Location and
function
subserved
Neuromuscular Junction:
depolarization of muscle end plate
--contraction of skeletal muscle
Autonomic ganglia: depolarization
-postganglionic impulse
Adrenal medulla: catecholamine release
CNS: Pre and postsynaptic excitation
prejunctional control of transmitter release
Nature Has Intrinsic ion channel, pentamer
of α2 β ε or γ and δ subunits
Has intrinsic ion channel, pentamer
of only α or α and β subunits
Transducer
mechanism
Opening of cation (Na+, K+) channels Opening of cation (Na+, K+) channels
Agonists Nicotine, Ach, Succinylcholine Dimethylphenylpiperazinium, Nicotine
Antagonists Tubocurarine, α-Bungarotoxin Trimethaphan, Mecamylamine

Subtypes of muscarinic receptors:-
Receptor Cellular and tissue location Functional response
M1 • CNS; most abundant in cerebral cortex
hippocampus, striatum, and thalamus
• Autonomic ganglia
• Glands (gastric and salivary)
• Increased cognitive function
(learning and memory)
• Increased seizure activity
• Increase in depolarization of
autonomic ganglia
• Increase in secretions
M2 • Widely expressed in CNS, hindbrain, thalamus,
cerebral cortex, hippocampus, striatum,
• Heart
• Glands
• Smooth muscle
• Autonomic nerve terminals
• Heart: decrease in heart rate
and conduction
• CNS: increase in cognition
• GIT secretion: increases
• GIT contraction: increases
• Glands: increases secretion
• Bronchi: bronchoconstriction
• Bladder: increase contraction
• Circular muscle of iris: miosis

M3 • Abundant in smooth muscle and glands
• Heart
• Widely expressed in CNS
• Smooth muscle: ↑
Contraction
• Glands: ↑
Secretion(predominant in
salivary gland
• GIT: contraction
• Bronchi:
bronchoconstriction
• Bladder: detrusor
contraction
• Circular muscle f iris:
miosis
M4&M5 Mostly present in CNS and has no clinical
significance
CONT…

Adrenergic transmission:-
 Norepinephrine (NE) is the principal transmitter of most sympathetic postganglionic
fibres
 Dopamine(DA) is the predominant transmitter of the mammalian extrapyramidal
system and of several mesocortical and mesolimbic neuronal pathways
 Epinephrine is the major hormone of the adrenal medulla
 Collectively, these three amines are called catecholamines

Synthesis of catecholamines

Synthesis
 Synthesized from the amino acid phenylalanine
 Phenylalanine is converted to tyrosine by hydroxylase enzyme
 Tyrosine converted to dopa by tyrosine hydroxylase
 Tyrosine hydroxylase is a specific and the rate limiting enzyme
Its inhibition by metyrosine results in depletion of CAs
 In dopaminergic neurons, synthesis terminates with dopamine
 Synthesis of norepinephrine occurs in all adrenergic neurons
 Epinephrine occurs only in the adrenal medullary cell

Release
Release of transmitter occurs
when an action potential
opens voltage-sensitive
calcium channels and
increases intracellular
calcium

Reuptake
 Axonal uptake(uptake1)
• An amine pump NE
Transporter(NET) transports NE by
Na+ coupled mechanism
• Inhibited by Cocaine, desipramine
 Extraneuronal uptake(uptake2)
• Carried out by extraneuronal amine
transporter(ENT)
• It is organic cation
transporter(OCT3)
• Movement of catecholamines into
non neuronal cell along their
electrochemical gradient

Metabolism of
Catecholamines
 Part of the NE leaking out
from vesicles into cytoplasm
as well as that taken up by
axonal transport is first
attacked by MAO.
 Diffused NE is first acted
upon by COMT in liver and
other tissues.
 In both cases, the alternative
enzyme can subsequently
act to produce
vanillylmandelic acid
(VMA).

