The document provides an overview of autonomic neurotransmission. It discusses the anatomy and functions of the sympathetic and parasympathetic nervous systems. The key points are: - The autonomic nervous system regulates involuntary functions and is composed of the sympathetic and parasympathetic divisions. - The sympathetic division originates in the thoracic and lumbar spinal cord and is involved in the "fight or flight" response. The parasympathetic division originates in the cranial and sacral regions and is active during rest. - Neurotransmission in the autonomic nervous system involves the release of acetylcholine or norepinephrine at neuroeffector junctions. These neurotransmitters are stored in vesicles and released via

1. AUTONOMIC
NEUROTRANSMISSION
By
Dr. Akhil Giradkar
JR-2, Dept. of Pharmacology
GMC, Nagpur

2. Overview
• Introduction
• Anatomic and general function
• Sympathetic and parasympathetic system
• Neurohumoral transmission
• Cholinergic transmission
• Adrenergic transmission
• summary

3. Introduction
• The autonomic nervous system, also called the visceral, vegetative, or involuntary
nervous system
• Distributed widely throughout the body and regulates autonomic functions that
occur without conscious control
• Supply all innervated structures of the body except skeletal muscle.
• The most distal synaptic junctions in the autonomic reflex arc occur in ganglia that
are entirely outside the cerebrospinal axis.
• Many autonomic nerves form extensive peripheral plexuses

4. Introduction
Differences between somatic and autonomic nervous system

5. 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.
• Carries sensations related to temperature
and tissue injury of mechanical, chemical, or
thermal origin.
• Sympathetic visceral sensory afferents arise
at the thoracic levels.
• Pelvic sensory afferents enter at S2–S4 and
are important for the regulation of sacral
parasympathetic outflow.
Afferent fibres
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.

6. 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 🡪 principal loci of integration of
ANS functions.
• 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 behavioural components.

7. Divisions of the Peripheral Autonomic System
• Two main divisions
• Most organs in the body are innervated by both divisions of the ANS.
• Thus, vagal parasympathetic innervation slowsthe heart rate, and sympathetic innervation
increases the heart rate.
• One system usually predominates in controlling the activity of a given organ.
Eg: in the heart, the vagus nerve is the predominant factor for controlling rate.
• This type of antagonism is considered to be dynamic and is fine-tuned at any given time to
control homeostatic organ functions.
• The activity of a system represents integration of influence of both divisions.
sympathetic or thoracolumbar outflow
parasympathetic or craniosacral outflow

8. Sympathetic System
• Preganglionic neurons 🡪 Thoracic and lumbar regions (T1 to L2) of the spinal cord.
• Synapse in two cordlike chains of ganglia that run close to and in parallel on each side
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.
• The adrenal medulla receives preganglionic fibres from the sympathetic system.
• Stimulation by neurotransmitter acetylcholine causes secretion of the hormone
epinephrine and lesser amount of norepinephrine into the blood

9. Functions of the sympathetic nervous system
• Continually active to some degree (example: maintaining the tone of vascular
beds)
• It has the property of adjusting in response to stressful situations, such as trauma,
fear, hypoglycemia, 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
• Functions as a unit and often discharges as a complete system.
Example, during severe exercise or in reactions to fear

10. Parasympathetic system
• The parasympathetic preganglionic fibers arise from :-
⮚cranial nerves III (oculomotor), VII (facial), IX (glossopharyngeal), and X (vagus)
⮚sacral region (S2 to S4) of the spinal cord and synapse in ganglia near or on the
effector organs.
• The vagus nerve accounts for 90% of preganglionic parasympathetic fibers in the body.
• Postganglionic neurons from this nerve innervate most of the organs in the thoracic
and abdominal cavity.
• The preganglionic fibers are long, and the postganglionic ones are short.
• In most instances there is a one-to-one connection between the preganglionic and
postganglionic neurons, enabling the discrete response of this division.

11. Functions of the parasympathetic nervous system
• The parasympathetic division is involved with maintaining homeostasis within
the body.
• To accomplish this, it maintains essential bodily functions, such as digestive
processes and elimination of wastes.
• The parasympathetic division is required for life.
• It usually acts to oppose or balance the actions of the sympathetic division.
• Generally dominant over the sympathetic system in “rest and digest” situations.
• The parasympathetic system is not a functional entity as such and it never
discharges as a complete system

12. Enteric nervous system
• The enteric nervous system is the third division of the ANS.
• It is a collection of nerve fibres that innervate the gastrointestinal (GI) tract, pancreas, and
gallbladder, and it constitutes the “brain of the gut.”
• Functions independently of the CNS and controls the motility, exocrine and endocrine
secretions, and microcirculation of the GI tract.
• It is modulated by both the sympathetic and parasympathetic nervous systems.
• Two nerve plexus ;- 1) Myentric (Auerbach) 2) Submucosal (meissner)
• Ach 🡪 Primary neurotransmitter providing excitatory inputs
• ATP(P2X), substance P(NK3), 5HT(5HT3) are also important in mediating integrative
processess

13. Difference between Sympathetic and
Parasympathetic system

15. Neurohumoral Transmission
• It implies that nerve transmit their message across synapses and neuroeffector junction by
the release of humoral ( chemical) messengers.
Evidence for Neurohumoral Transmission
• Demonstration of the presence of a physiologically active compound and its biosynthetic
enzymes at appropriate sites.
• Recovery of the compound from the perfusate of an innervated structure during periods of
nerve stimulation but not in the absence of stimulation.
• Demonstration that the compound is capable of producing responses identical to responses
to nerve stimulation.
• Demonstration that the responses to nerve stimulation and to the administered compound
are modified in the same manner by various drugs, usually competitive antagonists

16. Criteria for Neurotransmitter
❖ Criteria of Neurotransmitter (NT):
❑ Synthesis
❑ Release
❑ Synthesizing & degrading enzymes
❑ Receptor in target cell
❑ Applied exogenously
❑ Receptor antagonist

17. Steps:
I. Impulse conduction
II. Transmitter release
III. Transmitter action on postjunctional
membrane
IV. Postjunctional activity
V. Termination of transmitter action
Steps Involved in
Neurotransmission
Axonal Conduction
Transmitter release
Action on post junctional membrane

18. 1. Vesicular docking in the active zone:
Munc18 binds to syntaxin , stabilizing
the neuronal membrane SNARE
proteins
2. Priming I:
Syntaxin assembles with SNAP25,
allowing for the vesicle SNARE
protein synaptobrevin to bind to the
complex.
3.Priming II: Complexin binds to
the SNARE complex and allows for
the vesicular synaptotagmin to
bind Ca2+ that drives the full
fusion process.
4. Fusion pore opening:
Synaptotagmin interacts with the
SNARE complex and binds Ca2+,
permitting pore fusion and
exocytosis of neurotransmitter.
5. Return to ground state: After
fusion, the chaperone ATPase NSF
and its SNAP adapters catalyze
dissociation of the SNARE-
complex.

19. Presynaptic modulation of transmitter release
• Transmitter release in response to electrical activity in the
nerve fibre is often sensitive to transmitter substances and
to other substances that may be produced locally in tissues
• Such presynaptic effects most commonly act to inhibit
transmitter release, but may enhance it.
• The release of noradrenaline from nearby sympathetic nerve
terminals can also inhibit release of acetylcholine.
• Transmitter, by binding to its presynaptic receptors, affects
the nerve terminals from which it is being released.

20. Presynaptic Receptors
Heteroreceptors
• Presynaptic receptors that respond
to neurotransmitters
neuromodulators, 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

21. Neurotransmitters in ANS
❖Acetylcholine (Ach):
❖Norepinephrine (NE):
▪ Autonomic ganglia
▪ Postganglionic nerve in
parasympathetic system
▪ Adrenal medulla
▪ Sweat glands
▪ Skeletal muscles
▪ Postganglionic nerve in
sympathetic system

22. Co - transmission
• 'oneneurone- one transmitter ' model is a n over simplification.
• Most peripheral and central neurones release more than one active substance.
• In the ANS, cotransmitters besides the primary transmitters ACh and NA include
✔ purines (ATP, adenosine),
✔ peptides
✔ nitric oxide( NO)
✔ Prostaglandins
• In most autonomic cholinergic neurones VIP is associated with Ach.
• ATP is associated with both ACh and NA.
• The transmitter at some parasympathetic sites is NO and these are called nitrergic nerves.
• Vascular adrenergic nerves contain NPY which causes long lasting vasoconstriction.