Prejunctional modulation of NE release:-
• Release of the three sympathetic cotransmitters can be modulated by prejunctional
autoreceptors and heteroreceptors
• NE, NPY, and ATP—can feed back on prejunctional receptors to inhibit the release of
each other
• α2A and α2C prejunctional receptors that inhibit sympathetic neurotransmitter release

Cont…..
• NPY(Y2 receptors), and ATP-derived adenosine(P1 receptors), also can inhibit
sympathetic neurotransmitter release
• Heteroreceptors inhibiting the release of sympathetic neurotransmitters:
 M2 and M4 muscarinic
 5HT
 PGE2
 Histamine

Types of α-adrenoceptors

Types of β adrenoreceptors:-
β1 β2 β3
Location Heart, JG cells in
kidney
Bronchi, blood vessels,
uterus, liver, skeletal
muscles, GI smooth
muscles
Adipose tissue,
detrusor muscle of
bladder
Selective agonist Dobutamine Salbutamol,terbutalin Mirabegron
Selective antagonist Metoprolol, Atenolol α methyl propranolol
Relative potency of Adr
and NA
Adr ≥ NA Adr >> NA NA > Adr
Dominant Actions Dominant mediator of
positive inotropic and
chronotropic effects in
heart
Smooth muscle
relaxation
Tremors
Palpitations
Relaxation of detrusor
Lipolysis

Actions of Adrenoceptors stimulation:-
Vasoconstriction
Constriction of internal urethral sphincter
Mydriasis
Impaired ejaculation
Gut relaxation
❖α1 receptor:
Inhibits NE release
Inhibits Ach release
Inhibits Insulin release
Vasoconstriction
↓ central sympathetic outflow
❖α2 receptor:

Tachycardia
↑ myocardial contractility
↑ renin release
Vasodilatation
Bronchodilatation
Relaxed uterine smooth muscle
↑ muscle & liver glycogenolysis
Lipolysis
Lipolysis
❖ β1 receptor:
❖β3 receptor
❖β2 receptor:

Other ANS,ENS and NANC Neurotransmitters:-
• Acts as a transmitter or cotransmitter at many ANS-effector synapses
Adenosine triphosphate (ATP)
• Found in many noradrenergic neurons
• Present in some secretomotor neurons in the ENS and may inhibit secretion of water
and electrolytes by the gut
• Causes long-lasting vasoconstriction
• It is also a cotransmitter in some parasympathetic postganglionic neurons
Neuropeptide Y (NPY)
• A cotransmitter at inhibitory ENS and other neuromuscular junctions; may be
especially important at sphincters
• Cholinergic nerves innervating blood vessels appear to activate the synthesis of NO by
vascular endothelium
• NO is not stored, it is synthesized on demand by nitric oxide synthase
Nitric Oxide

• Present in some secretomotor and interneurons in the ENS
• Appear to inhibit ACh release and thereby inhibit peristalsis
• May stimulate secretion
Enkephalin and related opioid peptides
• Substance P is an important sensory neurotransmitter in the ENS and elsewhere
• Tachykinins appear to be excitatory cotransmitters with ACh at ENS neuromuscular junctions
• Found with CGRP in cardiovascular sensory neurons
• Substance P is a vasodilator (probably via release of nitric oxide)
Substance P, related tachykinins
• Found with substance P in cardiovascular sensory nerve fibres
• Present in some secretomotor ENS neurons and interneurons
• A cardiac stimulant
Calcitonin gene-related peptide(CGRP)
• Excitatory secretomotor transmitter in the ENS; may also be an inhibitory ENS neuromuscular
cotransmitter
• A probable cotransmitter in many cholinergic neurons
• A vasodilator (found in many perivascular neurons) and cardiac stimulant
Vasoactive intestinal peptide (VIP)

Summary:-
• ANS is divided into sympathetic, parasympathetic & enteric nervous system
• Primary NT of sympathetic nervous system is norepinephrine
• Primary NT of parasympathetic nervous system is acetylcholine
• Each step (synthesis of NT to post-synaptic receptor activation) involved in
neurotransmission represents potential point of therapeutic intervention

CONT….
• Cotransmitter may serve to regulate the presynaptic release of the transmitter
and/or postsynaptic sensitivity to it
• The release of the three neurotransmitters & cotransmitters can be modulated by
prejunctional autoreceptors and heteroreceptor
• Drugs acts through cholinoceptors and adrenoceptors produces variable actions

References:-
• Goodman & Gilman’s The Pharmacological Basis of Therapeutics
13th Edition ; page no 122-152
• Bertram G. Katzung & Anthony J. Trevor’s Basic & Clinical
Pharmacology 14th Edition; page no 89-110
• KD Tripathi Essentials of medical pharmacology 8th Edition; page no
136-152

NEXT PG ACTIVITY
0N 02/08/2022
TOPIC: SELECTION OF
END POINTS
INCLUDING
SURROGATE MARKER
AND BIOLOGICAL
MARKER IN CLINICAL
TRIALS
PRESENTOR: DR AMIT
DHOK JR3

AUTONOMIC NEUROTRANSMISSION.pptx

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