23. • Cotransmitter is stored in the same neuron but in distinct
synaptic vesicles or locations.
• However, ATP is stored with NA in the same vesicle.
• Cotransmitter may serve to regulate the presynaptic release of
the primary transmitter and/or postsynaptic sensitivity to it
(neuromodulator role).
• The cotransmitter may also serve as an alternative transmitter
in its own right and/or exert a trophic influence on the synaptic
structures

24. Cholinergic
Neurotransmission
Synthesis of Ach
choline + acetyl CoA
Choline acetyl transferase
ACh
• Acetyl CoA is synthesized in
mitochondria
• Uptake of choline is done by
Choline transporter 🡪Rate
limiting step
• Blocked by Hemicholinium
Storage of Ach
• ACh is transported into synaptic
vesicles by the Vesicular Ach
transporter( VAChT)
• Inhibited by the noncompetitive
and reversible inhibitor vesamicol
• Core of the vesicles contains both
ACh and ATP
• In some cholinergic terminals,
there is VIP, that act as
cotransmitters
Release of Ach
• Interaction between snare
proteins
• Causes docking, priming.
• AP reaches the terminal and
causes influx of calcium
• Calcium binds with
synaptogamin
• Fusion and Exocytosis
Acetylcholinesterase
• Causes immediate hydrolysis of
Ach
• Limits the receptor activation
and facilitates Rapid control of
responses

25. 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)
• At myenteric plexus or the cardiac SA node sympathetic and parasympathetic nerve
terminals often lie juxtaposed to each other.
• Inhibition of ACh release by NE or inhibition of NE release by ACh acting on
heteroreceptors on parasympathetic or sympathetic terminals 🡪 Opposite action
• Inhibitory heteroreceptors on parasympathetic terminals include -
adenosine A1 receptors, histamine H3 receptors, opioid receptors, and α2A and α2C
adrenergic receptors.

26. 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

27. 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: site specific excitation or inhibition
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+, Ca2+ )channels
Agonists PTMA, Nicotine,Ach, Succinylcholin DMPP, Nicotine, Epibatidine, Ach
Antagonsts Tubocurarine, α-Bungarotoxin Hexamethonium, Trimethaphan,
Mecamylamine

28. Subtypes of muscarinic receptors

29. Adrenergic transmission
• Norepinephrine (NE) is the principal transmitter of most sympathetic
postganglionic fibers and of certain tracts in the CNS
• DA is the predominant transmitter of the mammalian extrapyramidal system and
of several mesocortical and mesolimbic neuronal pathways
• EPI is the major hormone of the adrenal medulla.
• Collectively, these three amines are called catecholamines.

30. Synthesis of
catecholamines
Rate limiting step
Inside vesicle

31. Adrenergic
neuroeffector junction
Storage
• NE, ATP and NPY are stored
frequently in the same nerve
endings.
• The vesicular monoamine
transporter(VMAT2) moves NE
and other catecholamines from
cytosol to vesical.
• Reserpine blocks VMAT2
ATP
Forms stable complexes with
catecholamines
It facilitates accumulation of high
concentration of catecholamines
Acts as a transmitter at purinergic
receptors
NPY
NPY,ATP and NE are co-released
according to pattern of stimulation
Found in sympathetic nerves, adrenal
chromaffin cells, platelets,
endothelium, GI tract
Release
• Ca2+ entry results in exocytosis
of the vesicular contents
• Various SNARE proteins are
also involved here
Reuptake of Catecholeamines
Axonal uptake
An amine pump NE
Transporter(NET) transports NE by
Na+ coupled mechanism
Inhibited by Cocaine, desipramine
Vesicular uptake
VMAT 2 Transports monoamines
by exchanging with H+ ions

32. Metabolism of
Catecholamines
• Part of the NA leaking out
from vesicles into cytoplasm
as well as that taken up by
axonal transport is first
attacked by MAO.
• Diffused NA 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).

33. Prejunctional modulation of NE release
• The 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
• NPY(Y2 receptors), and ATP-derived adenosine(P1 receptors), also can inhibit sympathetic
neurotransmitter release.
• Heteroreceptors inhibiting the release of sympathetic neurotransmitters; these include-
M2 and M4 muscarinic, 5HT, PGE2, histamine, enkephalin, and DA receptors.
• Enhancement of sympathetic neurotransmitter release 🡪 activation of β2 adrenergic receptors,
angiotensin AT2 receptors, and nAChRs.

34. Adrenergic Receptors
• Ahlquist (1948) proposed the existence of more than one adrenergic receptor.
• Adrenergic agents could cause either contraction or relaxation of smooth muscle
depending on the site, the dose, and the agent chosen.
• Examples
• NE 🡪 Potent excitatory effects on smooth muscle.
🡪low activity as an inhibitor of smooth muscle
Isoproterenol 🡪opposite pattern of activity
Epinephrine 🡪both excite and inhibit smooth muscle
• Ahlquist proposed the designations α and β for receptors on smooth muscle
where catecholamines produce excitatory and inhibitory responses, respectively

35. Adrenergic receptors
• The original subclassification was based on the rank order of agonist potency:
• EPI ≥ NE >> isoproterenol for α adrenergic receptors.
• Isoproterenol > EPI ≥ NE for β adrenergic receptors.

36. α-adrenoceptors
• All adrenergic receptors are GPCRs that link to heterotrimeric G proteins.
• The initial distinction was based on functional and anatomic considerations:
• Presynaptic feedback-inhibitory α adrenergic receptors were designated α2
• Postsynaptic “excitatory” α receptors were designated α1
• Phenylephrine and Methoxamine selectively activate post synaptic α1 receptors
• Clonidine selectively binds α2 & less effect on α1
• It was found that α2 receptors are present at postjunctional or nonjunctional sites
in several tissues.

37. Types of α-adrenoceptors
• The anatomic concept of prejunctional α2 and postjunctional α1 adrenergic receptors
has been abandoned in favor of a pharmacological and functional classification
α1 receptor – α1A, α1B, α1D α2 receptor – α2A, α2B, α2C

38. α1 receptors

39. α2 receptors

40. β-adrenoceptors
• Classified as β1, β2 and β3 receptors
• All three of them couple to Gs and activate adenylyl cyclase.
• Stimulation of β adrenergic receptors leads to the accumulation of cAMP,
activation of the PKA, and altered function of numerous cellular proteins as a
result of their phosphorylation.
• In addition, Gs subunits can enhance directly the activation of voltage-sensitive
Ca2+ channels in the plasma membrane of skeletal and cardiac muscle cells

41. Characteristics of β receptors
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
Skeletal muscle
hypertrophy
Metabolic effects

42. 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:

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

44. 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

45. • 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 sensoryneurons.
• Substance P is a vasodilator (probably via release of nitric oxide).
Substance P, related tachykinins
• Found with substance P in cardiovascular sensory nerve fibers.
• 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)

46. 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
❖Drugs having cholinergic, anticholinergic, adrenergic & anti-adrenergic action have
been discovered with the knowledge of autonomic neurotransmission & are being
used in number of common clinical situations

47. References
• Goodman & Gilman’s The Pharmacological Basis of Therapeutics 13th Edition
• Bertram G. Katzung & Anthony J. Trevor’s Basic & Clinical Pharmacology 14th Edition
• Rang & Dales’s Pharmacology 7th Edition
• H. L. Sharma & K. K. Sharma’s Principles of Pharmacology 2nd Edition
• Lippincott Illustrated Reviews: Pharmacology 6th Edition